International Journal of Translational Medicine doi: 10.3390/ijtm4020012
Authors: Munish Puri
The liver is structurally organized into zonation, where Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role during chronic liver injury and the early stages of fibrosis. Fibrosis can be reversed if diagnosed early at the molecular level in zonation before progressing to advanced stages like bridging fibrosis. This study identified zonation marker genes using scRNA-seq and spatial transcriptomics molecular profiling technologies in a normal and diseased fibrotic human liver. DGE analysis was performed over LSECs, and we identified the top 20 expressed genes in the periportal, perivenous, and intermediate acinar zones. Multi-omics and scRNA-seq analysis over Visium images and ECs liver cells showed OIT3, DNASE1L3, CLEC4G, LYVE1, FCN2, and CRHBP as commonly expressed mid-lobular zonation-specific genes. Also, this study detected STAB2, F8, AQP1, TEK, TIMP3, TIE1, and CTSL genes as expressed in DILI and NASH EC populations. The connection between LSEC marker genes in zone 2 and liver fibrosis holds significant promise for advancing our understanding in developing new therapeutic strategies for fibrosis reversal and designing computational molecular biomarkers in NASH and DILI fibrotic liver diseases.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010011
Authors: Ben Turner David Cranston
For 80 years, high-intensity focused ultrasound (HIFU) has been the subject of interest in medical research. It is a non-invasive procedure that causes the death of cells in a very select area through one of two mechanisms, either heat or cavitation. While diagnostic ultrasound is well known in the medical profession and ultrasound is also used in physiotherapy, high-intensity focused ultrasound is less known but is becoming increasingly important as a non-invasive tool that can be used in many ways, including in the treatment of several cancers as well as benign uterine fibroids. Other interesting developments are underway, including its use in the treatment through an intact skull of essential tremors and the tremor associated with Parkinson’s disease, and in a modified form, it is used to target drug delivery to the brain due to its potential opening of the blood–brain barrier. The depth of penetration of HIFU is variable depending on the type of transducer used and the distance from it. Clinical trials of abdominal malignancies and benign uterine fibroids are reviewed in this article along with potential side effects of the procedure. Over the past two decades, the technology has improved considerably, and the clinical indications have broadened. The current limitations of the technology are also discussed, along with the potential advances in the field that may be made over the next decade.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010010
Authors: Ana Salomé Correia Nuno Vale
Major depressive disorder (MDD), a prevalent mental illness, is marked by a complex mixture of biological factors. This review focuses on the roles of oxidative stress, tryptophan-serotonin metabolism, brain-derived neurotrophic factor (BDNF), and the hypothalamic–pituitary–adrenal (HPA) axis in MDD’s pathophysiology. Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants, is closely linked to MDD’s neurobiological changes. The tryptophan (TRP)-/serotonin (5-HT) metabolic pathway is also known to be crucial in mood regulation, with its dysregulation being a central aspect of MDD. Additionally, BDNF, key for neuronal growth and plasticity, often shows alterations in MDD patients, supporting its role in the disorder’s progression. Furthermore, the HPA axis, which manages stress response, is frequently disrupted in MDD, further contributing to its complex pathology. In addition to exploring these biological mechanisms, this review also explores the pharmacotherapy of MDD, including new advances. These advancements in treatment strategies are crucial for managing MDD effectively. Understanding these mechanisms and the latest pharmacological interventions is essential for developing more effective treatments for MDD.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010009
Authors: João Stuart Pedro Miguel Dias dos Santos Carlos Costa Pereira Sandra F. Martins
Background: Low-quality tumoral surgical excision is the major relapse factor in rectal cancer. If the surgery is highly difficult, the quality of the resection might be compromised. In the literature, it is described how low pelvic dimensions can make this type of surgery difficult. The main aim was to study the influence of pelvic measures in surgical difficulty on the patients submitted to tumoral surgical resection with curative intent. Methods: A retrospective, observational and analytic study was conducted. A total of 73 patients over a period of 3 years were included. Demographic and surgical data, as well as measurements of the pelvis taken from MRI, were collected. An univariate and multivariate analysis was performed. Results: 11 (15.1%) patients were classified as having highly difficult surgeries. All 11 patients were male. Significant differences were found between groups regarding gender (p = 0.013), transverse diameter of the pelvis (p < 0.001), interspinal distance (p = 0.014) and intertuberous distance (p < 0.001). The logistic regression revealed that a small transverse diameter (O.R. 0.919, 95% I.C. 0.846–0.999, p = 0.047) increases the degree of difficulty of the surgery. Conclusions: Male patients with a small pelvic measurement deserve a thorough surgical plan that predicts a quality resection.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010008
Authors: Joseph S. D’Arrigo
Previous research has already shown that apolipoprotein (apo)A-I is adsorbed from the bloodstream onto the surface of certain colloidal lipid particles after the intravenous injection of such colloidal nanocarriers. As a result, various blood–brain barrier (BBB) scavenger receptors are targeted by these (apoA-I-coated) colloidal nanocarriers. This targeted molecular interaction is mediated/facilitated by the adsorbed apoA-I, which is then followed by receptor-mediated endocytosis and subsequent transcytosis of the nanocarrier particles across the BBB. A multifunctional combination therapy is obtained by adding the appropriate drug(s) to these biomimetic (lipid cubic phase) nanocarriers. This therapeutic targets specific cell-surface scavenger receptors, primarily class B type I (SR-BI), and crosses the blood–brain barrier. The lipid contents of artificial biomimetic (nanoemulsion) nanocarrier particles and of naturally occurring high-density lipoproteins (HDL) have been shown to be similar, which enables these nanocarrier particles to partially imitate or simulate the known heterogeneity (i.e., subpopulations or subspecies) of HDL particles. Hence, colloidal drug nanocarriers have the potential to be used in the biomedical treatment of complicated medical conditions including dementia, as well as certain elements of aging. Widespread inflammation and oxidative stress—two processes that include several pathophysiological cascades—are brought on by dementia risk factors. More recent studies suggest that proinflammatory cytokines may be released in response to a prolonged inflammatory stimulus in the gut, for example through serum amyloid A (SAA). Therefore, pharmacologically targeting a major SAA receptor implicated in the SAA-mediated cell signaling processes that cause aging and/or cognitive decline, and ultimately Alzheimer’s disease or (late-onset) dementia, could be an effective preventive and therapeutic approach.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010007
Authors: Sarah E. Basehore Alisa Morss Clyne
Pulmonary arterial hypertension (PAH) is a fatal disease that primarily affects women. In PAH, endothelial cells become dysfunctional, reducing production of the vasodilator nitric oxide while increasing proliferation. Other studies suggest altered glucose metabolism in PAH. Our recent study showed that increased endothelial glucose metabolism in disturbed flow increased O-GlcNAcylation of endothelial nitric oxide synthase (eNOS), the enzyme that makes nitric oxide, which then reduced nitric oxide production. We therefore hypothesized that elevated endothelial glycolytic activity in PAH endothelial cells would reduce nitric oxide production by increasing eNOS O-GlcNAcylation. We cultured human pulmonary artery endothelial cells (HPAECs) from failed lung transplant (“non-PAH”) and idiopathic PAH patients (“PAH”) and quantified glycolytic activity, nitric oxide production, and eNOS O-GlcNAcylation in each cell type. Our data show that PAH HPAECs had higher glucose uptake and glycolytic metabolites, as well as decreased nitric oxide production, compared to non-PAH HPAECs. However, PAH HPAECs had lower eNOS O-GlcNAcylation and UDP-GlcNAc, the substrate for O-GlcNAcylation. Interestingly, both glucose uptake and eNOS O-GlcNAcylation were higher in female as compared to male HPAECs. These data suggest that although endothelial glycolytic metabolism is altered in PAH, eNOS O-GlcNAcylation is not connected to decreased nitric oxide. In addition, differences in glucose metabolism and protein O-GlcNAcylation in HPAECs from male and female donors could relate to PAH sexual dimorphism.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010006
Authors: Chie Kohchi Miyuki Uehiro Taisuke Fukaya Norikazu Watanabe Hiroyuki Inagawa Gen-Ichiro Soma
The present study examined the effects of foods containing lipopolysaccharides from Pantoea agglomerans (LPSp) on eye–nose allergic symptoms using a double-blind, placebo-controlled, randomized, parallel-group comparative research design. Sixty-three Japanese individuals aged 20–65 years with eye–nose allergic symptoms were included in this study and assigned to the LPS (480 μg/day)-containing food and placebo groups. Data on the subjective eye–nose allergic symptoms and antiallergic medication during the 8-week period were evaluated. The immunoglobulin E (IgE) and eosinophil counts were measured as indicators that may be correlated with allergy. No significant group differences were found in the change in eye–nose allergic symptoms from baseline. However, the LPS group showed a significantly shorter duration of antiallergic medication use and lower total antiallergic drug score than the placebo group. The corrected nasal allergy score calculated by taking into account the antiallergic drug score at week 8 was predominantly lower in the LPS group. The IgE to house dust and cedar pollen and eosinophil counts tended to be lower in the LPS group, and the total IgE and eosinophil counts were significantly lower in the LPS group at week 4. In conclusion, our results indicate that LPS-containing foods alleviate eye–nose allergic symptoms and consequently lower the use of antiallergic drugs (UMIN000049974).
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010005
Authors: Pallavi Tonsekar Vidya Tonsekar Shuying Jiang Gang Yue
Background: The tooth is a repository of stem cells, garnering interest in recent years for its therapeutic potential. The aim of this systematic review and meta-analysis was to test the hypothesis that dental stem cell administration can reduce blood glucose and ameliorate polyneuropathy in diabetes mellitus. The scope of clinical translation was also assessed. Methods: PubMed, Cochrane, Ovid, Web of Science, and Scopus databases were searched for animal studies that were published in or before July 2023. A search was conducted in OpenGrey for unpublished manuscripts. Subgroup analyses were performed to identify potential sources of heterogeneity among studies. The risk for publication bias was assessed by funnel plot, regression, and rank correlation tests. Internal validity, external validity, and translation potential were determined using the SYRCLE (Systematic Review Center for Laboratory Animal Experimentation) risk of bias tool and comparative analysis. Results: Out of 5031 initial records identified, 17 animal studies were included in the review. There was a significant decrease in blood glucose in diabetes-induced animals following DSC administration compared to that observed with saline or vehicle (SMD: −3.905; 95% CI: −5.633 to −2.177; p = 0.0004). The improvement in sensory nerve conduction velocity (SMD: 4.4952; 95% CI: 0.5959 to 8.3945; p = 0.035) and capillary-muscle ratio (SMD: 2.4027; 95% CI: 0.8923 to 3.9132; p = 0.0095) was significant. However, motor nerve conduction velocity (SMD: 3.1001; 95% CI: −1.4558 to 7.6559; p = 0.119) and intra-epidermal nerve fiber ratio (SMD: 1.8802; 95% CI: −0.4809 to 4.2413; p = 0.0915) did not increase significantly. Regression (p < 0.0001) and rank correlation (p = 0.0018) tests indicated the presence of funnel plot asymmetry. Due to disparate number of studies in subgroups, the analyses could not reliably explain the sources of heterogeneity. Interpretation: The direction of the data indicates that DSCs can provide good glycemic control in diabetic animals. However, methodological and reporting quality of preclinical studies, heterogeneity, risk of publication bias, and species differences may hamper translation to humans. Appropriate dose, mode of administration, and preparation must be ascertained for safe and effective use in humans. Longer-duration studies that reflect disease complexity and help predict treatment outcomes in clinical settings are warranted. This review is registered in PROSPERO (number CRD42023423423).
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010004
Authors: Kung-Hao Liang Yuan-Chi Teng Yi-Ting Liao Aliaksandr A. Yarmishyn Su-Hua Chiang Wei-Chun Hung Chun-Yen Hsiao En-Tung Tsai Tai-Jay Chang De-Ming Yang Mong-Lien Wang
The coronavirus SARS-CoV-2 is the causative pathogen of the COVID-19 pandemic that has been causing global upheaval since 2019. The widespread administration of vaccines has partially deterred the spread of SARS-CoV-2, yet the virus is mutating its genome to reduce its antigenicity and evade the human herd immunity. It seems that SARS-CoV-2 will co-exist with the human population for many decades to come. While most infected individuals only experience mild to moderate symptoms, some develop severe pulmonary and systemic disease that can result in hospitalization or even death. The natural history model of SARS-CoV-2 infection has been proposed which includes three sequential stages: the early infection stage, pulmonary stage, and hyper-inflammatory stage. Recently, it has been observed that many people who recovered from an acute infection still experience persistent symptoms for weeks or months, a condition known as long COVID. Furthermore, some COVID-19 patients display escalated rates of both macro- and micro-thrombosis due to endotheliopathy. Hence, we added the thrombosis and convalescent stages to the natural history model, encompassing the entire period from early infection to long COVID. The early infection stage is characterized by symptomatic or asymptomatic elevation of viral titers. Some patients progress to the pulmonary stage characterized by opacities in chest X-rays and computed tomography. The thrombosis stage is characterized by heightened rates of pulmonary thrombosis and consistently elevated D-dimer levels. The hyper-inflammatory stage is characterized by storms of cytokines, such as IL-6, IL-17, and interferons, which is a systemic effect. In the convalescent stage, some people recover completely, while others suffer from long COVID with persistent symptoms such as fatigue, shortness of breath, or brain fog. The natural history model of SARS-CoV-2 infection can be used to elucidate treatment and care.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010003
Authors: Heidi Schwarzenbach
MicroRNAs (miRNAs), or small non-coding RNAs, modulate the expression of mRNAs and, consequently, a variety of signal transduction pathways. Due to their dysregulation in cancer, they exert oncogenic pressure and have an impact on the immune system with their protective functions. These immunosuppressive characteristics of miRNAs in cancer promote cancer progression and metastasis, causing the dysregulation of immune cells and the immune escape of tumor cells. In contrast, there are also tumor suppressor miRNAs that are able to activate the immune system. Therefore, studies on the altered expression of miRNAs that consider both the oncogenic and tumor-suppressive aspects of miRNAs have become an important research field for advancing immunotherapeutic interventions using miRNAs or their inhibitors as therapeutics. In the current review, their potential in the immunomodulation of immune cells and their use as immune stimulatory molecules to elicit specific cytotoxic responses against the tumor are discussed.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010002
Authors: Hiba Khan Natasha Singh Luis Yovera Leyva Johann Malawana Nishel M. Shah
Background: Preterm birth (PTB) is a leading cause of childhood disability, and it has become a key public health priority recognized by the World Health Organization and the United Nations. Objectives: This review will: (1) summarize current practice in the diagnosis and management of PTB, (2) outline developments in precision-based medicine for diagnostics to improve the care provided to pregnant women at risk of PTB, and (3) discuss the implications of current research in personalized medicine and the potential of future advances to influence the clinical care of women at risk of PTB. Methodology: This is a narrative literature review. Relevant journal articles were identified following searches of computerized databases. Key Results: Current and emerging technologies for the utility of personalized medicine in the context of PTB have the potential for applications in: (1) direct diagnostics to identify and target infection as one of the main known causes of PTB, (2) identifying novel maternal and fetal biomarkers, (3) the use of artificial intelligence and computational modeling, and (4) combining methods to enhance diagnosis and treatment. Conclusions: In this paper, we show how current research has moved in the direction of the targeted use of biomarkers in the context of PTB, with many novel approaches.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm4010001
Authors: Dana Antonia Țăpoi Ancuța-Augustina Gheorghișan-Gălățeanu Laura Maria Gosman Adrian Vasile Dumitru Ana Maria Ciongariu Mariana Costache
Intermediate-thickness melanomas display highly variable outcomes influenced by both clinical and histopathological characteristics. This study investigates several clinicopathological prognostic factors for pT3 cutaneous melanomas, focusing on a novel parameter, the width of invasion. This is a retrospective study of 49 patients diagnosed with cutaneous melanoma between 2012 and 2018 who were followed up for at least five years. We evaluated the age, gender, tumor location, Breslow depth of invasion, width of invasion, mitotic index, the presence/absence of ulceration, regression, microsatellites, lymphovascular invasion, and perineural invasion for their association with disease progression and survival. Cox univariate analysis revealed that progression-free survival (PFS) was significantly associated with age, depth of invasion, width of invasion, lymphovascular invasion, microsatellites, and perineural invasion. Overall survival (OS) was significantly associated with age, depth of invasion, width of invasion, microsatellites, and perineural invasion. Through multivariate Cox proportional hazards regression, the only factor associated with both PFS and OS was the width of the invasion. This is one of the few studies to assess the width of invasion and we have demonstrated that this parameter could become an important prognostic factor for cutaneous melanomas.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040036
Authors: Jhana O. Hendrickx Elke Calus Peter Paul De Deyn Debby Van Dam Guido R. Y. De Meyer
Due to global population growth, age-related disorders like cardiovascular disease and dementia are anticipated to increase. Recent data suggests a connection between cardiovascular disease and neurodegeneration, especially focusing on arterial stiffness (AS) and Alzheimer’s disease (AD). In light of this, we conducted a study to explore the impact of long-term nitric oxide synthase (NOS) isoform inhibition, which leads to AS, on neurobehavioral performance. We also compared these effects in an AD model and control mice. C57BL/6 and hAPP23+/− mice (an established AD model) were given 0.5 mg/mL N(G)-Nitro-L-Arginine Methyl Ester (L-NAME) in their drinking water for 16 weeks. Our findings indicate that chronic non-selective NOS inhibition increased AS and reduced spatiotemporal learning and memory in both C57BL/6 and hAPP23+/− mice. These effects were consistent across both groups, emphasizing the role of neuronal NOS (nNOS) in cognitive aging, regardless of genetic predisposition to AD.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040035
Authors: Mosa Alsehli Mario Gauthier
Amphiphilic dendritic copolymers of arborescent poly(γ-benzyl L-glutamate) (PBG) of generations G1 and G2, grafted at their chain ends with poly(ethylene oxide) (PEO) segments (PBG-eg-PEO) were synthesized, characterized, and evaluated as nanocarriers for doxorubicin (DOX). The copolymers were designed with hydrophobic PBG cores having three different branching densities and were characterized by proton nuclear magnetic resonance (1H NMR) spectroscopy, size exclusion chromatography (SEC), transmission electron microscopy (TEM), and atomic force microscopy (AFM). Dynamic light scattering (DLS) measurements revealed that these amphiphilic molecules behaved like unimolecular micelles without significant aggregation in aqueous media such as phosphate-buffered saline (PBS), with diameters in the 13–29 nm range depending on the generation number and the core structure. Efficient encapsulation of DOX by these unimolecular micelles was demonstrated with drug loading capacities of up to 11.2 wt%, drug loading efficiencies of up to 67%, and pH-responsive sustained drug release, as determined by UV spectroscopy. The generation number of the copolymers and the branching density of the dendritic PBG core were found to have influenced the encapsulation and release properties of the micelles. Given the tailorable characteristics, good water dispersibility, and biocompatibility of the components used to synthesize the amphiphilic arborescent copolymers, these systems should be useful as robust nanocarriers for a broad range of therapeutic and diagnostic agents.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040034
Authors: Masahide Omori Yoshihiro Shidoji Hisataka Moriwaki
Inhibitory effects of 4,5-didehydrogeranylgeranoic acid (dGGA) on the development of tumors were investigated in spontaneous hepatoma mice, C3H/HeNCrj. Experiment 1: Male mice at 8 weeks of age were raised on a basal diet, and then provided with a diet containing 0.02% dGGA from 32 to 91 weeks of age. Experiment 2: dGGA was administered to the animals only once at different time points, from 2 months to 17 months after birth, respectively. Experiment 3: dGGA was administered twice to the mice at different time points: at 5 months and 11 months, and at 8 months and 11 months, respectively. When the inhibitory effects on tumor development were evaluated with the incidences of tumors, average numbers, and weight of tumors per mouse, there was a marked relationship between the time of single or dual dosing and the inhibitory effects of dGGA. The greatest inhibitory effects were observed in Experiment 3 in the group of animals given dGGA at the ages of 8 and 11 months, which were far superior to the results with a large dose of the compounds for a long time. These results might indicate that dGGA administered at the right time in the right amount effectively prevents the development of cancer.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040033
Authors: Laura Paleari Mariangela Rutigliani Oriana D’Ecclesiis Sara Gandini Irene Maria Briata Tania Buttiron Webber Nicoletta Provinciali Andrea DeCensi
Background: Up to now, endometrial cancer (EC) treatments are mainly represented by surgery followed by adjuvant chemotherapy or radiotherapy. The updated guidelines give a 2A recommendation for the use of hormone therapy only in advanced low-grade ECs, underlying the need for more data on the role of hormone therapy in the adjuvant setting. Methods: The clinicopathological data of 158 early-stage EC patients was retrospectively collected. A Ki-67 cut-off value of 40% was established based on literature data. Disease-free survival (DFS) and Overall survival (OS) were evaluated. Results: Results: Multivariate analysis of DFS and OS showed a significantly increased risk of progression in patients with >40% Ki-67 [HR = 3.13 (95% CI; 1.35–7.14); p = 0.007] and a significantly higher relative risk of death [HR = 3.70 (95% CI; 1.69–8.33); p = 0.001]. The predictive role of the Ki-67 index was highlighted by the clinical benefit of adjuvant hormone in patients with high Ki-67. Conclusions: Our results suggest a positive role of the Ki-67 index as a prognostic and potentially predictive marker in EC, although further studies are warranted to reach a definitive conclusion.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040032
Authors: Mariana Pereira Nuno Vale
This comprehensive review explores two antiretroviral drugs, Etravirine (ETV) and Darunavir (DRV), a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor, that are commonly used in human immunodeficiency virus (HIV) infection treatment, often in combination with each other. The pharmacokinetic properties of these drugs are covered as well as the clinical trials of these two drugs combined. This paper also delves into the possible repurposing of these two drugs for other diseases, with drug repurposing being a significant factor in addressing global health challenges. DRV was extensively studied for treating COVID-19, as well as other infections, such as candidiasis and cryptococcosis, while ETV proved to be efficient in hampering Zika virus brain infection. The focus on cancer repurposing is also explored, with the results revealing that ETV has a particular inhibitory effect on ovarian cancer in vitro and on cancer molecules, such as anterior gradient protein 2 homolog (AGR2) and casein kinase 1 (CK1ε), and that DRV has an in silico inhibitory effect on human lactate dehydrogenase A (LDHA) and induces the in vitro and in vivo inhibition of pepsin, consequent laryngopharyngeal reflux, and possible laryngeal and hypopharyngeal carcinomas. The significance of fresh methods of drug development is emphasized in this work, as is the enormous potential for new therapeutic uses of the antiretroviral drugs ETV and DRV in viral and non-viral disorders.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040031
Authors: Marta Chiara Sircana Gianpaolo Vidili Antonio Gidaro Alessandro Palmerio Delitala Fabiana Filigheddu Roberto Castelli Roberto Manetti
Inborn errors of immunity (IEI) are multifaced diseases which can present with a variety of phenotypes, ranging from infections to autoimmunity, lymphoproliferation, and neoplasms. In recent decades, research has investigated the relationship between autoimmunity and IEI. Autoimmunity is more prevalent in primary humoral immunodeficiencies than in most other IEI and it can even be their first manifestation. Among these, the two most common primary immunodeficiencies are selective IgA deficiency and common variable immunodeficiency. More than half of the patients with these conditions develop non-infectious complications due to immune dysregulation: autoimmune, autoinflammatory, allergic disorders, and malignancies. Around 30% of these patients present with autoimmune phenomena, such as cytopenia, gastrointestinal and respiratory complications, and endocrine and dermatologic features. Complex alterations of the central and peripheral mechanisms of tolerance are involved, affecting mainly B lymphocytes but also T cells and cytokines. Not only the immunophenotype but also advances in genetics allow us to diagnose monogenic variants of these diseases and to investigate the pathogenetic basis of the immune dysregulation. The diagnosis and therapy of the primary humoral immunodeficiencies has been mostly focused on the infectious complications, while patients with predominant features of immune dysregulation and autoimmunity still present a challenge for the clinician and an opportunity for pathogenetic and therapeutic research.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040030
Authors: Bianca M. Glass Mira Al Jaberi John H. Irlam Samir M. Dalia
Primary lymphomas of the salivary gland are rare. The most common subtype is MALT lymphoma. MALT lymphoma has an indolent clinical course, and patients often present with a prolonged history. Evaluations of parotid masses begin initially with radiological imaging, but pathological and histological examination remains the mainstay of definitive diagnosis. This case describes a primary non-Hodgkin’s lymphoma of the parotid gland in a healthy 32-year-old male. This case report will evaluate the prevalence of primary MALT lymphoma and discuss the possible presentation.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040029
Authors: Nazanin Beheshtian Ehsan Karimi Javad Asili Nadia Beheshtin Hieu Huu Le Majid Shakeri
Naturopathy or herbal medicine has been widely used as an alternative treatment for several illnesses, such as cancer, as they are generally acknowledged as a treatment with lesser side effects. This research evaluated the bioactive compounds profiling, antioxidant, and anticancer potential in Mentha longifolia L. (essential oil and extract), using different solvent polarities (hexane, methanol, and diethyl ether). Meanwhile, the caspase 3 gene expression and cell cycle status of methanolic extract were determined in colorectal cancer cells (Caco-2 and SW48). The overall findings showed that methanolic extraction exhibited the highest total phenolic and flavonoid with respective values of 59.25 mg GAE (Gallic acid) eq./g DW (dry weight) and 20.02 mg RE (Rutin) eq./g DW, respectively, compared to hexane and diethyl ether. Furthermore, piperitenone oxid and piperitonone were found to be the dominant volatile compounds in methanolic extracts and essential oils. Additionally, the methanolic extract possesses higher antioxidant and anticancer activities. The molecular analysis indicated that methanolic extract up-regulated the expression of caspase 3 and increased the SubG1 (method to detecting cell death) peaks in treated Caco-2 and SW48 cell lines. To conclude, M. longifolia L. could serve as an effective therapeutic agent and a remedy for several illnesses, such as cancer caused by oxidative stress.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3040028
Authors: Soccorsa Sofia Giacomo Filonzi Leonardo Catalano Roberta Mattioli Laura Marinelli Elena Siopis Laura Colì Violante Mulas Davide Allegri Carlotta Rotini Beatrice Scala Alessio Bertini Michele Imbriani Michele Domenico Spampinato Paolo Orlandi
The 2019 coronavirus disease (COVID-19) pandemic is affecting millions of people worldwide. Chest high-resolution computed tomography (HRCT) is commonly used as a diagnostic test for suspected COVID-19; however, despite numerous attempts, there is no single scoring system that is widely accepted and used in clinical practice to estimate the probability of SARS-CoV-2 pneumonia. The aim of this single-center retrospective study is to develop a radiological score to predict the probability of COVID-19 with HRCT. Patients admitted to the emergency department with symptoms suggestive of COVID-19 who underwent both HRCT and RT-PCR on nasopharyngeal swab to detect SARS-CoV-2 infection between 1 March and 30 April 2020 were included. A multivariable regression analysis was conducted to identify all HRCT signs independently associated with a positive RT-PCR assay for SARS-CoV-2 and build the HRCT score. A total of 1153 patients were enrolled in this study. The number of segments with ground glass opacities (OR 1.18, 95% CI 1.11–1.26), number of segments with linear opacities (OR 1.21, 95% CI 1.05–1.42), crazy paving patterns (OR 6, 95% CI 3.79–9.76), and vascular ectasia in each segment (OR 2.46, 95% CI 1.1.5–5.8) were included in the score. The HRCT score showed high discriminatory power (area under the ROC curve of 0.8267 [95% CI 0.8–0.85]) with 72.2% sensitivity, 86.6% specificity, 78% PPV, and 83% NPV for its best cut-off. In summary, the HRCT score has good diagnostic and discriminatory accuracy for COVID-19 and is easy and quick to perform.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030027
Authors: Hiraku Ogata Yosuke Minami
FLT3 mutations are frequently identified in acute myeloid leukemia (AML). In particular, FLT3-ITD is known to be an indicator of a poor prognosis. FLT3 inhibitors have improved the treatment outcomes of AML patients with mutated FLT3. However, several drug-resistance mechanisms have been reported, and new clinical strategies to overcome drug resistance are needed. Heat shock protein (HSP) 90 is a molecular chaperone that mediates the correct folding and functionality of its client proteins, including FLT3. In the present study, we investigated the effects of an HSP90 inhibitor on FLT3 inhibitor-resistant AML cells. Using MOLM-13 (an AML cell line harboring FLT3-ITD), we established FLT3-selective inhibitor (FI-700)-resistant cell lines with an FLT3 N676K mutation. An HSP90 inhibitor (17-AAG) inhibited the growth of the cell lines, and combination treatment with FI-700 and 17-AAG showed synergistic inhibition. The underlying mechanism is thought to be as follows: HSP90 inhibits the association between HSP90 and FLT3, and thus reduces the phosphorylation of FLT3 and its downstream signaling proteins, which induces the consequent degradation of FLT3. In summary, we demonstrated that the HSP90 inhibitor could inhibit the cell growth of FLT3 inhibitor-resistant AML cells. Our results suggest that HSP90 is a promising molecular target in relapsed/refractory AML.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030026
Authors: Alexandra L. G. Mahoney Sergio Joshua Najah T. Nassif Ann M. Simpson
Type 1 Diabetes (T1D) is a chronic metabolic disorder for which current treatments are unable to prevent the onset of complications. Previously, we used an adeno-associated viral vector (AAV8) to deliver furin-cleavable human insulin (INS-FUR) to the livers of diabetic non-obese diabetic (NOD) mice to reverse T1D. The use of the traditional AAV8-INS-FUR vector could not bring about normoglycemia. However, this vector, coupled with a transposon system in the AAV8/piggyBac-INS-FUR vector, was able to do so. This study aimed to investigate the transcriptomic profiles of the livers of diabetic, AAV8-INS-FUR-transduced, and AAV8/piggyBac-INS-FUR-transduced NOD mice and compare these to the normal liver to identify genetic differences resulting from delivery of the AAV8/piggyBac-INS-FUR vector which produced normoglycemia. Differential gene expression was determined by RNA-Seq analysis and differentially expressed genes from each treatment were mapped onto cellular pathways to determine the treatments’ cell signaling and downstream effects. We observed distinct differences between the piggyBac-transduced and diabetic models, particularly in terms of metabolic function and the upregulation of key pancreatic markers in the liver of piggyBac-transduced animals. The success of the AAV8/piggyBac-INS-FUR vector in achieving normoglycemia through stable transduction was evident. However, further engineering is necessary to achieve complete pancreatic transdifferentiation of liver cells.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030025
Authors: Leonard M. Eisenberg Keerat Kaur John M. Castillo John G. Edwards Carol A. Eisenberg
Normal contractile function of the myocardium is essential for optimal cardiovascular health. Evaluating drug effects on cardiomyocyte function at the cellular level is difficult for long-term studies. Present culture systems rely on isolated, cardiomyocyte preparations or cardiomyocytes derived from pluripotent stem cells (PSCs), all of which have limitations. Isolated, endogenous cardiomyocytes do not remain contractile in culture long term. While PSC-derived cardiomyocytes show contractile activity for longer periods of time, their phenotype is more embryonic than adult. Here we report that dexamethasone (DEX) treatment of adult mouse atrial tissue can extend its functionality in culture. Normally, cardiac explants cease their capacity as a contractile tissue within the first month, as the tissue flattens and spreads out on the culture substrate, while the cells dedifferentiate and lose their myocardial phenotype. However, with DEX treatment, cardiac explants maintain their contractile function, 3D morphology, and myocyte phenotype for up to 6 months. Moreover, DEX also preserved the contractile phenotype of isolated rat cardiomyocytes. These data with DEX suggest that simple modifications in culture conditions can greatly improve the long-term utility of in vitro model systems for screening drugs and agents that could be employed to alleviate human cardiac disease.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030024
Authors: Mukulika Bose
Preferentially expressed antigen in melanoma (PRAME) is a cancer testis antigen (CTA) that is selectively expressed in certain somatic tissues, predominantly in the testis, and is overexpressed in various cancers. PRAME family proteins are leucine-rich repeat proteins that are localized in the nucleus and cytoplasm, with multifaceted roles in immunity, during gametogenesis and in the overall reproduction process. It is a widely studied CTA and has been associated with the prognosis and therapeutic outcomes in patients with epithelial and non-epithelial tumors. PRAME has also been studied extensively as a therapeutic target. Moreover, it has been found to play a role in most of the well-known cancer hallmarks. Interestingly, the role of PRAME in tumorigenesis is paradoxical. Over the last decade, PRAME has garnered substantial interest as a target for immunotherapy. There are multiple clinical trials and pre-clinical studies targeting PRAME alone or in combination with other tumor antigens. This review article is an attempt to update our knowledge and understanding of the context-dependent oncogenic functions of PRAME in various carcinomas, and the current immunotherapeutic strategies, challenges, and perspectives on developing newer strategies to target PRAME for a better outcome.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030023
Authors: Fernanda Wirth Esthael Cristina Querido Avelar Bergamaschi Fábio da Silva Forti João Paulo Machado Bergamaschi
Endoscopic spine surgery (ESS) began more than 20 years ago as percutaneous endoscopic discectomy and has evolved to the present day. This technique offers many advantages, including a short hospital stay, minimal trauma and blood loss, the option of local or epidural anesthesia with sedation, a low rate of nosocomial infections, early recovery, and a quick return to work and daily activities. The success rate of this technique ranges from 83% to 90% in operated patients. This article aims to provide an overview of indications, versatility of the technique, advantages, contraindications and limitations, and also a reflection on the possible contraindications and limitations of the technique.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030022
Authors: Tsunenori Ouchida Hiroyuki Suzuki Tomohiro Tanaka Mika K. Kaneko Yukinari Kato
Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is an important target of monoclonal antibody (mAb) therapy such as trastuzumab. Due to the development of trastuzumab–deruxtecan, an antibody-drug conjugate, the targetable HER2-positive breast cancer patients have been expanded. To evaluate the developing modalities using anti-HER2 mAbs, reliable preclinical mouse models are required. Therefore, sensitive mAbs against mouse HER2 (mHER2) should be established. This study developed anti-mHER2 mAbs using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mHER2 mAbs, H2Mab-300 (rat IgG2b, kappa) and H2Mab-304 (rat IgG1, kappa), reacted with mHER2-overexpressed Chinese hamster ovary-K1 (CHO/mHER2) and endogenously mHER2-expressed cell line, NMuMG (a mouse mammary gland epithelial cell) via flow cytometry. Furthermore, these mAbs never recognized mHER2-knockout NMuMG cells. The kinetic analysis using flow cytometry indicated that the dissociation constant (KD) values of H2Mab-300 and H2Mab-304 for CHO/mHER2 were 1.2 × 10−9 M and 1.7 × 10−9 M, respectively. The KD values of H2Mab-300 and H2Mab-304 for NMuMG were 4.9 × 10−10 M and 9.0 × 10−10 M, respectively. These results indicated that H2Mab-300 and H2Mab-304 could apply to the detection of mHER2 using flow cytometry and may be useful to obtain the proof of concept in preclinical studies.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030021
Authors: Chie Kohchi Miyuki Uehiro Masashi Yamashita Hiroyuki Inagawa Gen-Ichiro Soma
In this study, the effects of foods containing lipopolysaccharide (LPS) from Pantoea agglomerans (LPSp) on immunity were preliminarily investigated using a double-blind, placebo-controlled, randomized, parallel-group comparative study design. Thirty healthy subjects aged ≥ 20 years (four males and twenty-six females; mean age 49 ± 9.2 years) were randomly assigned to the LPS-containing food group (488 μg/day; LPS) or placebo group. Each food was consumed for 8 weeks, and a subjective survey of cold symptoms (Wisconsin Upper Respiratory Symptom Questionnaire) and allergic symptoms of the eyes and nose were conducted. Phagocytic capacity and lymphocyte counts were measured as indicators of immune function. There were no significant between-group differences with respect to any of the investigated items. On sub-group analysis of eye–nose allergy symptom score, confined only to subjects who reported eye–nose allergic symptoms in previous years, the LPS group showed a trend toward milder symptoms compared to the placebo group. In addition, when the symptom scores were compared only for subjects who developed eye–nose allergies during the study period, the LPS group showed significantly lower overall scores and eye symptom scores compared to the placebo group. These results suggest that the consumption of LPS-containing foods may alleviate or prevent eye–nose allergies. There were no statistically predominant changes in hematology and blood biochemistry tests, indicating that continued consumption of LPS-containing foods is safe. (UMIN000046154).
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030020
Authors: Shaila Cejudo-Arteaga Marco Antonio Ramírez-Reyes Marco Antonio Badillo-Santoyo Erika Martínez-Cordero Felipe Farías-Serratos María Maldonado-Vega
Androgen deprivation therapy (ADT) is the basis for the control of prostate cancer. High levels of prostate-specific antigen (PSA) and high Gleason grade correlate, define the aggressiveness of the cancer in order to establish its treatment and prognosis. This work evaluated the response of 910 patients diagnosed with prostate cancer, separated into three groups according to their response to treatment by ADT: (1) sensitive (TSPC); (2) palliative and did not accept treatment, and (3) group with recurrence or treatment resistance (TRPC). All patients with prostate cancer treated with ADT, and regardless of whether or not they had undergone surgery or taken to radiotherapy, presented with anemia. The hematological response due to the leukocyte/lymphocyte index (L/L) is increased at the end of treatment, possibly due to inflammatory processes generated by cancer, and baseline overweight and obesity. Patients with biochemical relapse exhibit a higher platelet count, suggesting that these cells could participate in the recurrence process and in metastasis (78%) in these patients. The coagulation index (INR) could be an indicator of the platelet response to be considered during the treatment and monitoring of patients.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3030019
Authors: Ruben De Wilde Michael Saerens Anne Hoorens Anja Geerts Celine Jacobs
Immune-related hepatitis (irH) is a fairly frequent complication of immune checkpoint inhibitors (ICIs). Its management is generally based on withholding ICIs and on the rapid initiation of corticosteroids, which is successful in 63 to 96% of cases. Mycofenolate mofetil (MMF) is accepted as a second-line immunosuppressant in the case of the failure of corticosteroids. In rare cases, though, irH is also resistant to MMF and may lead to liver failure. There are no standard third-line treatments and current guidelines are based on a limited number of case reports. We present a case of a metastatic melanoma patient with an immune-related hepatitis refractory to corticosteroids and MMF, that was successfully reversed with tacrolimus. Unfortunately, this was complicated with a serious infection and progressive disease, which illustrates the complexity of treatment of steroid-refractory immunotherapy-related adverse events. Furthermore, we provided a literature review regarding the management of steroid-refractory hepatitis and proposed a strategy to circumvent the current uncertainties in the management of steroid-refractory irH.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3020018
Authors: Adel Abdel-Moneim Eman H. Bakry Mohamed Y. Zaky
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a significant impact on the world’s demographics, resulting in over 6 million deaths globally. COVID-19 has been associated with a variety of disease manifestations in various organ systems, including kidney disease, in addition to pulmonary manifestations. Infection with SARS-CoV-2 can not only cause new kidney damage but also make treatment and care more difficult, as well as increase mortality in people who already have kidney problems. COVID-19 is indeed associated with a variety of renal pathologies, such as acute tubular necrosis, proteinuria, hematuria, and thrombosis complications. Cytokine storms, hypoxemia, direct viral invasion via angiotensin-converting enzyme 2 and cathepsin L, electrolyte imbalance, and fever are among the pathophysiological mechanisms underlying these clinical symptoms. Over the last two years, many COVID-19 vaccines have been discovered. However, there have been a few case reports of AKI, AKD, proteinuria, edema, gross hematuria, and other renal side effects that necessitated hospitalization after receiving COVID-19 vaccinations. Thus, the current review aimed to evaluate COVID-19-induced kidney dysfunction in terms of clinical features, pathogenesis, long-term outcomes, and vaccine harms based on the most up-to-date findings.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3020017
Authors: Francesco Bruno Paolo Abondio Valentina Laganà Rosanna Colao Sabrina M. Curcio Francesca Frangipane Gianfranco Puccio Raffaele Di Lorenzo Amalia C. Bruni Raffaele Maletta
Older adults with dementia present an increased risk of mortality due to seasonal influenza. Despite concerning evidence, the influenza vaccination program has been unsuccessful, with low rates of uptake in Italian people ≥65 years. In addition, being vaccinated does not eliminate the risk of contracting a virus, especially by coming into close contact with other possibly unvaccinated people, such as family caregivers in the home environment. Therefore, the refusal of family caregivers to get vaccinated for seasonal influenza could have dire consequences for their relatives with dementia. The aims of this study were to investigate the predictive role of the Theory of Planned Behavior model (TPB) and past vaccination behavior on the intention to receive a seasonal influenza vaccine among family caregivers of people with dementia. Data were collected from seventy-one respondents during July–September 2021 using a cross-sectional web-based survey design. Results of hierarchical binary logistic regression showed that TPB (i.e., attitudes towards vaccination, subjective norms, and perceived behavioral control) explained 51.6% of the variance in intention to receive a seasonal influenza vaccine; past vaccination behavior increased this to 58.8%. In conclusion, past vaccination behavior and the theory of planned behavior variables effectively predict influenza vaccine willingness of family caregivers of people with dementia and should be targeted in vaccination campaigns.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3020016
Authors: Viren Soni Akhil Nagar Ruchita Bardiya Jacob Mara Lukas Von Suskil Sabrina Rose Chetankumar Sonawane
Cancer stem cells (CSCs) are the cells in a primary tumor that have the opportunity to self-renew as well as differentiate into certain cell types, thus forming a mixed tumor. CSCs have been shown to be involved in every aspect of cancer development, including tumor initiation, proliferation, and metastatic activity; they are also involved in chemotherapeutic drug resistance and the recurrence of certain cancers. Based on these capabilities, CSCs have been explored as the next target for the treatment and management of cancer. Salinomycin (SAL), a polyether ionophore antibiotic being used in the poultry industry, was identified as a powerful anti-cancer compound that possesses broad-spectrum activities, especially against CSCs. Here we point out the noteworthy work reported on SAL’s mechanism of action, anticancer activities, toxicity, and clinic applications. In addition, SAL derivatives synthesized by different research groups and their biological activity will also be highlighted.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3020015
Authors: Valentina Giardini Carlo Gambacorti-Passerini Marco Casati Andrea Carrer Patrizia Vergani
Preeclampsia is an obstetric pathology with striking similarities to COVID-19. The renin-angiotensin system plays a key role in the pathogenesis of both diseases. This report reviews the pharmacological strategies that have been suggested for the prevention and treatment of preeclampsia and that are potentially useful also in the treatment of COVID-19. Of note, both pathologies have in common an Angiotensin II-mediated endothelial dysfunction secondary to an angiogenic imbalance, with effects on vasculature, coagulation, and inflammation. These considerations are drawn from cases of the initial SARS-CoV-2 primary infection and may not apply to more recent SARS-CoV-2 variants or infections after COVID vaccination. The treatment options discussed included albumin infusion, aspirin, corticosteroids, the monoclonal antibody eculizumab, hydroxychloroquine, low molecular weight heparin, magnesium, melatonin, metformin, nitric oxide, proton pump inhibitors, statins, therapeutic apheresis, and vitamin D.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3020014
Authors: Bekindaka Ngemani Obase Jude Daiga Bigoga Dickson Shey Nsagha
Malaria and HIV are geographically in the tropics and subtropics of the world, including sub-Saharan Africa. Understanding the overlapping effect of both infections, especially among pregnant women, is crucial in managing pregnant women during antenatal care visits, and postpartum babies. It was realized that the prevalence of malaria among HIV-positive pregnant women ranges between 31–61%, while for non-HIV infected pregnant women the prevalence still stands between 10 and 36%. Co-infection is between 0.52 and 56.3%. Even though the rate of mother-to-child transmission of HIV has dropped, MTCT of malaria still remains a problem. MTCT is associated with low birth-weight, anemia, and even immune dysregulation. The adoption of the Option B+ plan has proven to be effective in the fight against the MTCT of HIV. However, malaria in pregnancy still remains a problem. Concurrent administration of both antimalarial drugs and Cotrimozaxole to pregnant women is not recommended, because of the toxic effect of the interaction of both drugs. Nevertheless, studies looking at the effect of the current ART regimens on mothers and their children need to be carried out. Studies looking at exposed children over a longer period of time, to determine their susceptibility to malaria infection and also to monitor their immune response to malaria over time, are needed.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3020013
Authors: Gabriel Christian de Farias Morais Umberto Laino Fulco Edilson Dantas da Silva Claudio Bruno Silva de Oliveira Jonas Ivan Nobre Oliveira
Recently, some drugs were approved to control Monkeypox (MPX), among them tecovirimat. This was recently approved by regulatory agencies around the world, the paper of Zovi et al entitled Pharmacological Agents with Antiviral Activity against Monkeypox Infection highlight it as safe and effective, although the safety data are still not very robust. In this Comment, we present some theoretical evaluations of its safety, considering that for use in humans it is essential to have a rich scientific literature in the area. After a series of analyses, a potential risk of liver, respiratory and kidney damage was found in addition to carcinogenic potential. Thus, while we agree that there is a need for rapid responses to infection, we reinforce that well-designed and adequately powered studies should not only focus on investigating the pharmacological efficacy of tecovirimat but also demonstrate its safety in humans. Therefore, in this Comment, we present some concerns that may help in formulating a safer treatment for patients infected with Monkeypox virus (MPXV).
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010012
Authors: Ravi Philip Rajkumar
Depression and obesity are highly comorbid with one another, with evidence of bidirectional causal links between each disorder and a shared biological basis. Genetic factors play a major role in influencing both the occurrence of comorbid depression and obesity, their courses, and their response to existing treatments. The current paper is a scoping review of studies that have evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Based on a search of the PubMed and EMBASE databases, 28 studies were included in this review, covering 54 candidate genes. Positive associations were identified for 14 genetic loci (AKR1C2, APOA5, COMT, DAT1, FTO, KCNE1, MAOA, MC4R, MCHR2, NPY2R, NR3C1, Ob, PCSK9, and TAL1). Replicated findings across two or more independent samples were observed for the FTO and MC4R genes. Many of these gene products represent novel molecular targets for the pharmacological management of obesity that interact with each other and are not pharmacologically influenced by existing anti-obesity or antidepressant medications. The implications of these associations for future drug development are discussed, with an emphasis on recent evidence on the polygenic architecture of comorbid depression and obesity and on a precision-medicine approach to these conditions.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010011
Authors: Tom A. Gardiner Desmond B. Archer Giuliana Silvestri Winfried M. Amoaku
Exacerbation of the vascular pathology in radiation retinopathy as a result of pre-existing diabetes has been recognized for many years, as reflected by clinical reports and a few early experimental studies. However, the underlying pathogenetic mechanisms for the synergistic interaction of radiation retinopathy (RR) and diabetic retinopathy (DR) have not been compared and evaluated for insight on this phenomenon. The present work draws attention to the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as common mediators of both conditions and sources of ongoing cellular injury in the radiation-induced bystander effect (RIBE) and the senescence-associated secretory phenotype (SASP). Chronic hyperglycemia-mediated oxidative stress and depleted antioxidant defense in diabetes, together with impaired DNA damage sensing and repair mechanisms, were identified as the primary elements contributing to the increased severity of RR in diabetic patients. We conclude that apart from strategic genetic mutations affecting the DNA damage response (DDR), diabetes represents the most significant common risk factor for vascular injury as a side effect of radiotherapy.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010010
Authors: Corina Andrei Anca Zanfirescu Dragoș Paul Mihai Simona Negreș
Visceral pain is a unique clinical entity that lacks an effective and safe treatment. Proper preclinical models are essential for assessing new drugs developed for the treatment of this pathology. Few studies report that paclitaxel, an antineoplastic agent, can be used to induce visceral pain in laboratory animals. Our purpose was to investigate the reproducibility of these studies and to develop an animal method that would allow assessing consistent visceral pain. In this study, we used four doses of paclitaxel (3 mg × kg−1; 5 mg × kg−1; 10 mg × kg−1 and 15 mg × kg−1). Visceral pain was evaluated using a scale of abdominal pain immediately after the administration of a single dose of paclitaxel to rats. Tactile and thermal hypersensitivity were assessed using von Frey filaments and the tail flick test initially, at 24 h and 48 h after administration. Rats experienced visceral pain and mechanical and thermal hypersensitivity 24 h after the administration of paclitaxel. The intensity of the pain was increased in a dose-dependent manner with the highest intensity of effect being observed after the administration of a dose of 15 mg × kg−1. Paclitaxel induces visceral pain. The dosage varies depending on the employed strain of rat. This method allows for assessing the efficacy of analgesics to be useful against visceral pain if the paclitaxel dose is adjusted accordingly to the animal strain.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010009
Authors: Hawaabi F. M. Shaikh Pratima U. Oswal Manohar S. Kugaji Sandeep S. Katti Kishore G. Bhat Vinayak M. Joshi
The periodontal disease etiology has been a demesne of scrupulous research, with a myriad of bacterial phylotypes inhabiting the periodontal pockets. The aim of our study was to assess the frequency of Filifactor alocis in type 2 diabetes mellitus (DM) subjects having a healthy periodontium (DH) or chronic periodontitis (DCP) and its correlation with clinical parameters and red complex bacteria. Polymerase chain reaction was carried out for the detection of F. alocis and red complex bacteria from subgingival plaque samples. The data were analyzed using Fisher’s Exact Test and Pearson’s chi-square test. A p value < 0.05 was considered statistically significant. F. alocis was detected at considerably higher levels in DCP (p < 0.05). F. alocis presence was also positively correlated with T. forsythia detection and the clinical parameters PD and CAL (p < 0.05). Subjects with good glycemic control showed a considerably lower detection of F. alocis as compared to fair- and poor-glycemic-control subjects. This is the first paper reporting the co-occurrence of F. alocis and T. forsythia in diabetic subjects with chronic periodontitis. These findings show that F. alocis can play an important role in establishing synergistic collaborations with other pathogenic oral microorganisms and speeding up the course of periodontal disease in diabetics.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010008
Authors: IJTM Editorial Office IJTM Editorial Office
High-quality academic publishing is built on rigorous peer review [...]
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010007
Authors: Austin P. Morrissey Nagla Elzinad Chris El Hayek Saran Lotfollahzadeh Vipul C. Chitalia
COVID-19 is a devastating systemic disease characterized by multisystem involvement driven by exuberant hyperinflammatory and dysregulations in coagulation. In COVID-19 patients, renal failure contributes to morbidity and mortality, and its early detection and timely management are critical to minimize such untoward and irreversible complications. In the healthcare system, family physicians constitute the first node in the management of patients, yet there is a dearth of reports and guidelines focusing on them for specific organ affection. This review provides an overview of recent studies examining the renal manifestations following SARS-CoV-2 infection. We focus on the tell-tale signs and laboratory findings of renal affection in the pediatric and adult populations with COVID-19, specifically for family practitioners to assist in their appropriate triage. Among different manifestations, urinary abnormalities and a modest increase in creatinine are the early indicators of renal affection in COVID-19 patients. Although renal transplant patients are conventionally managed by specialized teams, they may present to family physicians during a pandemic. This review provides a framework for family physicians to promptly detect early indicators of renal involvement in patients infected with SARS-CoV-2, including providing triage guidance for kidney transplant recipients.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010006
Authors: Hans Christian Wulf Peter A. Philipsen Jakob Heydenreich
Phototherapy using ultraviolet radiation (UVR) treatment units of various designs is common in dermatology. The anatomical distribution of UVR should be even, regardless of individual body shapes. Using electronic dosimeters, we measured the irradiance at 31 body sites on 12 persons of different heights and body mass (BMI). Five different treatment unit designs were tested: cabinet units with standing patients, units with patients lying down, and a unit where patients rotated in front of flatly arranged UVR tubes. In treatment units with short tubes, persons taller than 170 cm received low irradiance on the face, neck, and shoulders. In cabinet-type units, higher BMI lowered the irradiance on the chest and belly. The relative standard deviation (RSD) of irradiance was smallest for the rotating unit, and for the unit with patients lying down while irradiated from above only. A higher RSD was found in the unit designs where patients stood inside cabinets, and where patients lay down and were simultaneously irradiated from both sides. In general, longer tubes lower the overall RSD. The irradiance of the different body areas is about 60% of the measured calibration values, but to avoid provoking any erythema, the treatment dose can only be increased by 10%.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010005
Authors: Natalia Salinas Parra Heather M. Ross Adnan Khan Marisa Wu Risa Goldberg Lokesh Shah Sarah Mukhtar Jacob Beiriger Alexis Gerber Dina Halegoua-DeMarzio
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with increasing global incidence. Morbidity and mortality associated with HCC remains high, and HCC is the leading cause of cancer death worldwide. Early detection and treatment of HCC can increase five-year survival by over 60%. Detection of HCC remains challenging, however, as HCC arises from a variety of environmental, genetic, and viral etiologies, and it demonstrates a complex pathophysiology and displays a heterogeneous morphology. Current diagnostic methods rely on abdominal ultrasound with or without concurrent AFP biomarker testing for high-risk individuals. This review provides an overview of HCC diagnostic modalities and highlights the promising nature of translational developments in biomarkers, next generation sequencing (NGS), artificial intelligence, molecular imaging, and liquid biopsy for earlier and more accurate diagnosis of HCC. Furthermore, we identify areas for improvement that must be addressed before the widespread usage and implementation of these methods.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010004
Authors: Ana Filipa Poeira Maria Otília Zangão
Throughout their life, women should pay attention to their mental health. Evidence indicates that poor sleep quality is related to depressive symptoms in pregnancy, justifying the intervention of health professionals in improving sleep quality to promote the mental health of pregnant women. The objective of our study is to analyze the relationship between sleep quality and perinatal depression, and to identify the obstetric nurse’s intervention in improving sleep quality in the perinatal period. A total of 53 pregnant women between the 28th week of pregnancy and the 7th day after delivery completed the Edinburgh Postnatal Depression Scale (EPDS) and Pittsburgh Sleep Quality Index (PSQI). Women were also asked about the strategies used by the obstetric nurse to improve their quality of sleep. Data analysis was performed using IBM SPSS Statistics software, version 25.0. The Mann–Whitney-U and Kruskal-Wallis tests were carried out. A p-value < 0.05 was considered statistically significant. The median PSQI score was 10 (±3.63), and 9.2% (n = 9) had good quality sleep. The median EPDS score was 12 (±4.43), and 27 participants (50.9%) had probable depression. The women with likely depression had worse sleep quality (p = 0.016). Most participants reported that the obstetric nurse showed no interest in their sleep quality during pregnancy. Women of other nationalities have a higher risk of depression (p = 0.013). Based on our results, it is crucial to assess sleep quality in the perinatal period to promote women’s health during the prenatal and postnatal periods, and more action is needed since we are facing one of the most significant challenges of this century, preventing depression.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010003
Authors: Selvakumar Murugesan Chinnasamy Ragavendran Amir Ali Velusamy Arumugam Dinesh Kumar Lakshmanan Palanikumar Palanichamy Manigandan Venkatesan Chinnaperumal Kamaraj Juan Pedro Luna-Arias Fernández-Luqueño Fabián Safir Ullah Khan Zia ur-Rehman Mashwani Muhammad Younas
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have triggered a recent pandemic of respiratory disease and affected almost every country all over the world. A large amount of natural bioactive compounds are under clinical investigation for various diseases. In particular, marine natural compounds are gaining more attention in the new drug development process. The present study aimed to identify potential marine-derived inhibitors against the target proteins of COVID-19 using a computational approach. Currently, 16 marine clinical-level compounds were selected for computational screening against the 4 SARS-CoV-2 main proteases. Computational screening resulted from the best drug candidates for each target based on the binding affinity scores and amino acid interactions. Among these, five marine-derived compounds, namely, chrysophaentin A (−6.6 kcal/mol), geodisterol sulfates (−6.6 kcal/mol), hymenidin (−6.4 kcal/mol), plinabulin (−6.4 kcal/mol), and tetrodotoxin (−6.3 kcal/mol) expressed minimized binding energy and molecular interactions, such as covalent and hydrophobic interactions, with the SARS CoV-2 main protease. Using molecular dynamic studies, the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (ROG), and hydrogen bond (H-Bond) values were calculated for the SARS-CoV-2 main protease with a hymenidin docked complex. Additionally, in silico drug-likeness and pharmacokinetic property assessments of the compounds demonstrated favorable druggability. These results suggest that marine natural compounds are capable of fighting SARS-CoV-2. Further in vitro and in vivo studies need to be carried out to confirm their inhibitory potential.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010002
Authors: Rafael Fernández-Martínez Carlos Fernández-Pereira Daniel Pérez-Rodríguez Angel Salgado-Barreira Cesar Veiga García Sara Teso-Cuesta Jose María Prieto-González José Manuel Olivares Díez Roberto Carlos Agís-Balboa
Peer Victimization (PV) or being bullied in childhood/adolescence has been associated with several negative outcomes in mental health conditions beyond the time of its occurrence. However, its possible association with personality disorders has been slightly explored. In the present study we have compared the frequency of DSM IV personality disorders among adult patients with (N = 28) or without (N = 418) a reported history of PV. For this purpose, axis II was evaluated with the Self-Report Checklist for Preliminary Items for Major Categories, whereas self-esteem and self-assessment of functioning were evaluated with single questions. Patients with PV history have met the diagnostic criteria of the avoidant (60.7% vs. 12.2%), depressive (28.5% vs. 5.2%) and paranoid (17.9% vs. 5%) personality disorders more frequently than patients without history of PV. Moreover, these patients with antecedents of being bullied have also reported lower self-esteem (2 vs. 3) and in the assessment of social functioning (4 vs. 5). Our study indicated that there is a clear association between PV and avoidant, depressive and paranoid personality patterns. These results suggest that the stress related with the experience of PV threatens a basic psychobiological need such as social acceptance with implications for the beginning of long-term dysfunctional personality trajectories.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm3010001
Authors: Ngan Thi Mai Giang Thi Huong Tran Anh Huu Dang Phuong Thi Bich Cao Trung Thanh Nguyen Huong Thi Lan Pham Tra Thi Thu Vu Hieu Van Dong Le Thi My Huynh
Estimating the basic reproduction number (R0) of an infectious disease is a crucial step to describe the contagiousness and provides suggestions for interventions. To lift the effectiveness of preventive measures for the COVID-19 pandemic, we need to minimize the newly infected cases by reaching adequate herd immunity. This study thus aimed to compare the R0 through four waves of COVID-19 outbreaks in Vietnam and to calculate the minimal vaccination coverage in different populations. The data on the number of daily confirmed COVID-19 patients were collected from 21 January 2020 to 16 November 2021 from the daily reports through the four waves of the pandemic in Vietnam. The R0 values were estimated by exponential growth and the maximum likelihood methods to range from 1.04 to 3.31 from the first to the third wave. The fourth wave was the most severe, especially in the southern provinces, and the highest R0 was in Ho Chi Minh City. The herd immunity would range from 43.50% to 95.76% by various R0 values from different populations. Overall, the presence of new viral mutants increased the infectiousness and the vaccination coverage was higher to establish the required herd immunity in a high-density population. The results provide the basis for policy recommendations and resource allocation for vaccine management and distribution at a time when the COVID-19 pandemic is not yet over.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040047
Authors: Takayuki Goto Hiroko Kimura Takayuki Yoshino Atsuro Sawada Shusuke Akamatsu Takashi Kobayashi Toshinari Yamasaki Shigemi Tazawa Masakazu Fujimoto Yu Hidaka Ryuji Uozumi Satoshi Morita Osamu Ogawa Takahiro Inoue
Background: Radiation or hormonal therapy is considered for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, these therapies have their own complications. To delay the start of these therapies, we investigated the efficacy and safety of Brazilian green propolis for the treatment for BCR after RP. Materials and Methods: This single-center, single-arm open trial included 22 patients who experienced BCR after RP between 2016 and 2019. The patients received nine softgels of Brazilian green propolis (containing 40 mg propolis per capsule) daily for 6 months. The primary outcome was the prostate-specific antigen (PSA) response rate. The secondary outcomes included progression-free time, PSA slope (1/PSA doubling time) response rate, quality of life, and safety profile. Results: The PSA response rate was 0%. The mean PSA slopes before and after baseline were 0.12 month−1 and 0.08 month−1, respectively. Fifteen patients (68%) showed a decreased PSA slope after treatment. There were no negative effects on quality of life or serious adverse events leading to treatment discontinuation. Conclusion: There was no significant anticancer response in patients who received Brazilian green propolis. However, the PSA slope was decreased after propolis administration. Further, Brazilian green propolis may be safely consumed by patients.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040046
Authors: Sameer Dixit Akanchha Shukla Santosh Kumar Upadhyay Praveen Chandra Verma
Plant secondary metabolites are well-recognized medicinally important compounds. Gossypol is an important plant secondary metabolite with several medicinal properties. Carbon nanotubes (CNTs) are allotropes of carbon with diverse applicability in chemical, physical, and biological sciences due to their high surface area. The current study demonstrates the enhancement of gossypol production in cotton cell suspension culture in culture media supplemented with water-soluble carbon nanotubes. The fresh and dry weights of cotton cell suspension culture grown in MS media with 20 µg/mL CNTs were, respectively, 1.9 and 2.13 fold higher than in control MS media after one month. The net enhancement of gossypol production in MS media supplemented with 20 µg/mL CNTs was 2.47 fold higher than the control. Confocal and SEM imaging showed the presence CNTs on the cell surface, which mediated the formation of extra channels that resulted in high biomass production in cotton cell suspension culture. The gossypol produced by this cell suspension culture showed antiproliferative activity against the prostate cancer cell line. Thus, this study demonstrated a new method for enhanced gossypol production, which can prove beneficial for the production of other plant-based biological active compounds.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040045
Authors: Andrew J. Chetwynd Julien Marro Sarah J. Northey Daniel J. Hughes Louise Oni
IgA Vasculitis (IgAV) is the most common form of vasculitis in children, and 1–2% of patients develop chronic kidney disease. In other forms of glomerulonephritis, there is strong evidence to support the role of the renin-angiotensin-aldosterone system (RAAS); however, data are lacking in IgAV nephritis. This study evaluated urinary RAAS components in children with IgA vasculitis, both with nephritis (IgAVN) and without nephritis (IgAVwoN). Urinary concentrations of renin, angiotensinogen and aldosterone were quantified using ELISAs. In total, 40 patients were included: IgAVN n = 9, IgAVwoN n = 17, HC n = 14, with a mean age of 8.3 ± 3.3 years. Urinary renin demonstrated no trend with nephritis. Urinary angiotensinogen was statistically significantly elevated in IgAV (1.18 ± 1.16 ng/mmol) compared to HC (0.28 ± 0.27 ng/mmol, p = 0.0015), and IgAVN (2.00 ± 1.22 ng/mmol) was elevated compared to IgAVwoN (0.74 ± 0.89 ng/mmol, p = 0.0492) and HC (p = 0.0233). Urinary aldosterone levels were significantly elevated in IgAV (1236 ± 1438 pg/mmol) compared to HC (73.90 ± 65.22 pg/mmol, p < 0.0001); this was most increased in IgAVwoN patients (1793 ± 1507 pg/mmol; IgAVN 183.30 ± 111.30 pg/mmol, p = 0.0035, HC p < 0.0001). As expected, the RAAS system is activated in patients with IgAVN and, more surprisingly, even in those without active nephritis. Further studies are needed to fully understand the role of the RAAS system in IgA vasculitis.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040044
Authors: Andrea Elmelid Amra Osmancevic Martin Gillstedt Mikael Alsterholm
The role of vitamin D in atopic dermatitis (AD) is controversial. Conflicting data could be due to the use of inadequate markers for assessing vitamin D status. So far, directly measured free 25(OH)D concentrations have not been reported in AD patients. Ten adults with AD were treated with narrow band ultraviolet light B (NB-UVB) for 10–12 weeks. SCORing atopic dermatitis (SCORAD) and the visual analogue scale (VAS) were used to assess disease severity before and after NB-UVB therapy. Total and free 25(OH)D and 1,25(OH)2D serum levels were analyzed before and after treatment. Free 25(OH)D concentrations were measured with a two-step immunosorbent assay (ELISA). The majority of patients had sufficient levels of 25(OH)D before treatment (mean 76.4 nmol/L). Mean free 25(OH)D was 11.9 pmol/L and mean 1,25(OH)2D was 108.9 pmol/L. Median SCORAD decreased from 37.1 to 19.8 and VAS improved significantly after phototherapy. Total and free 25(OH)D increased in all subjects. No correlations between disease severity and vitamin D levels were found. There was no correlation between total and free 25(OH)D levels. Larger studies are needed to test the applicability of the free hormone hypothesis in AD pathogenesis.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040043
Authors: Adedokun Oluwasegun Epole Ntungwe Ayinde Bunyamin Lucilia Saraiva Salvatore Princiotto Patrícia Rijo
Celosia trigyna is a well-known vegetable used in the preparation of many indigenous soups in Southwestern Nigeria. The aim of this study was to evaluate the anticancer property of C. trigyna of crude and solvent fractions using antioxidant, cytotoxic bench-top bioassays, and cancer cell line experiments. Cytotoxicity was carried out using Raniceps ranninus, Saccharomyces cerevisiae, and Sorghum bicolor models, as well as cytotoxicity studies against human breast (MCF), colon (HCT116), and lung (H460) cancer cell lines; radical scavenging potential against DPPH was likewise performed. A concentration of nondependent cytotoxicity against S. cerevisiae was observed in CTA, with the lowest inhibition of organism growth at 31.2 µg/mL (26.40 ± 1.92%) and highest activity at 250 µg/mL (56.00 ± 2.12%). Concentration-dependent inhibition was observed in CTA with 84.80 ± 1.97% at 250 µg/mL, which is significantly different from values observed in DMSO (negative control) at 33.84 ± 1.03% at p < 0.01. Moreover, 100% motility of R. ranninus (tadpoles) was recorded for all concentrations (20–40 µg/mL) in CT and CTA, with significantly different p < 0.05 from values obtained for the vehicle (distilled water). Concentration-dependent DPPH radical scavenging potential was likewise noted both in CT and CTA at 20–100 µg/mL. The lowest inhibition was observed at 20 µg/mL (41.35% and 32.31%), while the highest was noted at 100 µg/mL (63.26% and 41.73%) for CT and CTA, respectively. CT showed cytotoxic effects against all cancer cell lines examined, with CTA exhibiting improved activity compared to CT against human lung (H460), breast (MCF-7), and colon (HCT116) cancer cell lines, with IC50 51.69 ± 5.13, 39.16 ± 9.21, and 38.52 ± 7.65, respectively. Findings from this research experimentally justify the ethnomedicinal claim of usage of C. trigyna in the treatment of cancer in southwestern Nigeria.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040042
Authors: Niloofar Khoshdel Rad Maryam Vahidyeganeh Mahsa Mohammadi Anastasia Shpichka Peter Timashev Nikoo Hossein-Khannazer Massoud Vosough
Non-clear cell renal cell carcinomas (nccRCC) are a diverse group of kidney cancers with histopathologically and genetically heterogeneous features. About 25% of renal cell carcinomas (RCCs) are nccRCC types. The management and treatment of nccRCCs are rather limited, and the data are often estimated from studies in the more common clear cell renal cell carcinoma (ccRCC). Each subtype has its own distinctive biological and therapeutic profile. Our knowledge of the underlying biological features of nccRCC has directed and continues to shape the use of novel therapy targeting the main signaling pathways and leading to improved overall survival (OS) of the patients. This review discusses the characteristic molecular features of the major types of nccRCC and current cell-based and animal models for studying them. In the following, we highlighted major signaling pathways and therapeutic approaches for nccRCC patients.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040041
Authors: Abbas Jarrahi Rebecca Cantrell Cynthia Norris Krishnan Dhandapani John Barrett John Vender
Trigeminal neuralgia (TN) is a chronic pain condition causing lancinating pain in the distribution of one or more divisions of the trigeminal nerve. Gamma knife stereotactic radiosurgery (GKSRS) is a surgical option for TN refractory to medical therapy. To report our experience and to analyze the reasons for the variance in radiosurgery outcomes between patients in our diverse population, we conducted a retrospective analysis of a prospectively created database. The 178 patients completed a pain assessment questionnaire before surgery, and at 1 and 2 year follow-ups. We used the “Trigeminal Neuralgia Gamma Knife Outcome Scale” (TN GKOS) to report the response. At 1-year, 35.4% of patients had grade 1A outcome (pain-free and off all pain medications), 24.7% had grade 1B (pain-free on pain medications), 24.2% had grade 1C (some pain but improved with radiosurgery), 12.9% had grade 2 (same as before radiosurgery) and 2.8% had grade 3 (worse pain compared to before radiosurgery). At 2 years, 42.3% had grade 1A, 20.5% had grade 1B, 19.2% had grade 1C, 14.1% had grade 2 and 3.8% had grade 3 outcome. Remarkably, a statistically significant association was found between GKOS and age, racial background and obesity.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040040
Authors: Barbara Lattanzi Ingrid Febbraro Eliseo Pironti Marco Bianchi
Pancreatic pseudocysts represent a complication of acute interstitial edematous pancreatitis with a frequency of about 10–20%, and most of these resolve spontaneously. Treatment is indicated only in patients who develop symptoms such as abdominal pain, gastric outlet obstruction, jaundice for compression of the biliary system, or in case of infection. Pancreatic pseudocysts’ complications include pseudocyst infection leading to sepsis, rupture with pancreatic ascites, bleeding or formation of pseudoaneurysm, and, rarely, fistulization to other viscera. The most common sites for fistulas are between cysts and the stomach, duodenum, and colon. Here, we present the case of a patient with severe acute pancreatitis who developed multiple infected fluid collections with a cysto-duodenum fistula that was successfully treated with endoscopic intervention.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040039
Authors: Michael Bushell Filip Kunc Xiaomei Du Andre Zborowski Linda J. Johnston David C. Kennedy
Cerium oxide nanoparticles are promising materials as novel nanoscale therapeutics and are commonly used materials in industrial processes. Most cytotoxicity studies on cerium oxide nanoparticles are made from in-lab prepared materials making comparison between studies challenging, especially when performed on unique cell lines under non-standard conditions. Using commercially available nanoparticles we show that particle stability/agglomeration may be critical in determining the cytotoxicity in some cell lines, while in other cell lines, larger sized primary particles are linked to higher cytotoxicity, contrasting what has been reported in the literature for smaller cerium nanoparticles. To accelerate the development of cerium oxide enabled commercial processes and biomedical innovations, a clearer understanding of the interactions between cerium oxide nanoparticles and cells is needed to better understand their fate in and impact on biological systems.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2040038
Authors: Suji Ryu Ha Yeon Lee Seoul-Hee Nam Jong-Suep Baek
Hot-melt extrusion (HME) has been an alternative technique to improve the solubility and bioavailability of active molecules with low water solubility. In this study, HME-Angelica gigas Nakai (AGN) was prepared to increase the aqueous solubility of decursin (D) and decursinol angelate (DA), the active ingredients of AGN. Compared with unprocessed AGN, HME-AGN showed enhanced water solubility of D and DA. The HME-AGN exhibited improved antioxidant activity by the DPPH radical scavenging method. The antifungal activity was confirmed against Candida albicans (C. albicans). There was a decrease in CFU in the plate treated with the HME-AGN extract compared with the plate treated with the AGN extract, and F2 showed the highest antifungal activity.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030037
Authors: Shoshana Revel-Vilk Gabriel Chodick Varda Shalev Roni Lotan Kaja Zarakowska Noga Gadir
Early and accurate diagnosis of Gaucher disease, a rare, autosomal recessive condition characterized by hepatosplenomegaly, thrombocytopenia, and anemia, is essential to facilitate earlier decision-making and prevent unnecessary tests and procedures. However, diagnosis can be challenging for non-specialists, owing to a wide variability in age, severity of disease, and types of clinical manifestation. The Gaucher Earlier Diagnosis Consensus (GED-C) scoring system was developed by a panel of 22 expert physicians using Delphi methodology on the signs and covariables considered important for diagnosing Gaucher disease. This study aimed to use the scoring system in a real-world dataset. We applied the GED-C scoring system to 265 confirmed cases of Gaucher disease identified in the Maccabi Health Services (MHS) database from 1998 to 2022. Overall Delphi scores were calculated using features applicable to type 1 Gaucher disease. Based on all available patient data up to one year after diagnosis, the median (interquartile range (IQR)) Delphi score was 8.0 (5.5–11.5), with patients reporting up to 15 variables each. A score of 9.5 (6.5–12.5) was determined for 205 patients diagnosed from 2000 to 2022. The overall GED-C score was highly dependent on the extraction of all relevant data. The number of features collected in the MHS database was fewer than those required to achieve a high score on the GED-C score.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030036
Authors: Ana Salomé Correia Armando Cardoso Nuno Vale
Depression is a prevalent and debilitating disease worldwide. This pathology is very complex and the lack of efficient therapeutic modalities, as well as the high rates of relapse, makes the study and treatment of depression a global healthcare challenge. Thus, an intense investigation of this disease is crucial and urgent. In this study, we focused on hydrogen peroxide and corticosterone-induced stress on SH-SY5Y and HT-22 cells. Additionally, we aimed to study the potential attenuation of these induced stress with the exposure of both cells to mirtazapine and L-tryptophan, focusing on cell viability assays (MTT and Neutral Red) and reactive oxygen species production assays (DCFDA fluorescence). Taken together, our results indicate that mirtazapine and L-tryptophan counteract the cellular stress induced by hydrogen peroxide but not by corticosterone, revealing a potential role of these agents on oxidative stress relief, highlighting the role of serotonergic pathways in the oxidative stress present in depressed individuals. This study allows the investigation of depression using cellular models, enabling the screening of compounds that may have potential to be used in the treatment of depression by acting on cellular mechanisms such as oxidative stress protection.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030035
Authors: Jishizhan Chen
Osteoarthritis leads to the progressive decay of articular cartilage. Due to its intrinsic avascular character, cartilage shows an inadequate capacity for regeneration. Cartilage loss may result in chronic pain, movement disorder and morbidity, which lack effective treatments except for joint replacement for late-stage osteoarthritis. To overcome this challenge, tissue engineering has emerged as a promising method. Scaffolds provide mechanical and biochemical support to stem cells that undergo differentiation and secrete a cartilage-specific matrix, and this strategy has been proven to have positive results. However, there is still a gap between the current strategy and perfection. Researchers are confronted with difficulties such as poor cell survival, insufficient differentiation, hypertrophy and endochondral calcification of neocartilage, and inadequate integration into the host tissue. The current research focuses on modifying scaffold parameters, including composition, stiffness, pore size, surface morphology, hydrophilicity and electric charge. On the other hand, cell regulation is another focus, including predifferentiation, gene editing, dynamic mechanical stimulus, and hypoxia. This review aims to provide a comprehensive discussion of existing challenges, scaffold types and properties, practical methods to improve chondrogenic potential and an outlook on future trends in cartilage bioengineering.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030034
Authors: Assaf Mizrahi Françoise Jaureguy Héloise Petit Gauthier Péan de Ponfilly Etienne Carbonnelle Alban Le Monnier Jean-Ralph Zahar Benoît Pilmis
Background: Sepsis caused by multi-drug-resistant Gram-negative bacilli lead physicians to prescribe broad-spectrum antibiotic therapy, such as carbapenems. Rapid susceptibility testing can help with the rational use of antibiotics. The aim of this study was to measure the clinical impact associated with rapid reporting of Beta-Lacta test (BLT) directly on blood cultures positive with Gram-negative bacilli. Methods: In an observational, multicentric, prospective study, we included patients with sepsis caused by Enterobacterales observed on Gram staining of the positive blood cultures. BLT and antimicrobial susceptibility testing (AST) were performed directly on the blood cultures. Clinical impact was measured on the proportion of patients for whom the probabilistic antibiotic therapy was modified according to BLT, including patients receiving carbapenem. Results: 170 patients were included, of whom 44 (25.9%) were receiving inadequate empirical antibiotic therapy. Among them, 27 (15.9%) benefited from an early modification, according to the BLT results. Among 126 (74.1%) patients receiving appropriate probabilistic antibiotic therapy, we modified the antibiotic therapy for 28 (16.5%) of them, including 4/14 (28.5%) de-escalation from carbapenem to a third-generation cephalosporin. Conclusions: Implementation of BLT performed directly on blood cultures allowed us to rapidly modify the empirical antibiotic therapy for about one-third of patients with sepsis caused by Enterobacterales.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030033
Authors: Yoshinobu Kariya Yukiko Kariya
Despite significant advances in the understanding of cancer biology, cancer is still a leading cause of death worldwide. Expression of the tumor microenvironment component, osteopontin, in tumor tissues, plasma, and serum, has been shown to be associated with a poor prognosis and survival rate in various human cancers. Recent studies suggest that osteopontin drives tumor development and aggressiveness using various strategies. In this review, we first provide an overview of how osteopontin promotes tumor progression, such as tumor growth, invasion, angiogenesis, and immune modulation, as well as metastasis and chemoresistance. Next, we address how the functional activities of osteopontin are modulated by the interaction with integrins and CD44 receptors, but also by the post-translational modification, such as proteolytic processing by several proteases, phosphorylation, and glycosylation. Then, we review how osteopontin activates tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), and functions as an immunosuppressor by regulating immune surveillance and immune checkpoint in the tumor microenvironment. Finally, we discuss the potential applications of osteopontin as a biomarker and as a therapeutic target.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030032
Authors: Snigdha Pusalavidyasagar Laurie B. Hovde Jessie Lee Lei Zhang Adnan Abbasi Reena V. Kartha
Patients with obstructive sleep apnea (OSA) have an increased risk of cardiovascular disease (CVD). Nitric oxide (NO) and heme oxygenase-1 (HO-1) affect vascular tone and are vasoprotective. Furthermore, hydrogen sulfide (H2S), an HO-1 inducer, is known to be a major effector molecule driving apneas. This study was conducted to examine the molecular relationships between these gasotransmitters and HO-1 in patients with OSA. Individuals who presented for evaluation for possible OSA were recruited and underwent overnight polysomnography. Individuals with an apnea-hypopnea index (AHI) of >5 per hour (OSA diagnosis) were considered cases (n = 19), while those with an AHI of <5 per hour (n = 6) were the controls. Blood samples were obtained before sleep and again from OSA cases prior to initiating treatment. H2S, NO, and HO-1 levels were assayed. Patients with OSA showed lower NO and H2S levels at baseline compared to controls. NO levels further decreased significantly from baseline in patients at the time of OSA diagnosis, while H2S levels largely showed an increasing trend, which was observed only when the subjects showing a baseline H2S level of >0.5 μM were excluded. Interestingly, analysis of HO-1 did not show a significant change from baseline, confirming the inverse relationship between the two gasotransmitters. The alterations in the bioavailability of endogenous H2S and its molecular interactions with NO and HO-1 regulating vascular tone may play a role in the pathogenesis of CVD in OSA patients.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030031
Authors: Armando Morales-Jr Walter Pereira Pinto Vanessa Correa Fanchini Luana Cristina de Almeida Silva Thiago José Martins Gonçalves Pamela Nithzi Bricher Choque Fernanda Kussi Lia Sumie Nakao Rosilene Motta Elias Maria Aparecida Dalboni
Chronic kidney disease (CKD) affects 10% of the world’s population. Uremic toxins, such as indoxyl sulfate (IS), p-Cresylsulfate (PCS) and indole acetic acid (IAA), are not sufficiently removed by conventional hemodialysis (HD) and have been associated with inflammation, poor quality of life, bone mineral disease (BMD) and endothelial injury. Online hemodiafiltration (OL-HDF) may promote greater clearance of uremic toxins than HD. However, there are few studies evaluating the effect of OL-HDF on serum levels of IS, PCS, IAA, and biomarkers associated with inflammatory, endothelial, and bone and mineral disorder in the elderly population. We evaluated the effect of 6 months of OL-HDF on the serum concentration of uremic toxins, biomarkers of inflammation, endothelial and bone mineral disorder in older patients on OL-HDF. IS, PCS, and IAA were measured by high-performance liquid chromatography. We included 31 patients (77.4 ± 7.1 years, 64.5% male, 35.5% diabetic, on maintenance dialysis for 45 ± 20 days). From baseline to 6 months there was a decrease in serum concentration of IS but not PCS and IAA. We found no change in serum concentration of inflammatory, endothelial, or mineral and bone biomarkers. In summary, OL-HDF was capable to reduce IS in older patients. Whether this reduction may have an impact on clinical outcomes deserves further evaluation.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030030
Authors: Miriam Ting Jon B. Suzuki
Oral antiseptic mouthwashes have been widely used for their antibacterial activity. As a result of the SARS-CoV-2 pandemic, the antiviral properties of these oral antiseptics have been aggressively studied. To demonstrate the direct antiviral activity of mouthwashes against SARS-CoV-2, this review will focus on the in vitro virucidal effects of these mouthwashes. Knowledge of the type, concentration, and exposure time of available mouthwashes can provide insights into effective protocols for their clinical use. With an understanding of the characteristics of each oral antiseptic mouthwash, proper mouthwash selection against SARS-CoV-2 may become a useful adjunct to personal protective equipment.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030029
Authors: Nik V. Kouznetsov
The human immune system is compromised in microgravity (MG) conditions during an orbital flight and upon return to Earth. T cells are critical for the immune response and execute their functions via actin-mediated immune cell-cell interactions that could be disturbed by MG conditions. In our study, we have applied two conventional platforms to simulate MG conditions: fast rotating clinostat (CL) and random positioning machine (RPM), followed by global T cell transcriptome analysis using RNA sequencing. Noteworthily, both selected rotational simulated MG platforms employ forced cell movement in cultural medium and expose cells to shear forces, therefore inducing certain cell response to hydrodynamic stress. We demonstrate that the T cell transcriptome profile in response to simulated MG treatment was clearly distinguishable from the T cell transcriptome response to hydrodynamic stress (HS). Gene expression profiling of genes related to or involved in actin cytoskeleton networks using RT-qPCR confirmed two sets of differentially regulated genes in the T cell response to MG or to HS. Several key genes potentially involved in T cell gravisensing (Fam163b, Dnph1, Trim34, Upk-1b) were identified. A number of candidate biomarker genes of the response to MG (VAV1, VAV2, VAV3, and NFATC2) and of the response to HS (ITGAL, ITGB1, ITGB2, RAC1, and RAC2) could be used to distinguish between these processes on the gene transcription level. Together, MG induces changes in the overall transcriptome of T cells, leading to specific shifts in the expression of cytoskeletal network genes.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030028
Authors: Bhavya Banjan Mohammed F. Albeshr Shahid Mahboob Irfan Manzoor Ranajit Das
The world is currently faced with a pandemic of coronavirus disease 2019 (COVID-19). Several genome-wide and exome-wide studies (GWAS and EWAS) have been performed to identify the variability in the host genetic constitution that likely underlines the inter-individual variabilities in COVID-19 severity and clinical manifestation. Due to the magnitude of the articles available, creating a list of host-specific genetic variants and genes associated with COVID-19 can be both time-consuming and extremely challenging for COVID-19 researchers. To this end, the COVID-19 Host Genome database was built. This is currently the only dedicated, free-to-use database that deals solely with COVID-19 host-specific genetic variants and genes. HyperText Markup language (HTML), Cascading Style Sheets (CSS), Hypertext Preprocessor (PHP), and My Structured Query Language (MySQL) server (version 5.7.38) were used to develop the website, storage, and extraction of the data. So far, 787 genetic variants from 63 previously published articles were collected. The tabular data are hyperlinked to the original articles and the users can download all data from the database. COVID-19 Host GenomeDB is being revised constantly every month, and can benefit the research community studying the genetic variants to improve COVID-19 treatment and prevention strategies.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030027
Authors: Kenji Imai Koji Takai Shinji Unome Takao Miwa Toshihide Maeda Tatsunori Hanai Yohei Shirakami Atsushi Suetsugu Masahito Shimizu
This study evaluated the factors that affect the recurrence of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-positive patients, who had received curative treatment for initial HCC, using decision tree analysis in 111 curative cases. The enrolled patients were divided into three groups by the decision tree analysis as follows: Patients who achieved sustained virological response (SVR) after curative treatment belonged to Group 1 (n = 33), those who did not achieve SVR and with alpha-fetoprotein (AFP) levels < 11 ng/mL belonged to Group 2 (n = 30), and those who did not achieve SVR and with AFP levels ≥ 11 ng/mL belonged to Group 3 (n = 48). The Kaplan–Meier method revealed that Group 1 had significantly longer recurrence-free survival than Group 2 or 3 (p = 0.004). Moreover, there was no significant difference between patients achieving SVR with direct-acting antivirals and interferon therapy (p = 0.251). Group 3 had significantly poorer recurrence-free survival than Group 2 (p < 0.001). The Cox proportional hazards model demonstrated that SVR achievement was the only independent factor associated with low HCC recurrence (p = 0.005). In conclusion, patients who achieved SVR were the least prone to HCC recurrence, whereas those who did not achieve SVR and had AFP levels ≥ 11 ng/mL were the most prone to HCC recurrence.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030026
Authors: Ursula Windberger Veronika Glanz Leon Ploszczanski
Rats impress by their high platelet count resulting in hypercoagulability, which protects the animals from severe bleeding. However, platelets also import numerous stiff junction points into the fibrous system of a clot, also enhancing the pre-stress of the fibrin fibers, which lowers their deformability. Clot deformation is clinically important since large strains are present in the arterial tree (caused by the propagation of pressure and pulse waves), and a clot is considered “safe” when it can deform over a long range of strain amplitudes. We tested clot formation and the behavior of fully formed blood clots of laboratory rats at large sinusoidal shear stress amplitudes by rheometry and compared outcomes to human reference data. We found that fiber density (by scanning electron microscopy) and clot stiffness (by rheometry) was pronounced compared to humans and differed with sexual dimorphism and with rat strain. Using our large amplitude oscillation (LAOS) protocol, we detected that rat clots yielded with a frustrated attempt to stiffen instead of showing the macroscopic stiffening response that is typical for human clots. We attribute this behavior to the appearance of multiple microfractures until, finally, a few leading fibers uptake the load. Rat clots also failed to align fibers in shear direction to initiate affine deformation. The rat clot phenotype differs substantially from the human one, which must be considered in research and toxicological testing. If microfractures in the fiber meshwork are concentrated in vivo, parts of a clot may break off and be washed away. However, homogenously distributed microfractures may open pores and allow the penetration of plasminogen activators. What occurs in the rat vasculature depends on the on-site clot composition.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030025
Authors: Leonor Saldanha Nuno Vale
In the past decade, mRNA vaccines have been highly discussed as a promising therapy for cancer. With the pandemic of COVID-19, some researchers redirected their studies to the development of a new vaccine for COVID-19 due to the urgent need. With the pandemic’s deceleration due to the vaccines’ success, the research and development of mRNA vaccines have turned to cancer again. Considering the new evidence and results generated by the vaccination of millions of people with mRNA vaccines, this article intends to provide a perspective on how the results from COVID-19 vaccination could now provide new insights for the development of an mRNA cancer vaccine. Many lessons were learned, and new evidence is available to re-focus and enhance the potential of the mRNA technology to cancer. Pfizer-BioNTech and Moderna’s mRNA technologies, and their significant advancements, allowed mRNA to overcome many of the challenges and blockers related to this platform in the past, now providing a new breadth of hope on using the mRNA technology to treat many diseases, namely cancer. This study also reports a better understanding of how it was possible to boost an accelerated development process of COVID-19 vaccines from a regulatory point of view. It is also relevant to consider other synergies and factors that contributed to gathering all the conditions ensuring the development of these vaccines in such a short period. Suppose the same efforts from all stakeholders could be applied to the development of new cancer vaccines, aligned now with the new scientific evidence generated from the current mRNA vaccines for COVID-19. In that case, mRNA cancer vaccines are near, and a new era for cancer treatment is about to begin.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2030024
Authors: Tawee Chotpitayasunondh Dale Andrew Fisher Po-Ren Hsueh Ping-Ing Lee Katya Nogales Crespo Kiat Ruxrungtham
This paper provides a comprehensive summary of evidence to explore and position the role of serology testing in the context of coronavirus disease 19 (COVID-19) immunization and policy response in the Asia-Pacific (APAC) region. The document builds on a review of academic literature and existing policies followed by a process of discussion, validation, and feedback by a group of six experts. Six countries and territories—Australia, Hong Kong, India, Indonesia, Thailand, and Taiwan—were sampled to highlight the differing contexts and scenarios in the region. The review includes an overview of (1) the impact of the COVID-19 pandemic, including the emergence of Variants of Concern (VOCs), especially Omicron, (2) the introduction of immunization, (3) the available testing options and potential use of serology testing, (4) the landscape of guidelines and recommendations for their use, and (5) the barriers and challenges to implementing serology testing as a tool to support COVID-19 immunization. Based on the findings, the co-authors propose a set of recommendations to resolve knowledge gaps, to include the use of serology testing as part of the policy response, and to ensure adequate means of implementation. This paper’s target audience includes members of the academic community, medical societies, health providers and practitioners, and decision-makers.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020023
Authors: Bruna de Paula Dias Ricardo Lemes Gonçalves Cyntia Silva Ferreira Camila Cavadas Barbosa Orlando Alfredo Pineda Arrieta Samara Mayra Soares Alves dos Santos Wellington Carvalho Malta Mariela Alves e Silva Maria Laura Maximiano Dias Gomes Adriana Gibara Guimarães Lysandro Pinto Borges Breno de Mello Silva
An accurate and rapid diagnosis of COVID-19 is an effective strategy for pandemic control, allowing disease screening and timely therapeutic intervention. We analyzed scientific reports about rapid tests for the diagnosis of COVID-19 to assess their reliability parameters. Medical Subject Headings terms or keywords related to point-of-care and rapid diagnostic testing for SARS-CoV-2 and COVID-19 were searched in data published from November 2020 to November 2021 in PubMed and Google Scholar databases. Notable differences were observed in sensitivity among direct tests that used different samples, and good accuracy was reported in a significant number of studies (>80%). Pediatric samples and samples with high Ct values (RT-PCR) had suboptimal sensitivity (range 45.4% to 66%). Further, a lack of sensitivity (<46.2%) was observed in point-of-care tests and in rapid diagnostic tests for antibody detection in the first days after infection, with increasing values in postinfection analysis (>60%). For serological detection of IgM or Antigen rapid diagnostic tests, no cross-reactivity was found with other coronaviruses. Therefore, although these tests are very important in facing the pandemic, they still need to be improved to test cross-reactivity against other pathogens, especially against other coronaviruses.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020022
Authors: Massimiliano Ortore Elisa Grazioli Eliana Tranchita Carlo Minganti Alessia Manteca Ludovico Tinto Claudia Cerulli Igino Fabi Antonella Foti Giovanna Borriello Paolo Riondino Attilio Parisi
Background: In the last two years, the COVID-19 pandemic has spread all over the world, affecting millions of people. The same infection can manifest in different clinical conditions, ranging from mild situations to severe patient impairment, up to their death. The COVID-19 infection can activate innate and adaptive immune systems and cause massive inflammatory responses that is important to treat as soon as possible. Methods: In the initial phase of the pandemic, a group of 240 unvaccinated subjects with COVID-19 disease was administered phytotherapy with immunostimulant and antioxidant property to evaluate the role of this phytotherapeutic preparation in counteracting the progression of the COVID-19 disease both in duration and complexity. Results: 161 patients were treated with phytotherapy alone and the prevailing symptoms in the acute phase were rhinitis, fever, cough, osteo-muscular pains; the other 79 patients were given a therapy with NSAIDs, symptomatic drugs, monoclonal antibodies, corticosteroids, antibiotics, and/or heparin. The coexistence of comorbidity (such as diabetes, hypertension, gastro-intestinal disease) was recorded in 74 out of 240 subjects, more frequently in the older subjects; there was no statistically significant correlation between the presence of comorbidity and the duration of disease. Hospitalization rate in this population was 1.6% and lethality rate was 0%. Conclusion: The use of phytotherapy can represent a valid weapon against COVID-19, since it showed no side effects and can also be used in association with other pharmacological therapies to reduce the massive inflammatory responses of this infection.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020021
Authors: Miriam Ting Jon B. Suzuki
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appears to be diminishing in infectivity and hospitalizations in the United States and many parts of the world. This review will provide current information on the pathogenesis of SARS-CoV-2 and long haul COVID, emerging research on systemic complications, and antibody responses of vaccines and boosters.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020020
Authors: Dan Alexandru Toc Razvan Marian Mihaila Alexandru Botan Carina Nicoleta Bobohalma Giulia Andreea Risteiu Bogdan Nicolae Simut-Cacuci Bianca Steorobelea Stefan Troanca Lia Monica Junie
(1) Background: Based on the uncontrolled use of antibiotics and the lack of worldwide-accepted healthcare policies, the COVID-19 pandemic has provided the best premises for the emergence of life-threatening infections. Based on changes described in the intestinal microbiome, showing an increased number of Enterococcus bacteria and increased intestinal permeability due to viral infection, infections with Enterococcus have taken the spotlight in the healthcare setting; (2) Methods: We conducted a brief review in order to analyze the relationship between the two pathogens: the SARS-CoV-2 virus and the Enterococcus bacterial genus. We searched in PubMed, the Cochrane Library electronic database and MedNar and included twenty-one studies based on relevance; (3) Results: The existing studies show a statistically significant difference in the composition of the intestinal microbiome, favoring Enterococcus genus, when compared to a control group. Changes also seem to persist over a period of time, suggesting possible implications for long COVID. Regarding bloodstream infections, Enterococcus is statistically significantly isolated more often when compared to the pre-COVID-19 era, and to a control group of non-COVID-19 patients. (4) Conclusions: The intimate synergy between COVID-19 and Enterococcus has the potential to pose a real threat to human healthcare, and more extensive research is needed to explore the relationship between these two pathogens.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020019
Authors: Tatiana Markova Aysylu Murtazina Vladimir Kenis Evgenii Melchenko Maria Ampleeva Tatiana Nagornova Aynur Alieva Elena Dadali Sergey Kutsev
Multiple epiphyseal dysplasia type 1 is one of the most common autosomal dominant types of the genetically heterogeneous group of skeletal dysplasias characterized by impaired ossification of the epiphyses of long bones. To date, it is known that the disease is caused by heterozygous variants in the COMP gene and is characterized by a significant variability in the clinical manifestations. We report the first case of a patient with MED 1 caused by novel homozygous single nucleotide variant c.2170dupG (p.Val724Glyfs*20) in the COMP gene identified by whole-exome sequencing. The following segregation analysis in the family found a detected variant in heterozygous state in healthy consanguineous parents of the proband. Clinical and radiological examination revealed the atypical signs of epiphyseal dysplasia including limited range of extension and supination of both forearms, severe bilateral ulnar clubhand, plano-valgus deformity of the feet and generalized muscle weakness with gait disturbances. Among the clinical features, myopathic signs were the most prominent. The radiological and neurophysiological data can be helpful in the differential diagnostics with the congenital myopathies. The novel homozygous variant in the COMP gene that caused multiple epiphyseal dysplasia 1 with autosomal recessive inheritance can contribute to the more detailed description of genotype–phenotype correlations, which will allow research to understand better the role of the C-terminal domain of COMP.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020018
Authors: Irina Fevraleva Olga Glinshchikova Tatiana Makarik Andrey Sudarikov
Background: Up to 40% of test results for COVID-19 in the presence of clinical manifestations of the disease might be negative. The reason for a false-negative result might originate from any step of the analysis: poor-quality or empty swab, poor RNA isolation, inactivation of reverse transcriptase or Taq polymerase in the test. Methods: Here we describe a PCR approach for SARS-CoV-2 detection with swab quality and integrity controlled by human ABL1 mRNA amplification. Designed primers work with the cDNA of the ABL1 gene, not genomic DNA. Results: The simultaneous appearance of three signals corresponding to the nucleocapsid, spike, and ABL1 gene indicates infection with the Omicron strain. The amplification of ABL1 gene and nucleocapsid only indicate other than Omicron infection. The appearance of ABL1 amplification only indicates a true negative result for SARS-CoV-2. All other variants are null and void. Conclusions: A system has been developed for multiplex PCR diagnostics of SARS-CoV-2, which makes it possible to eliminate errors leading to false-negative and false-positive results at all stages of analysis. This is accomplished by the presence of specific primers for human RNA, controlling proper swab application, handling, and all the stages of RT-PCR.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020017
Authors: Alexander I. Mosa
Point-of-care detection of viral infection is required for effective contact-tracing, epidemiological surveillance, and linkage to care. Traditional diagnostic platforms relying on either antigen detection or nucleic amplification are limited by sensitivity and the need for costly laboratory infrastructure, respectively. Recently, CRISPR-based diagnostics have emerged as an alternative, combining equipment light workflows with high specificity and sensitivity. However, as a nascent technology, several outstanding challenges to widespread field deployment remain. These include the need for pre-detection amplification of target molecules, the lack of standardization in sample preparation and reagent composition, and only equivocal assessments of the unit-economics relative to traditional antigen or polymerase chain reaction-based diagnostics. This review summarizes recent advances with the potential to overcome existing translational barriers, describes the events in CRISPR-based detection of target molecules, and offers perspective on how multiple approaches can be combined to decrease the limit of detection without introducing pre-amplification.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020016
Authors: Valentina Giardini Carlo Gambacorti-Passerini Marco Casati Andrea Carrer Patrizia Vergani
COVID-19 has been primarily identified as a respiratory infection characterized by signs and symptoms associated with the dysfunction of the renin-angiotensin system (RAS). This is attributed to the SARS-CoV-2 virus invading the respiratory mucosa via angiotensin-converting enzyme 2 (ACE2), which is an important element of the RAS. Meanwhile, preeclampsia is an obstetric pathology that, surprisingly, resembles the pathology of COVID-19. It is a systemic syndrome that occurs during the second half of pregnancy and is determined to be a major cause of maternal and perinatal morbidity and mortality. This disease typically presents with new-onset hypertension and proteinuria or other specific end-organ dysfunctions. RAS-mediated mechanisms may explain its primary clinical-pathological features, which are suggestive of an underlying microvascular dysfunction in both diseases, with induction of vasculopathy, coagulopathy, and inflammation. In this report, we review the medical literature on this subject. Further, the underlying similarities between the two conditions are discussed to assess preeclampsia as a model for COVID-19. These considerations are valid in the case of original SARS-CoV-2 primary infection. Emerging SARS-CoV-2 variants as well as the vaccination could alter various aspects of the virus biology, including human ACE-2 receptor binding affinity and therefore the RAS mediated consequences.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020015
Authors: Yoshiyasu Takefuji
This is the world’s first tutorial article on Python programing on set operations for beginners and practitioners in translational medicine or medicine in general. This tutorial will allow researchers to demonstrate and showcase their tools on PyPI packages around the world. Via the PyPI packaging, a Python application with a single source code can run on Windows, MacOS, and Linux operating systems. In addition to the PyPI packaging, the reproducibility and quality of the source code must be guaranteed. This paper shows how to publish the Python application in Code Ocean after the PyPI packaging. Code Ocean is used in IEEE, Springer, and Elsevier for software reproducibility validation. First, programmers must understand how to scrape a dataset over the Internet. Second, the dataset files must be read in Python. Third, a program must be built to compute the target values using set operations. Fourth, the Python program must be converted to the PyPI package. Finally, the PyPI package is uploaded. Code Ocean plays a key role in publishing validation for software reproducibility. This paper depicts a vaers executable package as an example for calculating the number of deaths due to COVID-19 vaccines. Calculations were based on gender (male and female), age group, and vaccine group (Moderna, Pfizer, and Novartis), respectively.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020014
Authors: Garth L. Nicolson Paul C. Breeding
Background: Chemically exposed veterans of the 1991 Gulf War have few options for treatment of conditions and symptoms related to their chemical exposures. Membrane Lipid Replacement (MLR) with oral membrane glycerolphospholipids is a safe and effective method for slowly removing hydrophobic organic molecules from tissues, while enhancing mitochondrial function and decreasing the severity of certain signs and symptoms associated with multi-symptom illnesses. Methods: A preliminary open-label study utilizing 20 male veterans who were deployed to combat areas, exposed to environmental toxic chemicals and subsequently diagnosed with Gulf War Illnesses (GWI) were utilized. These subjects took 6 g per day oral glycerolphospholipids for 6 months, and the severities of over 100 signs and symptoms were self-reported at various times using illness survey forms. Results: In the sixteen patients that fully complied and completed the study, there were gradual and significant reductions of symptom severities in categories related to fatigue, pain, musculoskeletal, nasopharyngeal, breathing, vision, sleep, balance, and urinary, gastrointestinal and chemical sensitivities. There were no adverse incidents during the study, and the all-natural oral study supplement was extremely well tolerated. Conclusions: MLR with oral glycerolphospholipids appears to be a simple, safe and potentially effective method of slowly reducing the severities of multiple symptoms in chemically exposed veterans.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020013
Authors: Colya N. Englisch Daniel Röhricht Mariesa Walz Kerstin Junker Anja Beckmann Carola Meier Friedrich Paulsen Martin Jung Thomas Tschernig
In the context of renal proteinuric diseases, TRPC6 has been shown to play an important role in ultrafiltration associated with the slit diaphragm through the control of the intracellular Ca2+ concentration in the podocytes of glomeruli. However, to date, the properties of TRPC6 have been studied mainly in cell lines or in animal models. Therefore, the aim of the study presented here was to investigate the presence and distribution of TRPC6 in human kidneys in order to possibly verify the applicability of the results previously obtained in nonhuman experiments. For this purpose, kidneys from nine cadavers were prepared for immunohistochemical staining and were supplemented with a fresh human kidney obtained by nephrectomy. TRPC6 was detected in glomeruli and in the parietal epithelial cells of Bowman’s capsule. Larger amounts were detected in the tubular system and collecting ducts. In contrast to the peritubular capillary bed, which showed no immune reaction, the cortical resistance vessels showed mild TRPC6 staining. In conclusion, our studies on the expression of TRPC6 in human kidney tissue support the translational concept of the involvement of TRPC6 in various renal diseases and reveal new aspects of the distribution of TRPC6 in the human kidney.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020012
Authors: Anisha Valluri Logan Lawrence Krista L. Denning Jonathan Cuda Guo-Zhang Zhu
Glioblastomas (GBMs) are a form of malignant gliomas characterized by a dismal prognosis. Standard treatment for glioblastoma patients is combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with Temozolomide (TMZ). Among the histological characteristics that contribute to GBM progression are the rapid proliferation and neo-angiogenetic processes. The Na+/K+-ATPase is a transporter that promotes the migration of cancer cells, and its aberrant expression and activity have been associated with several cancers, including GBM. Using cardiac glycosides, we examined the effects of direct inhibition of the Na+/K+-ATPase in glioblastoma cells in vitro. We found that cardiac glycoside Digoxin is an effective anticancer agent on several glioma cell lines via Na+/K+-ATPase inhibition. Drug cytotoxicity assays showed that Digoxin as monotherapy significantly increased cell death and increased the efficacy of Temozolomide (TMZ) in the glioma cell lines T98G, U-97 MG, and primary GBM cells BNC-6. Additionally, Digoxin exhibited important anti-migratory effects on the highly aggressive and chemotherapy-resistant T98G glioma cell-line, demonstrating a potential therapeutic role for cardiac glycosides.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2020011
Authors: Ana Salomé Correia Diana Duarte Vera Miranda-Gonçalves Nuno Vale
Protein aggregation is a common characteristic of several human diseases such as Alzheimer’s disease. Recent evidence has indicated that the aggregation of peptides such as p53 is also marked in cancer cells. The aim of this study was to correlate Thioflavin T (ThT) data with different cellular viability assays (Neutral Red and MTT) in SH-SY5Y neuroblastoma cells and HT-29 colon cancer cells treated with doxorubicin, a classical antineoplastic agent. We also studied the effects of the well-known peptide Aβ42 on the aggregation process in these cells. Our data suggest that both cancer cell lines are responsive to doxorubicin and formed aggregates, highlighting a relationship between ThT and cellular viability methodologies. We observed that lower values of cell viability corresponded with pronounced aggregation. Thus, these results indicated that the ThT methodology used in cells may complement the cell viability assays. In addition, this methodology may be of interest to evaluate the role of protein aggregation in other cancer cells.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010010
Authors: Sachithra Gunasekara Miruthula Tamil Selvan Craig A. Miller Jennifer M. Rudd
The ongoing COVID-19 pandemic continues to affect the lives, wellbeing, and stability of communities worldwide. The race to save human lives is critical, and the development of useful translational animal models to elucidate disease pathogenesis and prevention, and to test therapeutic interventions, is essential to this response. However, significant limitations exist with the currently employed animal models that slow our ability to respond to the pandemic. Non-human primates serve as an excellent animal model for SARS-CoV-2 disease and interventions, but the availability of these animals is scarce, and few facilities are able to house and utilize this model. Adapted murine models are accessible and improving but lack natural hACE-2 receptors and are only moderate representatives of human COVID-19 disease, transmission, and immune responses. On the other hand, there are several animal species that are both naturally and experimentally infected, such as domestic cats, hamsters, ferrets, and mink. Several of these have proven animal-to-animal transmission and evidence of significant clinical and histopathologic disease that mimics acute COVID-19 in humans. Mobilizing these nontraditional animal models could have a crucial role in SARS-CoV-2 research efficiency and impact. This review focuses on what is known about these nontraditional animal models, including their immune responses to SARS-CoV-2 infection, evidence of clinical and histopathologic disease, transmission potential, and the practicality of each model in a research setting. Comparative insight into these animal models for COVID-19 can strengthen the efforts to mitigate this pandemic.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010009
Authors: François-Xavier Lejeune Farid Ichou Etienne Camenen Benoit Colsch Florence Mauger Caroline Peltier Ivan Moszer Emmanuel Gilson Morgane Pierre-Jean Edith Le Floch Victor Sabarly Arthur Tenenhaus Jean-François Deleuze Claire Ewenczyk Marie Vidailhet Fanny Mochel
Parkinson’s disease (PD) is the second most common neurodegenerative disease clinically characterized by classical motor symptoms and a range of associated non-motor symptoms. Due to the heterogeneity of symptoms and variability in patient prognosis, the discovery of blood biomarkers is of utmost importance to identify the biological mechanisms underlying the different clinical manifestations of PD, monitor its progression and develop personalized treatment strategies. Whereas studies often rely on motor symptoms alone or composite scores, our study focused on finding relevant molecular markers associated with three clinical models describing either motor, cognitive or emotional symptoms. An integrative multiblock approach was performed using regularized generalized canonical correlation analysis to determine specific associations between lipidomics, transcriptomics and clinical data in 48 PD patients. We identified omics signatures confirming that clinical manifestations of PD in our cohort could be classified according to motor, cognition or emotion models. We found that immune-related genes and triglycerides were well-correlated with motor variables, while cognitive variables were linked to triglycerides as well as genes involved in neuronal growth, synaptic plasticity and mitochondrial fatty acid oxidation. Furthermore, emotion variables were associated with phosphatidylcholines, cholesteryl esters and genes related to endoplasmic reticulum stress and cell regulation.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010008
Authors: Julie Pires da Silva Ashley E. Pietra Angela N. Baybayon-Grandgeorge Anastacia M. Garcia
There are growing numbers of infants and children living with single-ventricle congenital heart disease (SV). However, cardiac dysfunction and, ultimately, heart failure (HF) are common in the SV population and the ability to predict the progression to HF in SV patients has been limited, primarily due to an incomplete understanding of the disease pathogenesis. Here, we tested the hypothesis that non-invasive circulating metabolomic profiles can serve as novel biomarkers in the SV population. We performed systematic metabolomic and pathway analyses on a subset of pediatric SV non-failing (SVNF) and failing (SVHF) serum samples, compared with samples from biventricular non-failing (BVNF) controls. We determined that serum metabolite panels were sufficient to discriminate SVHF subjects from BVNF subjects, as well as SVHF subjects from SVNF subjects. Many of the identified significantly dysregulated metabolites were amino acids, energetic intermediates and nucleotides. Specifically, we identified pyruvate, palmitoylcarnitine, 2-oxoglutarate and GTP as promising circulating biomarkers that could be used for SV risk stratification, monitoring response to therapy and even as novel targets of therapeutic intervention in a population with few other options.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010007
Authors: Roxana Covali Demetra Socolov Ioana Pavaleanu Mona Akad Lucian Vasile Boiculese Razvan Socolov
Background: Critical COVID-19 patients account for 1.7 to 13% of all pregnant COVID-19 patients. Methods: Patients admitted to the COVID-19 intensive care unit of Elena Doamna Obstetrics and Gynecology University Hospital in Iasi between 1 January and 1 December 2021, with critical forms of the disease, were included and retrospectively studied. The patients’ age range was 25–44 years in the Alpha group (n = 12) and 27–52 years in the Delta group (n = 9). Results: Most critically ill pregnant COVID-19 patients in the Alpha group delivered when admitted to the intensive care unit, while less than half of those in the Delta group delivered when admitted; the rest were released home and continued their pregnancy normally. There was a significant difference regarding the number of patients released to home care and the number of days after admission when delivery occurred (p = 0.02 and 0.022, respectively). Conclusions: There was no significant difference in maternal and fetal outcomes between the two groups, except for the number of patients released to home care and the number of days after admission when delivery occurred. There was no correlation between any Brixia scores (H, L, A, E) and any maternal or fetal outcomes in both groups.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010006
Authors: Francesca K Martino Giacomo Novara
Urinary tract infections (UTIs) are among the most common infective disease in the adult population. UTI diagnosis is based essentially on the presence of lower urinary tract symptoms (e.g., dysuria, urgency, and frequency) and the evidence of bacteriuria (by dipstick testing and/or urine culture). UTI diagnosis is not always easy because symptoms can be vague, or patient basal conditions can interfere negatively with the diagnostic process, whereas urine culture is still ongoing. In those cases, the differential diagnosis among UTIs and asymptomatic bacteriuria (ABU) may be challenging, while the clinician has to decide whether to start an antibiotic treatment shortly. The purpose of the present review is to analyze the biomarkers that could help in UTI diagnosis. Some biomarkers, such as procalcitonin, interleukin-6, neutrophil gelatinase-associated lipocalin, chemokines, lactoferrin, and bone morphogenetic protein-2, seem promising in UTI diagnosis, while other biomarkers failed to show any utility. Whereas a single biomarker was not enough, a combination of biomarkers could have more chances to help in the diagnosis.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010005
Authors: IJTM Editorial Office IJTM Editorial Office
Rigorous peer-reviews are the basis of high-quality academic publishing [...]
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010004
Authors: Tom A. Gardiner Alan W. Stitt
Diabetic retinopathy (DR) remains a prevalent complication of diabetes and a major cause of vision loss among the working population. Selective loss of pericytes and vascular smooth muscle cells (SMCs), the mural cells of the retinal blood vessels, is pathognomonic of the vasodegenerative element of diabetic retinopathy, and recent studies suggest a central role for autophagy-dependent cell death in this pathology. Our first study of archival electron micrographs from diabetic donor retina provided evidence for the involvement of autophagy in mural cell death during DR and the current report extends those observations to the fate of mural cell corpses in the vascular wall. Here we show that the efferocytosis, or phagocytic removal of dying mural cells, is carried out by a population of juxtavascular microglia (JVM). This population of microglia are well-characterised in the brain but previously unreported in the retina. We demonstrate that JVM are distinct from perivascular macrophages as they participate in the glia limitans of the retinal vasculature and constitute an integral component of the neurovascular unit of the retina. Importantly, mural cells undergoing active phagocytic engulfment appeared to represent relatively early stages in autophagy-dependent cell death, suggesting that the more degraded pericyte and SMC corpses, known as “ghosts”, have evaded efficient efferocytosis and undergone secondary necrosis. The alternative fates of mural cell corpses in the retinal vasculature may have important implications for inflammatory processes in the vasodegenerative pathology characteristic of DR.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010003
Authors: Tom A. Gardiner Alan W. Stitt
Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of vision loss worldwide. The premature death of the microvascular mural cells represents both a pathological hallmark of vasodegeneration in DR and a basis for therapeutic intervention to halt progression to the sight-threatening stages. Recent studies suggest that retinal microvascular mural cells, classed as pericytes in the capillaries and vascular smooth muscle cells in the larger vessels (VSMC), may undergo autophagy-dependent cell death during DR. The present investigation was undertaken to assess electron microscopic evidence for involvement of autophagy in mediation of cell death in the mural cells of the retinal vasculature, in eyes from human diabetic donors and diabetic dogs. All specimens examined showed widespread evidence of autophagosomes in processes of viable pericytes and VSMCs, and the membranous remnants of excessive autophagic activity in their “ghost cell” remnants within the vascular walls. Autophagy was termed “excessive” when it occupied the greater part of the cytoplasm in mural cell processes. This was notable in specimens from short-term diabetic donors with no evidence of basement-membrane thickening or mural cell loss, in which regions of mural cell cytoplasm filled with autophagic bodies appeared to be undergoing cytoplasmic cleavage. No equivalent evidence of autophagy was detected in the adjacent endothelial cells of the retinal vessels. We conclude that increased autophagy in the retinal pericytes and VSMCs is linked to the diabetic milieu, and over time may also act as a trigger for mural cell loss and progressive vasodegeneration.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010002
Authors: Jorge Camacho Mario Muñoz Vicente Genovés Joaquín L. Herraiz Ignacio Ortega Adrián Belarra Ricardo González David Sánchez Roberto Carlos Giacchetta Ángela Trueba-Vicente Yale Tung-Chen
During the COVID-19 pandemic, lung ultrasound has been revealed as a powerful technique for diagnosis and follow-up of pneumonia, the principal complication of SARS-CoV-2 infection. Nevertheless, being a relatively new and unknown technique, the lack of trained personnel has limited its application worldwide. Computer-aided diagnosis could possibly help to reduce the learning curve for less experienced physicians, and to extend such a new technique such as lung ultrasound more quickly. This work presents the preliminary results of the ULTRACOV (Ultrasound in Coronavirus disease) study, aimed to explore the feasibility of a real-time image processing algorithm for automatic calculation of the lung ultrasound score (LUS). A total of 28 patients positive on COVID-19 were recruited and scanned in 12 thorax zones following the lung score protocol, saving a 3 s video at each probe position. Those videos were evaluated by an experienced physician and by a custom developed automated detection algorithm, looking for A-Lines, B-Lines, consolidations, and pleural effusions. The agreement between the findings of the expert and the algorithm was 88.0% for B-Lines, 93.4% for consolidations and 99.7% for pleural effusion detection, and 72.8% for the individual video score. The standard deviation of the patient lung score difference between the expert and the algorithm was ±2.2 points over 36. The exam average time with the ULTRACOV prototype was 5.3 min, while with a conventional scanner was 12.6 min. Conclusion: A good agreement between the algorithm output and an experienced physician was observed, which is a first step on the feasibility of developing a real-time aided-diagnosis lung ultrasound equipment. Additionally, the examination time was reduced to less than half with regard to a conventional ultrasound exam. Acquiring a complete lung ultrasound exam within a few minutes is possible using fairly simple ultrasound machines that are enhanced with artificial intelligence, such as the one we propose. This step is critical to democratize the use of lung ultrasound in these difficult times.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm2010001
Authors: Antolín Cantó Javier Martínez Giuliana Perini-Villanueva María Miranda Eloy Bejarano
Diabetes mellitus is a chronic disease often accompanied by diabetic retinopathy (DR), one of the most common diabetic complications. DR is an eye condition that causes vision deficiency and often leads to blindness. DR develops when blood vessels damage the retina, the light-sensitive tissue at the back of the eye. Before changes in retinal blood vessel permeability, different molecular and anatomical modifications take place in the retina, including early neural changes. This review will summarize the current status of knowledge regarding pathophysiological mechanisms underlying DR, with a special focus on early neural modifications associated with DR. We describe hyperglycemia-associated molecular and cellular alterations linked to the initiation and progression of DR. We also discuss retinal neurodegeneration as a shared feature in different in vitro and in vivo models of DR. Given how ubiquitous diabetes is and how severe the effects of DR are, we also examine the current pharmacological and genetic approaches for combatting this disease.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm1030024
Authors: Elahe Soltani-Fard Sina Taghvimi Zahra Abedi Kichi Christian Weber Zahra Shabaninejad Mortaza Taheri-Anganeh Seyyed Hossein Khatami Pegah Mousavi Ahmad Movahedpour Lucia Natarelli
Non-coding RNAs (ncRNAs) are functional RNA molecules that comprise about 80% of both mammals and prokaryotes genomes. Recent studies have identified a large number of small regulatory RNAs in Escherichia coli and other bacteria. In prokaryotes, RNA regulators are a diverse group of molecules that modulate a wide range of physiological responses through a variety of mechanisms. Similar to eukaryotes, bacterial microRNAs are an important class of ncRNAs that play an important role in the development and secretion of proteins and in the regulation of gene expression. Similarly, riboswitches are cis-regulatory structured RNA elements capable of directly controlling the expression of downstream genes in response to small molecule ligands. As a result, riboswitches detect and respond to the availability of various metabolic changes within cells. The most extensive and most widely studied set of small RNA regulators act through base pairing with RNAs. These types of RNAs are vital for prokaryotic life, activating or suppressing important physiological processes by modifying transcription or translation. The majority of these small RNAs control responses to changes in environmental conditions. Finally, clustered regularly interspaced short palindromic repeat (CRISPR) RNAs, a newly discovered RNA regulator group, contains short regions of homology to bacteriophage and plasmid sequences that bacteria use to splice phage DNA as a defense mechanism. The detailed mechanism is still unknown but devoted to target homologous foreign DNAs. Here, we review the known mechanisms and roles of non-coding regulatory RNAs, with particular attention to riboswitches and their functions, briefly introducing translational applications of CRISPR RNAs in mammals.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm1030023
Authors: Allen K. Murray
Glycogen is present in all tissues, but it is primarily stored in the liver and in muscle. As a branched chain carbohydrate, it is broken down by phosphorylase and debrancher enzymes, which are cytoplasmic. It is also degraded by a lysosomal α-glucosidase (GAA) also known as acid α-glucosidase and lysosomal acid α-glucosidase. The deficiency of GAA in patients is known as Pompe disease, and the phenotypes as infantile, juvenile and later onset forms. Pompe disease is treated by enzyme replacement therapy (ERT) with a recombinant form of rhGAA. Following ERT in Pompe mice and human patients there is residual carbohydrate material present in the cytoplasm of cells. The goal of this work is to improve ERT and attempt to identify and treat the residual cytoplasmic carbohydrate. Initial experiments were to determine if rhGAA can completely degrade glycogen. The enzyme cannot completely degrade glycogen. There is a residual glycosylated protein as well as a soluble glycosylated protein, which is a terminal degradation product of glycogen and as such serves as a biomarker for lysosomal glycogen degradation. The glycosylated protein has a very unusual carbohydrate composition for a glycosylated protein: m-inositol, s-inositol and sorbitol as the major carbohydrates, as well as mannitol, mannose, glucose and galactose. This work describes the residual material which likely contains the same protein as the soluble glycosylated protein. The biomarker is present in serum of control and Pompe patients on ERT, but it is not present in the serum of Pompe mice not on ERT. Pompe mice not on ERT have another glycosylated protein in their serum which may be a biomarker for Pompe disease. This protein has multiple glycosylation sites, each with different carbohydrate components. These glycosylated proteins as well as the complexity of glycogen structure are discussed, as well as future directions to try to improve the outcome of ERT for Pompe patients by being able to monitor the efficacy of ERT in the short term and possibly to adjust the timing and dose of enzyme infusions.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm1030022
Authors: Cristina Arce Diana Vicente Fermí Monto Laura González Cristina Nuñez Víctor M. Victor Francesc Jiménez-Altayó Pilar D’Ocon
Nitric oxide (NO) is a proangiogenic factor acting through the soluble guanylate cyclase (sGC) pathway. However, angiogenic growth increases energy demand, which may be hampered by NO inhibition of cytochrome c oxidase (CcO). Then, NO activity would be the balanced result of sGC activation (pro-angiogenic) and CcO inhibition (anti-angiogenic). NO activity in a rat and eNOS−/− mice aortic ring angiogenic model and in a tube formation assay (human aortic endothelial cells) were analyzed in parallel with mitochondrial O2 consumption. Studies were performed with NO donor (DETA-NO), sGC inhibitor (ODQ), and NOS or nNOS inhibitors (L-NAME or SMTC, respectively). Experiments were performed under different O2 concentrations (0–21%). Key findings were: (i) eNOS-derived NO inhibits angiogenic growth by a mechanism independent on sGC pathway and related to inhibition of mitochondrial O2 consumption; (ii) NO inhibition of the angiogenic growth is more evident in hypoxic vessels; (iii) in the absence of eNOS-derived NO, the modulation of angiogenic growth, related to hypoxia, disappears. Therefore, NO, but not lower O2 levels, decreases the angiogenic response in hypoxia through competitive inhibition of CcO. This anti-angiogenic activity could be a promising target to impair pathological angiogenesis in hypoxic conditions, as it occurs in tumors or ischemic diseases.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm1030021
Authors: Athanasios Xanthopoulos Iliana Daskalopoulou Sofia Frountzi Evangelia Papadimitriou
Angiogenesis is essential during development or when tissue restoration and oxygenation is required. Limited or excessive formation of blood vessels is a hallmark of several pathologies, and many angiogenesis-related pathways are being studied to highlight potential targets for effective angiogenesis-stimulating or inhibiting therapeutic approaches. A few studies point to the adrenergic system as a significant regulator of angiogenesis, directly or indirectly. Functional adrenergic receptors are expressed on endothelial cells and affect their response to the adrenergic system. The latter can also upregulate the release of growth factors by mural cells of the vessel wall, blood cells or cancer cells, thus subsequently affecting endothelial cell functions and angiogenesis. In the present study we summarize up-to-date literature on the known effects of the adrenergic receptors on physiological and pathological angiogenesis.
]]>International Journal of Translational Medicine doi: 10.3390/ijtm1030020
Authors: Ellie Bowditch Andrew Chang Hemal Mehta
Diagnosis and management of proliferative diabetic retinopathy are reliant upon retinal imaging. A systematic literature review of non-invasive imaging to guide diagnosis and treatment of proliferative diabetic retinopathy was performed. There is a trend of moving away from invasive (e.g., fundus fluorescein angiography) to non-invasive (e.g., wide-field optical coherence tomography (OCT), OCT angiography and colour fundus photography) imaging modalities to allow for more objective assessments that can be readily repeated in a time-efficient manner without compromising patient safety. Such quantitative assessments generating large amounts of data could benefit from artificial intelligence approaches to aid clinical decision making. These non-invasive imaging modalities continue to improve both in terms of the quality of image acquisition and progress in image interpretation. It is important that newer non-invasive imaging modalities are appropriately validated in large-scale prospective observational studies or randomised clinical trials.
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