Int. J. Transl. Med., Volume 2, Issue 3 (September 2022) – 14 articles

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article