bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Androgen Receptor Inhibitors in Non-Metastatic, Castration-Resistant Prostate Cancer: A Systematic Review and Network Meta-Analysis
Authors: Mulati Yelin , Fan Yu , Yu Wei , Zhang Qian , He Zhisong
Published: October 2021

Introduction

Enzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications.

Methods

PubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies.

Results

Three eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66–0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50–0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0–1.7) and serious AEs (OR, 1.3; 95% CI, 0.99–1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5–3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1–2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4–2.7) and serious AEs (OR, 1.9; 95% CI, 1.3–2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies.

Conclusions

SGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients.
The Presence of Circulating Tumor Cell Cluster Characterizes an Aggressive Hepatocellular Carcinoma Subtype
Authors: Yu Jing-Jing , Shu Chang , Yang Hui-Yuan , Huang Zhao , Li Ya-Ni , Tao Ran , Chen Yue-Yue , Chen Qian , Chen Xiao-Ping , Xiao Wei
Published: October 2021

Background

Growing evidence suggests that circulating tumor cell (CTC) clusters may be an important factor in the metastatic process, but their role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to characterize the molecular and clinical features of CTC cluster-positive human HCC and to assess its prognostic value in HCC patients.

Methods

The CTCs and CTC clusters were evaluated in 204 HCC patients using CellSearch™ System. The counts of CTCs and CTC clusters were correlated with different clinical features, while their associations with progression-free survival (PFS) and overall survival (OS) were evaluated integrally and hierarchically by Kaplan–Meier estimates or Cox proportional regression analysis. Five cases each of CTC cluster-negative and cluster-positive patients were selected for RNA-sequencing analysis. The results of gene enrichment analysis were further verified using tissue microarray (TMA) by immunohistochemistry (IHC).

Results

CTCs and CTC clusters were detected in 76 (37.3%) and 19 (9.3%) of 204 preoperative samples, respectively. CTC cluster-positive HCC represented an aggressive HCC phenotype with larger tumor size, more frequent microvascular invasion, and higher tumor stages. The survival of HCC patients utilizing CTCs and CTC clusters individually showed prognostic significance, while joint analysis revealed patients in Group III (CTC ≥ 2 and CTC cluster > 0) had the worst outcome. Stratified analysis of outcomes in Barcelona Clinic Liver Cancer (BCLC) and tumor–node–metastasis (TNM) stages indicated that patients with CTC clusters had significantly poorer prognosis in each stage than those without CTC clusters. Moreover, the RNA sequencing and TMA staining results showed that CTC cluster-positive HCCs were usually associated with Wnt/β-catenin signaling activation.

Conclusion

The presence of CTC clusters characterizes an aggressive HCC subtype. CTC clusters may be used as a biomarker in predicting the prognosis on each stage of malignancy in HCC, which provides evidence for formulating therapeutic strategies for more precise treatment.
High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy
Authors: Fiorillo Marco , Ózsvári Béla , Sotgia Federica , Lisanti Michael P.
Published: October 2021

Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the “metabolically fittest” cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Therefore, we propose that the “energetically fittest” cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be naturally-selected for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model in vivo. Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells.
MiR-149-5p: An Important miRNA Regulated by Competing Endogenous RNAs in Diverse Human Cancers
Authors: Ren Fu-jia , Yao Yao , Cai Xiao-yu , Cai Yu-ting , Su Qian , Fang Guo-ying
Published: October 2021

MicroRNAs (miRNAs) consist of a large family of small, non-coding RNAs with the ability to result in gene silencing post-transcriptionally. With recent advances in research technology over the past several years, the physiological and pathological potentials of miRNAs have been gradually uncovered. MiR-149-5p, a conserved miRNA, was found to regulate physiological processes, such as inflammatory response, adipogenesis and cell proliferation. Notably, increasing studies indicate miR-149-5p may act as an important regulator in solid tumors, especially cancers in reproductive system and digestive system. It has been acknowledged that miR-149-5p can function as an oncogene or tumor suppressor in different cancers, which is achieved by controlling a variety of genes expression and adjusting downstream signaling pathway. Moreover, the levels of miR-149-5p are influenced by several newly discovered long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). However, there is blank about systematic function and mechanism of miR-149-5p in human cancers. In this review, we firstly summarize the present comprehension of miR-149-5p at the molecular level, its vital role in tumor initiation and progression, as well as its potential roles in monitoring diverse reproductive and digestive malignancies.
Intratumor Heterogeneity as a Prognostic Factor in Solid Tumors: A Systematic Review and Meta-Analysis
Authors: Yu Tao , Gao Xin , Zheng Zicheng , Zhao Xinyu , Zhang Shiyao , Li Chunqiang , Liu Gang
Published: October 2021

Background

The landscape of intratumor heterogeneity (ITH) is present from the tumor evolution. ITH is a promising clinical indicator, but the association between ITH and prognosis remains controversial. Therefore, a meta-analysis was performed to explore whether ITH can serve as a valuable prognostic indicator in solid tumors.

Methods

All included studies were from PubMed, Embase, Cochrane, and Web of Science databases up to October 10, 2020. Studies based on ITH with available prognostic information were included. Three researchers independently completed study selection and data extraction following PRISMA guidelines. The random-effect model was used for synthesis. Hazard ratio (HR) and 95% confidence intervals (CI) were used with the endpoint defined by overall survival (OS), disease-specific survival (DFS), and progression-free survival (PFS).

Results

A total of 9,804 solid tumor patients from 21 studies were included. Analysis of specific cancers in the TCGA database showed similar results based on different ITH assessment methods, which provided the logical support for data consolidation. Available evidence revealed a negative relationship between ITH and prognosis for a specific cancer (such as lung cancer). However, the OS results from 14 tumor types showed that high ITH associated with shorter survival time [HR 1.65 (95% CI, 1.42–1.91)]. PFS and DFS analyses showed similar results [HR 1.89 (95% CI, 1.41–2.54) and HR 1.87 (95% CI, 1.15–3.04)] in general. The status of tumor metastasis and sampling models were not the confounding factors.

Conclusions

High ITH is associated with worse prognosis in many solid tumors in general although this association was absent for some cancers. ITH is expected to be a promising clinical prognostic factor for the improvement of assessment, treatment, and surveillance strategy.
MiR-629-5p Promotes Prostate Cancer Development and Metastasis by Targeting AKAP13
Authors: Liu Yangzhou , Zhao Shankun , Wang Jiamin , Zhu Zhiguo , Luo Lianmin , Xiang Qian , Zhou Mingda , Ma Yuxiang , Wang Zuomin , Zhao Zhigang
Published: October 2021

Prostate cancer (PCa) has become the most frequently occurring cancer among western men according to the latest report, and patients’ prognosis is often poor in the event of tumor progression, therefore, many researches are devoted to exploring the molecular mechanism of PCa metastasis. MicroRNAs (miRNA) have proved to play an important role in this process. In present study, by combining clinical samples with public databases, we found that miR-629-5p increased to varying degrees in primary localized PCa tissues and metastatic PCa tissues compared with adjacent normal tissues, and bioinformatics analysis suggested that high level of miR-629-5p was related to poor prognosis. Functionally, miR-629-5p drove PCa cell proliferation, migration and invasion in vitro, and promoted growth of PCa cells in vivo. Moreover, A-kinase Anchor Protein 13 (AKAP13) was screened as a direct target of miR-629-5p, that expression was negatively correlated with the malignant phenotype of tumor cells. In the end, through verification in clinical specimens, we found that AKAP13 could be independently used as a clinical prognostic indicator. Overall, the present study indicates that miR-629-5p plays an oncogenic role in PCa by targeting AKAP13, which provides a new idea for clinical diagnosis and treatment of complex refractory PCa.
Symptoms, SARS-CoV-2 Antibodies, and Neutralization Capacity in a Cross Sectional-Population of German Children
Authors: Laub Otto , Leipold Georg , Toncheva Antoaneta A. , Peterhoff David , Einhauser Sebastian , Neckermann Patrick , Borchers Natascha , Santos-Valente Elisangela , Kheiroddin Parastoo , Buntrock-Döpke Heike , Laub Sarah , Schöberl Patricia , Schweiger-Kabesch Andrea , Ewald Dominik , Horn Michael , Niggel Jakob , Ambrosch Andreas , Überla Klaus , Gerling Stephan , Brandstetter Susanne , Wagner Ralf , Kabesch Michael ,   Corona Virus Antibodies in Children from Bavaria (CoKiBa) Study Group
Published: October 2021

Background:Children and youth are affected rather mildly in the acute phase of COVID-19 and thus, SARS-CoV-2 infection infection may easily be overlooked. In the light of current discussions on the vaccinations of children it seems necessary to better identify children who are immune against SARS-CoV-2 due to a previous infection and to better understand COVID-19 related immune reactions in children.

Methods:In a cross-sectional design, children aged 1–17 were recruited through primary care pediatricians for the study (a) randomly, if they had an appointment for a regular health check-up or (b) if parents and children volunteered and actively wanted to participate in the study. Symptoms were recorded and two antibody tests were performed in parallel directed against S (in house test) and N (Roche Elecsys) viral proteins. In children with antibody response in either test, neutralization activity was determined.

Results:We identified antibodies against SARS-CoV-2 in 162 of 2,832 eligible children (5.7%) between end of May and end of July 2020 in three, in part strongly affected regions of Bavaria in the first wave of the pandemic. Approximately 60% of antibody positive children (n= 97) showed high levels (>97th percentile) of antibodies against N-protein, and for the S-protein, similar results were found. Sufficient neutralizing activity was detected for only 135 antibody positive children (86%), irrespective of age and sex. Initial COVID-19 symptoms were unspecific in children except for the loss of smell and taste and unrelated to antibody responses or neutralization capacity. Approximately 30% of PCR positive children did not show seroconversion in our small subsample in which PCR tests were performed.

Conclusions:Symptoms of SARS-CoV-2 infections are unspecific in children and antibody responses show a dichotomous structure with strong responses in many and no detectable antibodies in PCR positive children and missing neutralization activity in a relevant proportion of the young population.
Evolution of a Bidirectional Pediatric Critical Care Educational Partnership in a Resource-Limited Setting
Authors: Gardner Yelton Sarah E. , McCaw Julia M. , Reuland Carolyn J. , Steppan Diana A. , Evangelista Paula Pilar G. , Shilkofski Nicole A.
Published: October 2021

Introduction: Children in resource-limited settings are disproportionately affected by common childhood illnesses, resulting in high rates of mortality. A major barrier to improving child health in such regions is limited pediatric-specific training, particularly in the care of children with critical illness. While global health rotations for trainees from North America and Europe have become commonplace, residency and fellowship programs struggle to ensure that these rotations are mutually beneficial and do not place an undue burden on host countries. We created a bidirectional, multimodal educational program between trainees in Manila, Philippines, and Baltimore, Maryland, United States, to improve the longitudinal educational experience for all participants.

Program Components: Based on stakeholder input and a needs assessment, we established a global health training program in which pediatricians from the Philippines traveled to the United States for observerships, and pediatric residents from a tertiary care center in Baltimore traveled to Manila. Additionally, we created and implemented a contextualized simulation-based shock curriculum for pediatric trainees in Manila that can be disseminated locally. This bidirectional program was adapted to include telemedicine and regularly scheduled “virtual rounds” and educational case conferences during the COVID-19 pandemic. Providers from the two institutions have collaborated on educational and clinical research projects, offering opportunities for resource sharing, bidirectional professional development, and institutional improvements.

Conclusion: Although creating a mutually beneficial global health partnership requires careful planning and investment over time, establishment of a successful bidirectional educational and professional development program in a limited-resource setting is feasible and benefits learners in both countries.
Cost-Effectiveness of Testing for NS5A Resistance to Optimize Treatment of Elbasvir/Grazoprevir for Chronic Hepatitis C in China
Authors: Liu Jinyu , Zhang Yu , Wu Bin , Wang Sen , Bin-Chia Wu David , You Ruxu
Published: October 2021

Objectives: Baseline presence of nonstructural protein 5A (NS5A) resistance-associated variants can attenuate the efficacy of new direct-acting antivirals. A potential method to attain the higher efficacy would be to screen for NS5A polymorphisms prior to the initiation of therapy and to adjust the treatment length based on the test results. However, baseline testing adds additional costs and it is unclear whether this would represent a high value strategy for chronic hepatitis C in China.

Methods: A hybrid model compared 1) standard 12-weeks treatment (no testing), 2) shortened 8-weeks treatment (no testing), and 3) baseline testing with 12-/8-weeks treatment for those with/without NS5A polymorphisms from a lifetime Chinese health care payer perspective. All model inputs were retrieved from clinical trials and publically available literature. And sensitivity analyses were also conducted to assess the impact of uncertainty.

Results: Baseline testing was associated with overall increase in total health care cost of USD 13.50 and in QALYs of 0.002 compared with standard 12-weeks treatment (no testing), yielded in an ICER of USD 6750/QALY gained. Scenario analyses suggested that shortened 8-weeks treatment (no testing) was found to be lower costs and great QALYs compared with other two strategies when the sustained virologic response (SVR) rate increased to 95%. Sensitivity analyses indicated that the results were robust.

Conclusions: Our results suggest prior assessment of NS5A sensitivity followed by optimizing treatment duration was an economic strategy. In addition, shortened 8-weeks treatment (no testing) was shown to be dominant with the SVR rate increased to 95%.
The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury
Authors: Liu Wenhui , Zeng Xiangchang , Liu Yating , Liu Jinfeng , Li Chaopeng , Chen Lulu , Chen Hongying , Ouyang Dongsheng
Published: October 2021

Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.
β-Adrenergic Receptor Inhibitor and Oncolytic Herpesvirus Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects on Colorectal Cancer
Authors: Hu Jiali , Chen Cuiyu , Lu Ruitao , Zhang Yu , Wang Yang , Hu Qian , Li Wanting , Wang Shiyu , Jing Ouyang , Yi Hanying , Zhang Wei , Chen Ling , Huang Weihua , Luo Jia , McLeod Howard L. , Xu Ran , He Yijing
Published: October 2021

Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, despite the development of novel OVs with improved efficacy and tumor selectivity, their limited efficacy as monotherapeutic agents remains a significant challenge. This study extended our previously observed combination effects of propranolol, a nonselective β-blocker, and the T1012G oncolytic virus into colorectal cancer models. A cell viability assay showed that cotreatment could induce synergistic killing effects on human and murine colorectal cell lines. Moreover, cotreatment caused sustained tumor regression compared with T1012G monotherapy or propranolol monotherapy in human HCT116 and murine MC38 tumor models. The propranolol activity was not via a direct effect on viral replication in vitro or in vivo. Western blotting showed that cotreatment significantly enhanced the expression of cleaved caspase-3 in HCT116 and MC38 cells compared with the propranolol or T1012G alone. In addition, propranolol or T1012G treatment induced a 35.06% ± 0.53% or 35.49% ± 2.68% reduction in VEGF secretion in HUVECs (p < 0.01/p < 0.01). Cotreatment further inhibited VEGF secretion compared with the monotherapies (compared with propranolol treatment: 75.06% ± 1.50% decrease, compared with T1012G treatment: 74.91% ± 0.68%; p＜0.001, p < 0.001). Consistent with the in vitro results, in vivo data showed that cotreatment could reduce Ki67 and enhance cleaved caspase 3 and CD31 expression in human HCT116 and murine MC38 xenografts. In summary, β-blockers could improve the therapeutic potential of OVs by enhancing oncolytic virus-mediated killing of colorectal cancer cells and colorectal tumors.
Beta-Adrenergic Blockade in Critical Illness
Authors: Bruning Rebecca , Dykes Hannah , Jones Timothy W. , Wayne Nathaniel B. , Sikora Newsome Andrea
Published: October 2021

Catecholamine upregulation is a core pathophysiological feature in critical illness. Sustained catecholamine β-adrenergic induction produces adverse effects relevant to critical illness management. β-blockers (βB) have proposed roles in various critically ill disease states, including sepsis, trauma, burns, and cardiac arrest. Mounting evidence suggests βB improve hemodynamic and metabolic parameters culminating in decreased burn healing time, reduced mortality in traumatic brain injury, and improved neurologic outcomes following cardiac arrest. In sepsis, βB appear hemodynamically benign after acute resuscitation and may augment cardiac function. The emergence of ultra-rapid βB provides new territory for βB, and early data suggest significant improvements in mitigating atrial fibrillation in persistently tachycardic septic patients. This review summarizes the evidence regarding the pharmacotherapeutic role of βB on relevant pathophysiology and clinical outcomes in various types of critical illness.
Bioactivities and Structure–Activity Relationships of Fusidic Acid Derivatives: A Review
Authors: Long Junjun , Ji Wentao , Zhang Doudou , Zhu Yifei , Bi Yi
Published: October 2021

Fusidic acid (FA) is a natural tetracyclic triterpene isolated from fungi, which is clinically used for systemic and local staphylococcal infections, including methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. FA and its derivatives have been shown to possess a wide range of pharmacological activities, including antibacterial, antimalarial, antituberculosis, anticancer, tumor multidrug resistance reversal, anti-inflammation, antifungal, and antiviral activity in vivo and in vitro. The semisynthesis, structural modification and biological activities of FA derivatives have been extensively studied in recent years. This review summarized the biological activities and structure–activity relationship (SAR) of FA in the last two decades. This summary can prove useful information for drug exploration of FA derivatives.
Effects of Prenatal Exposure to Alcohol and Smoking on Fetal Heart Rate and Movement Regulation
Authors: Lucchini Maristella , Shuffrey Lauren C. , Nugent J. David , Pini Nicoló , Sania Ayesha , Shair Margaret , Brink Lucy , du Plessis Carlie , Odendaal Hein J. , Nelson Morgan E. , Friedrich Christa , Angal Jyoti , Elliott Amy J. , Groenewald Coen A. , Burd Larry T. , Myers Michael M. , Fifer William P.
Published: October 2021

Negative associations of prenatal tobacco and alcohol exposure (PTE and PAE) on birth outcomes and childhood development have been well documented, but less is known about underlying mechanisms. A possible pathway for the adverse fetal outcomes associated with PTE and PAE is the alteration of fetal autonomic nervous system development. This study assessed PTE and PAE effects on measures of fetal autonomic regulation, as quantified by heart rate (HR), heart rate variability (SD-HR), movement, and HR-movement coupling in a population of fetuses at ≥ 34 weeks gestational age. Participants are a subset of the Safe Passage Study, a prospective cohort study that enrolled pregnant women from clinical sites in Cape Town, South Africa, and the Northern Plains region, United States. PAE was defined by six levels: no alcohol, low quit early, high quit early, low continuous, moderate continuous, and high continuous; while PTE by 4 levels: no smoking, quit early, low continuous, and moderate/high continuous. Linear regression analyses of autonomic measures were employed controlling for fetal sex, gestational age at assessment, site, maternal education, household crowding, and depression. Analyses were also stratified by sleep state (1F and 2F) and site (South Africa,N= 4025, Northern Plains,N= 2466). The final sample included 6491 maternal-fetal-dyad assessed in the third trimester [35.21 ± 1.26 (mean ± SD) weeks gestation]. PTE was associated with a decrease in mean HR in state 2F, in a dose dependent fashion, only for fetuses of mothers who continued smoking after the first trimester. In state 1F, there was a significant increase in mean HR in fetuses whose mother quit during the first trimester. This effect was driven by the Norther Plains cohort. PTE was also associated with a significant reduction in fetal movement in the most highly exposed group. In South Africa a significant increase in mean HR both for the high quit early and the high continuous group was observed. In conclusion, this investigation addresses a critical knowledge gap regarding the relationship between PTE and PAE and fetal autonomic regulation. We believe these results can contribute to elucidating mechanisms underlying risk for adverse outcomes.
Diabetes, Heart Failure, and COVID-19: An Update
Authors: Hebbard Carleigh , Lee Brooke , Katare Rajesh , Garikipati Venkata Naga Srikanth
Published: October 2021

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the WHO in March 2020. As of August 2021, more than 220 countries have been affected, accounting for 211,844,613 confirmed cases and 4,432,802 deaths worldwide. A new delta variant wave is sweeping through the globe. While previous reports consistently have demonstrated worse prognoses for patients with existing cardiovascular disease than for those without, new studies are showing a possible link between SARS-CoV-2 infection and an increased incidence of new-onset heart disease and diabetes, regardless of disease severity. If this trend is true, with hundreds of millions infected, the disease burden could portend a potentially troubling increase in heart disease and diabetes in the future. Focusing on heart failure in this review, we discuss the current data at the intersection of COVID, heart failure, and diabetes, from clinical findings to potential mechanisms of how SARS-CoV-2 infection could increase the incidence of those pathologies. Additionally, we posit questions for future research areas regarding the significance for patient care.
Crescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells
Authors: Al Mushafi Ahmed , Ooi Joshua D. , Odobasic Dragana
Published: October 2021

Chronic kidney disease (CKD) leads to significant morbidity and mortality worldwide. Glomerulonephritis (GN) is the second leading cause of CKD resulting in end stage renal failure. The most severe and rapidly progressive type of GN is characterized by glomerular crescent formation. The current therapies for crescentic GN, which consist of broad immunosuppressive drugs, are partially effective, non-specific, toxic and cause many serious side effects including infections, cancer, and cardiovascular problems. Therefore, new and safer therapies are needed. Human amniotic epithelial cells (hAECs) are a type of stem cell which are isolated from the placenta after birth. They represent an attractive and novel therapeutic option for the treatment of various inflammatory conditions owing to their unique and selective immunosuppressive ability, as well as their excellent safety profile and clinical applicability. In this review, we will discuss the immunopathogenesis of crescentic GN, issues with currently available treatments and how hAECs offer potential to become a new and harmless treatment option for this condition.
TMT-Based Plasma Proteomics Reveals Dyslipidemia Among Lowlanders During Prolonged Stay at High Altitudes
Authors: Pooja  , Sharma Vandana , Meena Ram Niwas , Ray Koushik , Panjwani Usha , Varshney Rajeev , Sethy Niroj Kumar
Published: October 2021

Acute exposure to high altitude perturbs physiological parameters and induces an array of molecular changes in healthy lowlanders. However, activation of compensatory mechanisms and biological processes facilitates high altitude acclimatization. A large number of lowlanders stay at high altitude regions from weeks to months for work and professional commitments, and thus are vulnerable to altitude-associated disorders. Despite this, there is a scarcity of information for molecular changes associated with long-term stay at high altitudes. In the present study, we evaluated oxygen saturation (SpO2), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) of lowlanders after short- (7 days, HA-D7) and long-term (3 months, HA-D150) stay at high altitudes, and used TMT-based proteomics studies to decipher plasma proteome alterations. We observed improvements in SpO2 levels after prolonged stay, while HR, SBP, and DBP remained elevated as compared with short-term stay. Plasma proteomics studies revealed higher levels of apolipoproteins APOB, APOCI, APOCIII, APOE, and APOL, and carbonic anhydrases (CA1 and CA2) during hypoxia exposure. Biological network analysis also identified profound alterations in lipoprotein-associated pathways like plasma lipoprotein assembly, VLDL clearance, chylomicron assembly, chylomicron remodeling, plasma lipoprotein clearance, and chylomicron clearance. In corroboration, lipid profiling revealed higher levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) for HA-D150 whereas high density lipoproteins (HDL) levels were lower as compared with HA-D7 and sea-level indicating dyslipidemia. We also observed higher levels of proinflammatory cytokines IL-6, TNFα, and CRP for HA-D150 along with oxidized LDL (oxLDL), suggesting vascular inflammation and proartherogenic propensity. These results demonstrate that long-term stay at high altitudes exacerbates dyslipidemia and associated disorders.
Sarcolemmal Excitability, M-Wave Changes, and Conduction Velocity During a Sustained Low-Force Contraction
Authors: Rodriguez-Falces Javier , Place Nicolas
Published: October 2021

This study was undertaken to investigate whether sarcolemmal excitability is impaired during a sustained low-force contraction [10% maximal voluntary contraction (MVC)] by assessing muscle conduction velocity and also by analyzing separately the first and second phases of the muscle compound action potential (M wave). Twenty-one participants sustained an isometric knee extension of 10% MVC for 3min. M waves were evoked by supramaximal single shocks to the femoral nerve given at 10-s intervals. The amplitude, duration, and area of the first and second M-wave phases were computed. Muscle fiber conduction velocity, voluntary surface electromyographic (EMG), perceived effort, MVC force, peak twitch force, and temperature were also recorded. The main findings were: (1) During the sustained contraction, conduction velocity remained unchanged. (2) The amplitude of the M-wave first phase decreased for the first ~30s (−7%, p<0.05) and stabilized thereafter, whereas the second phase amplitude increased for the initial ~30s (+7%, p<0.05), before stabilizing. (3) Both duration and area decreased steeply during the first ~30s, and then more gradually for the rest of the contraction. (4) During the sustained contraction, perceived effort increased fivefold, whereas knee extension EMG increased by ~10%. (5) Maximal voluntary force and peak twitch force decreased (respectively, −9% and −10%, p<0.05) after the low-force contraction. Collectively, the present results indicate that sarcolemmal excitability is well preserved during a sustained 10% MVC task. A depression of the M-wave first phase during a low-force contraction can occur even in the absence of changes in membrane excitability. The development of fatigue during a low-force contraction can occur without alteration of membrane excitability.
Accuracy of Flash Glucose Monitoring During Postprandial Rest and Different Walking Conditions in Overweight or Obese Young Adults
Authors: Zhang Xiaoyuan , Sun Fenghua , Wongpipit Waris , Huang Wendy Y. J. , Wong Stephen H. S.
Published: October 2021

Aims: To investigate the accuracy of FreeStyle LibreTM flash glucose monitoring (FGM) relevant to plasma glucose (PG) measurements during postprandial rest and different walking conditions in overweight/obese young adults.

Methods: Data of 40 overweight/obese participants from two randomized crossover studies were pooled into four trials: (1) sitting (SIT, n = 40); (2) walking continuously for 30 min initiated 20 min before individual postprandial glucose peak (PPGP) (20iP + CONT, n = 40); (3) walking continuously for 30 min initiated at PPGP (iP + CONT, n = 20); and (4) accumulated walking for 30 min initiated 20 min before PPGP (20iP + ACCU, n = 20). Paired FGM and PG were measured 4 h following breakfast.

Results: The overall mean absolute relative difference (MARD) between PG and FGM readings was 16.4 ± 8.6% for SIT, 16.2 ± 4.7% for 20iP + CONT, 16.7 ± 12.2% for iP + CONT, and 19.1 ± 6.8% for 20iP + ACCU. The Bland–Altman analysis showed a bias of −1.03 mmol⋅L–1 in SIT, −0.89 mmol⋅L–1 in 20iP + CONT, −0.82 mmol⋅L–1 in iP + CONT, and −1.23 mmol⋅L–1 in 20iP + ACCU. The Clarke error grid analysis showed that 99.6–100% of the values in all trials fell within zones A and B.

Conclusion: Although FGM readings underestimated PG, the FGM accuracy was overall clinically acceptable during postprandial rest and walking in overweight/obese young adults.
Role of Known Transient Receptor Potential Vanilloid Channels in Modulating Cardiac Mechanobiology
Authors: Miller Michael , Koch Sheryl E. , Veteto Adam , Domeier Timothy , Rubinstein Jack
Published: October 2021

The transient receptor potential (TRP) channels have been described in almost every mammalian cell type. Several members of the Vanilloid (TRPV) subtype have been found to play important roles in modulating cardiac structure and function through Ca2+ handling in response to systemic and local mechanobiological cues. In this review, we will consider the most studied TRPV channels in the cardiovascular field; transient receptor potential vanilloid 1 as a modulator of cardiac hypertrophy; transient receptor potential vanilloid 2 as a structural and functional protein; transient receptor potential vanilloid 3 in the development of hypertrophy and myocardial fibrosis; and transient receptor potential vanilloid 4 in its roles modulating the fibrotic and functional responses of the heart to pressure overload. Lastly, we will also review the potential overlapping roles of these channels with other TRP proteins as well as the advances in translational and clinical arenas associated with TRPV channels.
Classical and Non-classical Fibrosis Phenotypes Are Revealed by Lung and Cardiac Like Microvascular Tissues On-Chip
Authors: Akinbote Akinola , Beltran-Sastre Violeta , Cherubini Marta , Visone Roberta , Hajal Cynthia , Cobanoglu Defne , Haase Kristina
Published: October 2021

Graphical Abstract
Calcium-Activated Chloride Channels in Myometrial and Vascular Smooth Muscle
Authors: Wray Susan , Prendergast Clodagh , Arrowsmith Sarah
Published: October 2021

In smooth muscle tissues, calcium-activated chloride channels (CaCC) provide the major anionic channel. Opening of these channels leads to chloride efflux and depolarization of the myocyte membrane. In this way, activation of the channels by a rise of intracellular [Ca2+], from a variety of sources, produces increased excitability and can initiate action potentials and contraction or increased tone. We now have a good mechanistic understanding of how the channels are activated and regulated, due to identification of TMEM16A (ANO1) as the molecular entity of the channel, but key questions remain. In reviewing these channels and comparing two distinct smooth muscles, myometrial and vascular, we expose the differences that occur in their activation mechanisms, properties, and control. We find that the myometrium only expresses “classical,” Ca2+-activated, and voltage sensitive channels, whereas both tonic and phasic blood vessels express classical, and non-classical, cGMP-regulated CaCC, which are voltage insensitive. This translates to more complex activation and regulation in vascular smooth muscles, irrespective of whether they are tonic or phasic. We therefore tentatively conclude that although these channels are expressed and functionally important in all smooth muscles, they are probably not part of the mechanisms governing phasic activity. Recent knockdown studies have produced unexpected functional results, e.g. no effects on labour and delivery, and tone increasing in some but decreasing in other vascular beds, strongly suggesting that there is still much to be explored concerning CaCC in smooth muscle.
Effects of Different Tissue Flossing Applications on Range of Motion, Maximum Voluntary Contraction, and H-Reflex in Young Martial Arts Fighters
Authors: Kalc Miloš , Mikl Samo , Žökš Franci , Vogrin Matjaž , Stöggl Thomas
Published: October 2021

The purpose of this study was to investigate the effects of tissue flossing applied to the ankle joint or to the calf muscles, on ankle joint flexibility, plantarflexor strength and soleus H reflex. Eleven young (16.6 ± 1.2 years) martial arts fighters were exposed to three different intervention protocols in distinct sessions. The interventions consisted of wrapping the ankle (ANKLE) or calf (CALF) with an elastic band for 3 sets of 2 min (2 min rest) to create vascular occlusion. A third intervention without wrapping the elastic band served as a control condition (CON). Active range of motion for ankle (AROM), plantarflexor maximum voluntary contraction (MVC), and soleus H reflex were assessed before (PRE), after (POST), and 10 min after (POST10) the intervention. The H reflex, level of pain (NRS) and wrapping pressure were also assessed during the intervention. Both CALF and ANKLE protocols induced a significant drop in H reflex during the intervention. However, the CALF protocol resulted in a significantly larger H reflex reduction during and after the flossing intervention (medium to large effect size). H reflexes returned to baseline levels 10 min after the intervention in all conditions. AROM and MVC were unaffected by any intervention. The results of this study suggest that tissue flossing can decrease the muscle soleus H reflex particularly when elastic band is wrapped around the calf muscles. However, the observed changes at the spinal level did not translate into higher ankle joint flexibility or plantarflexor strength.
Endothelial Injury in Diving: Atomic Force-, Electronic-, and Light-Microscopy Study of the Ovine Decompressed Blood Vessels
Authors: Arieli Ran
Published: October 2021

We suggested that the nanobubbles, which appear at the active hydrophobic spots (AHSs) at the luminal aspect of the blood vessels, are the gas micronuclei from which the decompression bubbles evolve and the endothelial injury during the decompression is due to the tearing off the cell membranes with the detaching bubbles. Ovine blood vessels were stretched over the polycarbonate plates or glass microscopic slides and were exposed under saline to the hyperbaric pressure (1,013 kPa, 19 h). Following decompression, the blood vessels were photographed for the identification (by bubble formation) of the AHS. Nanobubbles could not be demonstrated at the AHS by using the atomic force microscopy (AFM) because of the roughness of the surface, which disabled the close contact of the probe. In the electron microscopy, no endothelial cells were observed in the samples from the area near to the AHS, but the underlying elastin layer of the intima was observed adjacent to the media. Some intact endothelial cells were observed only in the locations far from an AHS. In the optical microscopy, no endothelial cells were observed in the blood vessels in close proximity to the AHS and in some sections, debris or a detached cluster of the endothelial cells were observed. Intact endothelial cells could be found at the sites distant from an AHS. This study supports the assumption, where the detached bubbles tear off the endothelial cells and cause the initial endothelial injury following the decompression.
Establishing Reference Values for Isometric Knee Extension and Flexion Strength
Authors: Šarabon Nejc , Kozinc Žiga , Perman Mihael
Published: October 2021

Single-joint isometric and isokinetic knee strength assessment plays an important role in strength and conditioning, physical therapy, and rehabilitation. The literature, however, lacks absolute reference values. We systematically reviewed the available studies that assessed isometric knee strength. Two scientific databases (PubMed and PEDro) were searched for the papers that are published from the inception of the field to the end of 2019. We included studies that involved participants of both genders and different age groups, regardless of the study design, that involved isometric knee extension and/or flexion measurement. The extracted data were converted to body-mass-normalized values. Moreover, the data were grouped according to the knee angle condition (extended, mid-range, and flexed). A meta-analysis was performed on 13,893 participants from 411 studies. In adult healthy males, the pooled 95% confidence intervals (CI) for knee extension were 1.34–2.23Nm/kg for extended knee angle, 2.92–3.45Nm/kg for mid-range knee angle, and 2.50–3.06Nm/kg for flexed knee angle, while the CIs for flexion were 0.85–1.20, 1.15–1.62, and 0.96–1.54Nm/kg, respectively. Adult females consistently showed lower strength than adult male subgroups (e.g., the CIs for knee extension were 1.01–1.50, 2.08–2.74, and 2.04–2.71Nm/kg for extended, mid-range, and flexed knee angle condition). Older adults consistently showed lower values than adults (e.g., pooled CIs for mid-range knee angle were 1.74–2.16Nm/kg (male) and 1.40–1.64Nm/kg (female) for extension, and 0.69–0.89Nm/kg (male) and 0.46–0.81Nm/kg (female) for flexion). Reliable normative for athletes could not be calculated due to limited number of studies for individual sports.
Parkour-Based Activities in the Athletic Development of Youth Basketball Players
Authors: Williams Mark David , Strafford Ben William , Stone Joseph Antony , Moran Jason
Published: October 2021

While ideas from long-term athlete development (LTAD) models have been adopted and integrated across different sports, issues related to early specialization, such as increased risk of injury and burnout, are still common. Although some benefits may be associated with early sport specialization, sports sampling is purported to be a more effective approach to the long-term health and wellbeing of children. Furthermore, the concept of developing what are commonly referred to as “fundamental movement skills” (FMS) is central to the rationale for delaying single sports specialization. However, in place of sports sampling, it appears that the practice of strength and conditioning (S&C) has become a driving force behind developmental models for youth athletes, highlighted by the growing body of literature regarding youth athletic development training. In this perspective piece, we explore how conventional S&C practice may insufficiently develop FMS because typically, it only emphasizes a narrow range of foundational exercises that serve a limited role toward the development of action capabilities in youth athletic populations. We further discuss how this approach may limit the transferability of physical qualities, such as muscular strength, to sports-specific tasks. Through an ecological dynamics lens, and using basketball as an example, we explore the potential for parkour-based activity within the LTAD of youth basketball players. We propose parkour as a training modality to not only encourage movement diversity and adaptability, but also as part of an advanced strength training strategy for the transfer of conventional S&C training.