Tumor-Derived Sarcopenia Factors Are Diverse in Different Tumor Types: A Pan-Cancer Analysis.

Cancer-associated muscle wasting is a widespread syndrome in people with cancer and is characterized by weight loss and muscle atrophy, leading to increased morbidity and mortality. However, the tumor-derived factors that affect the development of muscle wasting and the mechanism by which they act remain unknown. To address this knowledge gap, we aimed to delineate differences in tumor molecular characteristics (especially secretion characteristics) between patients with and without sarcopenia across 10 tumor types from The Cancer Genome Atlas (TCGA). We integrated radiological characteristics from CT scans of TCGA cancer patients, which allowed us to calculate skeletal muscle area (SMA) to confirm sarcopenia. We combined TCGA and GTEx (The Genotype-Tissue Expression) data to analyze upregulated secretory genes in 10 tumor types compared with normal tissues. Upregulated secretory genes in the tumor microenvironment and their relation to SMA were analyzed to identify potential muscle wasting biomarkers (560 samples). Meanwhile, their predictive values for patient survival was validated in 3530 samples in 10 tumor types. A total of 560 participants with transcriptomic data and SMA were included. Among those, 136 participants (24.28%) were defined as having sarcopenia based on SMA. Enrichment analysis for upregulated secretory genes in cancers revealed that pathways associated with muscle wasting were strongly enriched in tumor types with a higher prevalence of sarcopenia. A series of SMA-associated secretory protein-coding genes were identified in cancers, which showed distinct gene expression profiles according to tumor type, and could be used to predict prognosis in cancers (p value ≤ 0.002). Unfortunately, those genes were different and rarely overlapped across tumor types. Tumor secretome characteristics were closely related to sarcopenia. Highly expressed secretory mediators in the tumor microenvironment were associated with SMA and could affect the overall survival of cancer patients, which may provide a valuable starting point for the further understanding of the molecular basis of muscle wasting in cancers. More importantly, tumor-derived pro-sarcopenic factors differ across tumor types and genders, which implies that mechanisms of cancer-associated muscle wasting are complex and diverse across tumors, and may require individualized treatment approaches.

The Role of NCS1 in Immunotherapy and Prognosis of Human Cancer.

The Neural Calcium Sensor1 (NCS1) is a crucial protein that binds to Ca2+ and is believed to play a role in regulating tumor invasion and cell proliferation. However, the role of NCS1 in immune infiltration and cancer prognosis is still unknown. Our study aimed to explore the expression profile, immune infiltration pattern, prognostic value, biological function, and potential compounds targeting NCS1 using public databases. High expression of NCS1 was detected by immune histochemical staining in LIHC (Liver hepatocellular carcinoma), BRCA (Breast invasive carcinoma), KIRC (Kidney renal clear cell carcinoma), and SKCM (Skin Cutaneous Melanoma). The expression of NCS1 in cancer was determined by TCGA (The Cancer Genome Atlas Program), GTEx (The Genotype-Tissue Expression), the Kaplan-Meier plotter, GEO (Gene Expression Omnibus), GEPIA2.0 (Gene Expression Profiling Interactive Analysis 2.0), HPA (The Human Protein Atlas), UALCAN, TIMER2.0, TISIDB, Metascape, Drugbank, chEMBL, and ICSDB databases. NCS1 has genomic mutations as well as aberrant DNA methylation in multiple cancers compared to normal tissues. Also, NCS1 was significantly different in the immune microenvironment, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrate-associated cells in different cancers, which could be used for the typing of immune and molecular subtypes of cancer and the presence of immune checkpoint resistance in several cancers. Univariate regression analysis, multivariate regression analysis, and gene enrichment analysis to construct prognostic models revealed that NCS1 is involved in immune regulation and can be used as a prognostic biomarker for SKCM, LIHC, BRCA, COAD, and KIRC. These results provide clues from a bioinformatic perspective and highlight the importance of NCS1 in a variety of cancers.

MicroRNA-29a-3p prevents Schistosoma japonicum-induced liver fibrosis by targeting Roundabout homolog 1 in hepatic stellate cells.

BACKGROUND: Schistosomiasis is a serious but neglected parasitic disease in humans that may lead to liver fibrosis and death. Activated hepatic stellate cells (HSCs) are the principal effectors that promote the accumulation of extracellular matrix (ECM) proteins during hepatic fibrosis. Aberrant microRNA-29 expression is involved in the development of fibrotic diseases. However, less is known about the role of miR-29 in Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis. METHODS: The levels of microRNA-29a-3p (miR-29a-3p) and Roundabout homolog 1 (Robo1) were examined in liver tissues during S. japonicum infection. The possible involvement of the miR-29a-3p-Robo1 signaling pathway was determined. We used MIR29A conditional knock-in mice and mice injected with an miR-29a-3p agomir to investigate the role of miR-29a-3p in schistosomiasis-induced hepatic fibrosis. The functional contributions of miR-29a-3p-Robo1 signaling in liver fibrosis and HSC activation were investigated using primary mouse HSCs and the human HSC cell line LX-2. RESULTS: MiR-29a-3p was downregulated in humans and mice with schistosome-induced fibrosis, and Robo1 was upregulated in liver tissues. The miR-29a-3p targeted Robo1 and negatively regulated its expression. Additionally, the expression level of miR-29a-3p in schistosomiasis patients was highly correlated with the portal vein and spleen thickness diameter, which represent the severity of fibrosis. Furthermore, we demonstrated that efficient and sustained elevation of miR-29a-3p reversed schistosome-induced hepatic fibrosis. Notably, we showed that miR-29a-3p targeted Robo1 in HSCs to prevent the activation of HSCs during infection. CONCLUSIONS: Our results provide experimental and clinical evidence that the miR-29a-3p-Robo1 signaling pathway in HSCs plays an important role in the development of hepatic fibrosis. Therefore, our study highlights the potential of miR-29a-3p as a therapeutic intervention for schistosomiasis and other fibrotic diseases.

A Nomogram for Optimizing Sarcopenia Screening in Community-dwelling Older Adults: AB3C Model.

OBJECTIVES: Sarcopenia is associated with significantly higher mortality risk, and earlier detection of sarcopenia has remarkable public health benefits. However, the model that predicts sarcopenia in the community has yet to be well identified. The study aimed to develop a nomogram for predicting the risk of sarcopenia and compare the performance with 3 sarcopenia screen models in community-dwelling older adults in China. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A total of 966 community-dwelling older adults. METHODS: A total of 966 community-dwelling older adults were enrolled in the study, with 678 participants grouped into the Training Set and 288 participants grouped into the Validation Set according to a 7:3 randomization. Predictors were identified in the Training Set by univariate and multivariate logistic regression and then combined into a nomogram to predict the risk of sarcopenia. The performance of this nomogram was assessed by calibration, discrimination, and clinical utility. RESULTS: Age, body mass index, calf circumference, congestive heart failure, and chronic obstructive pulmonary disease were demonstrated to be predictors for sarcopenia. The nomogram (named as AB3C model) that was constructed based on these predictors showed excellent calibration and discrimination in the Training Set with an area under the receiver operating characteristic curve (AUC) of 0.930. The nomogram also showed perfect calibration and discrimination in the Validation Set with an AUC of 0.897. The clinical utility of the nomogram was supported by decision curve analysis. Comparing the performance with 3 sarcopenia screen models (SARC-F, Ishii, and Calf circumference), the AB3C model outperformed the other models regarding sensitivity and AUC. CONCLUSIONS AND IMPLICATIONS: AB3C model, an easy-to-apply and cost-effective nomogram, was developed to predict the risk of sarcopenia, which may contribute to optimizing sarcopenia screening in community settings.

Effect of Anti-HBs on Mortality Among Resolved HBV Infection: a Population-Based Prospective Cohort Study.

INTRODUCTION: Surveillance programs after hepatitis B surface antigen (HBsAg) loss are not yet well established, and the role of hepatitis B surface antibodies (anti-HBs) remains controversial. We aimed to evaluate the risk factors for increased mortality and the association between anti-HBs and all-cause and cause-specific mortality in a representative US (United States) population of patients with resolved HBV (Hepatitis B virus) infections. METHODS: Data were taken from the US National Health and Nutrition Examination Survey (NHANES) 1999-2018. A total of 3455 US adults with resolved HBV infection [defined as hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive] were enrolled in this study. The primary outcome measures were all-cause and cause-specific mortality from baseline until 31 December 2019. RESULTS: During a mean follow-up of 10.3 years, 741 deaths occurred. Age, race, marital status, smoking status, physical activity level, and presence of cirrhosis, diabetes, cardiovascular diseases, chronic obstructive pulmonary diseases, cancer, and anti-HBs were significant factors for increased mortality, and a nomogram tool was developed and validated for the risk stratification of mortality. Compared with participants who were anti-HBs positive, those who were anti-HBs negative had a 23% (hazard ratio 1.23, 95% CI 1.02-1.46) higher risk of all-cause mortality in NHANES 1999-2018. For cause-specific mortality, the fully adjusted hazard ratios of participants who were anti-HBs negative were 0.71 (95% CI 0.48-1.06) for heart disease, 1.44 (95% CI 1.01-2.05) for cancer, and 1.44 (95% CI 1.13-1.83) for other conditions, compared to those of participants who were anti-HBs positive. CONCLUSIONS: Among US adults with resolved HBV infections, anti-HBs-negative status was associated with an increased risk of death from all causes and cancer, implying that the role of anti-HBs in resolved HBV infection should not be ignored. On the public health level, more rigorous surveillance was needed for populations of individuals who were isolated anti-HBc positive.

Prevalence of Cirrhosis/Advanced Fibrosis Among HBsAg-Negative and HBcAb-Positive US Adults: A Nationwide Population-Based Study.

INTRODUCTION: Evaluation of cirrhosis appears to be easily overlooked in the clinic for the HBsAg-negative (hepatitis B surface antigen-negative) and HBcAb-positive (hepatitis B core antibody-positive) population. Herein, we determine the prevalence of cirrhosis/advanced fibrosis among HBsAg-negative/HBcAb-positive US adults. METHODS: Data came from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. A total of 3115 HBsAg-negative/HBcAb-positive US adults were enrolled in this study. We assessed cirrhosis by using the Fibrosis-4 (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI) score. RESULTS: Out of 50,201 NHANES adults, 45,087 were tested for HBcAb/HBsAg, of whom 3115 met the inclusion criteria (HBsAg-negative/HBcAb-positive with available data for FIB-4/APRI). The weighted proportion of HBsAg-negative/HBcAb-positive among US adults was 4.46% (95% CI 4.17-4.75%), affecting 9.87 million US adults. According to the results of the FIB-4, the weighted prevalence of cirrhosis/advanced fibrosis among HBsAg-negative/HBcAb-positive US adults was 3.76% (95% CI 2.80-4.72%), which corresponds to 371,112 (95% CI 276,360-465,864) HBsAg-negative/HBcAb-positive American adults who had already developed cirrhosis. Among those, cirrhosis/advanced fibrosis in the HBsAb-negative (hepatitis B surface antibody) group (6.28%, 95% CI 4.10-8.45%) was significantly higher than in the HBsAb-positive group (3.08%, 95% CI 2.07-4.08%). Results were similar when APRI was used. CONCLUSION: According to the FIB-4, 3.76% of HBsAg-negative and HBcAb-positive US adults had cirrhosis/advanced fibrosis, much higher than in the general population of the USA. Our data highlight the importance of cirrhosis screening in the HBsAg-negative/HBcAb-positive population to prevent advanced liver disease, especially in those who are HBsAb-negative.

The relationship between brachial-ankle pulse wave velocity and peripheral blood lymphocyte subsets in hypertensives: a cross-sectional study.

Arteriosclerosis is the common pathological basis of hypertension-related target organ damage, and pulse wave velocity (PWV) is commonly used to assess the degree of arterial stiffness. Previous studies have reported the correlation between peripheral blood inflammatory indicators and PWV in hypertensives, but few studies examined the role of immune cells in arteriosclerosis in the context of human hypertension. In order to enrich the understanding of this topic, we conducted a cross-sectional study on hospitalized hypertensives in Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2015 to February 2017 to investigate the relationship between brachial-ankle pulse wave velocity (baPWV) and peripheral blood lymphocyte subsets. Sixty-four eligible patients were enrolled in our study. The patients' blood pressure, height, body weight, and baPWV were collected, along with the lab results of their peripheral complete blood count, blood chemistry, and lymphocyte subsets. We studied the Spearman correlation between baPWV and lymphocyte subsets and other variables. We further used multivariable stepwise linear regression analysis and the results showed that baPWV was significantly correlated with age, height, systolic blood pressure, and the level of T lymphocytes (CD3+CD45+) in hypertensive patients (ß = 8.77, P = 0.006; ß = -17.50, P = 0.001; ß = 6.70, P = 0.002, and ß = -7.093, P = 0.024, respectively). According to our findings, baPWV was independently and negatively correlated with the level of peripheral blood T lymphocytes in hypertensives, and infiltration of T lymphocytes into the vessels wall may be a key part of the immune mechanism of arteriosclerosis in hypertension.