PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.

Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.

Identification and Validation of a Metabolism-Related Prognostic Signature Associated with M2 Macrophage Infiltration in Gastric Cancer.

High levels of M2 macrophage infiltration invariably contribute to poor cancer prognosis and can be manipulated by metabolic reprogramming in the tumor microenvironment. However, the metabolism-related genes (MRGs) affecting M2 macrophage infiltration and their clinical implications are not fully understood. In this study, we identified 173 MRGs associated with M2 macrophage infiltration in cases of gastric cancer (GC) using the TCGA and GEO databases. Twelve MRGs were eventually adopted as the prognostic signature to develop a risk model. In the high-risk group, the patients showed poorer survival outcomes than patients in the low-risk group. Additionally, the patients in the high-risk group were less sensitive to certain drugs, such as 5-Fluorouracil, Oxaliplatin, and Cisplatin. Risk scores were positively correlated with the infiltration of multiple immune cells, including CD8+ T cells and M2 macrophages. Furthermore, a difference was observed in the expression and distribution between the 12 signature genes in the tumor microenvironment through single-cell sequencing analysis. In vitro experiments proved that the M2 polarization of macrophages was suppressed by Sorcin-knockdown GC cells, thereby hindering the proliferation and migration of GC cells. These findings provide a valuable prognostic signature for evaluating clinical outcomes and corresponding treatment options and identifying potential targets for GC treatment.

The Burden of Modifiable Risk Factors in Newly Defined Categories of Blood Pressure.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association Guideline introduced new categories of high blood pressure. The vast majority of individuals in these newly defined categories are recommended for nonpharmacological intervention rather than antihypertensive therapy. This study sought to determine the burden of potentially modifiable risk factors of hypertension among untreated adults in the newly defined categories of blood pressure. METHODS: We analyzed data from the 1999-2014 National Health and Nutrition Examination Survey (N = 37,448). Potentially modifiable risk factors included abdominal obesity, high non-high-density lipoprotein (HDL) cholesterol, secondhand smoking, binge drinking, suboptimal physical activity, and low-fiber diet. RESULTS: Although the prevalence of certain modifiable risk factors decreased during the study period, the prevalence of low fiber intake, suboptimal physical activity, abdominal obesity, and binge drinking remained high during the last combined survey cycle (2011-2014). Modifiable risk factors generally demonstrated dose-response relationships with high blood pressure categories. The most common type of risk factor clustering included low fiber intake, suboptimal physical activity, high non-HDL cholesterol, and abdominal obesity, with its prevalence increasing gradually from 9.5% (95% confidence interval, 8.8%-10.3%) in the normal blood pressure group to 16.5% (95% confidence interval, 14.8%-18.3%) in the stage 2 hypertension group (Ptrend < .001). The prevalence of 4 or more modifiable risk factors per participant increased stepwise, ranging from 28.5% in the normal blood pressure group to 48.0% in the stage 2 hypertension group (Ptrend < .001). CONCLUSIONS: The burden of potentially modifiable risk factors for hypertension shows progressive increase along the blood pressure categories and represents an important target for nonpharmacologic intervention.

Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study.

CONTEXT: Demographic, personal, clinical, and behavioral factors predicting chemotherapy-induced nausea and vomiting (CINV) have been assessed in the past, but inconsistencies exist in the literature, studies have methodological shortcomings, and many risk factors have been examined in cross-sectional studies and univariate analyses. OBJECTIVES: To evaluate the predictive power of personal and treatment-related characteristics in the development of CINV, using a large and prospectively evaluated sample of a heterogeneous group of cancer patients receiving routine chemotherapy. METHODS: This was a multicountry, multisite prospective study over three cycles of chemotherapy. Adult patients from eight European countries about to receive highly and moderately emetogenic chemotherapy were recruited. Clinicians completed a case report form at or before the initial chemotherapy treatment, recording patient demographic and baseline clinical characteristics. Participants completed a daily patient diary for six days per chemotherapy cycle describing their CINV experience. Baseline patient data also included a history of nausea/vomiting (yes/no), patient expectation of nausea (0-100 mm visual analogue scale [VAS]), prechemotherapy anxiety (0-100 mm VAS), and prechemotherapy nausea (0-100 mm VAS) measured during the 24-hour period before chemotherapy initiation. RESULTS: There were 991 evaluable patients with complete Cycle 1 data, 888 for Cycle 2 data, and 769 for Cycle 3 data. A complex picture of predictor variables was shown, with different contribution of variables to the acute, delayed, and overall phases of CINV. Key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and no CINV complete response in an earlier cycle (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway. CONCLUSION: The results of this study provide clarity for the relative contribution of a set of characteristics in the development of CINV. Following evidence-based clinical antiemetic guidelines is of paramount importance, alongside treating patients with increased risk for CINV more aggressively, which both could lead to more optimal CINV management. These data can assist clinicians in making decisions about the antiemetic management of their patients.

Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study.

PURPOSE: Consensus guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) are variably implemented in practice. The purpose of this study was to evaluate the impact of guideline-consistent/guideline-inconsistent CINV prophylaxis (GCCP/GICP) on the incidence of no CINV after cycle 1 of highly or moderately emetogenic chemotherapy (HEC or MEC). PATIENTS AND METHODS: This prospective observational study enrolled chemotherapy-naive adult outpatients who received single-day HEC or MEC at four oncology practice networks, all using electronic health record (EHR) systems, in Georgia, Tennessee, and Florida. Results from the Multinational Association of Supportive Care in Cancer Antiemesis Tool, a validated tool to measure CINV, administered 5 to 8 days postchemotherapy, were merged with EHR data. The primary end point, no CINV, defined as no emesis and no clinically significant nausea (score < 3 on 0-10 scale), was compared between cohorts using logistic regression. RESULTS: A total of 1,295 patients were enrolled (mean age, 59.3 years; 70.0% female; 35.5% HEC). The overall prevalence of GCCP was 57.3%. When corticosteroids were prescribed on days 2 to 4 after all HEC, GCCP for HEC increased from 28.7% to 89.8%; when NK1-receptor antagonists were prescribed after all MEC, GCCP for MEC increased from 73.1% to 97.8%. Over 5 days postchemotherapy, the incidence of no CINV was significantly higher in the GCCP cohort than the GICP cohort (53.4% v 43.8%; P < .001). The adjusted odds of no CINV with GCCP was 1.31 (95% CI, 1.07 to 1.69; P = .037). CONCLUSION: Increased adherence to antiemetic guidelines could significantly reduce the incidence of CINV after HEC and MEC.