Association of endothelial dysfunction and peripheral arterial disease with sarcopenia in chronic kidney disease.

BACKGROUND: Endothelial dysfunction and peripheral arterial disease (PAD), which disturb skeletal muscle microperfusion, are highly prevalent in patients with chronic kidney disease (CKD). We evaluated the association of endothelial dysfunction and PAD with sarcopenia in patients with non-dialysis CKD. METHODS: This cross-sectional study included 420 patients with stages 3-5 non-dialysis CKD aged 69.0 ± 11.8 years. Skeletal muscle index (skeletal muscle mass/height2), handgrip strength, 6-m gait speed and strength of hip flexion and knee extension were measured. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019. Endothelial dysfunction and PAD were assessed using the vascular reactivity index (VRI) and ankle-brachial index (ABI), respectively. A VRI < 1.0 was classified as poor endothelial function, and an ABI < 0.9 was defined as PAD. Additionally, endothelial and inflammatory biomarkers, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), asymmetric dimethylarginine, endothelin-1 (ET-1) and interleukin-6, were measured in a subgroup of 262 patients. RESULTS: Among the participants, 103 (24.5%) were classified as having sarcopenia. Compared with patients without sarcopenia, those with sarcopenia had significantly lower ABI (1.04 ± 0.16 vs. 1.08 ± 0.15, P = 0.028 for the right ABI; 1.01 ± 0.16 vs. 1.06 ± 0.16, P = 0.002 for the left ABI) and VRI (0.83 ± 0.57 vs. 1.08 ± 0.56, P < 0.001) and had higher serum levels of ICAM-1 (P < 0.001), VCAM-1 (P = 0.003) and ET-1 (P = 0.037). Multivariate logistic regression revealed that, beyond age and body mass index, the average ABI (odds ratio [OR]: 0.81/0.1 increase; 95% confidence interval [CI]: 0.67-0.98; P = 0.032) and VRI (OR: 0.93/0.1 increase; 95% CI: 0.88-0.98; P = 0.010) were independently associated with sarcopenia. Among the endothelial biomarkers measured, ICAM-1 (OR: 2.47/1-SD increase; 95% CI: 1.62-3.75) and VCAM-1 (OR: 1.91/1-SD increase; 95% CI: 1.27-2.87) were independent predictors of sarcopenia. Group stratification based on the cut-offs of VRI and ABI showed that those with both poor VRI and ABI had the greatest risk for sarcopenia (OR: 4.22; 95% CI: 1.69-10.49), compared with those with normal VRI and ABI. CONCLUSIONS: Endothelial dysfunction and PAD are independently associated with sarcopenia in patients with stages 3-5 CKD, suggesting the dominant role of vascular dysfunction in sarcopenia.

Novel equations incorporating the sarcopenia index based on serum creatinine and cystatin C to predict appendicular skeletal muscle mass in patients with nondialysis CKD.

BACKGROUND & AIMS: Skeletal muscle mass measurements are important for customizing nutritional strategies for patients with chronic kidney disease (CKD). The serum creatinine-to-cystatin C ratio (Cr/CysC) is a potential indicator of sarcopenia. We developed simple equations to predict the appendicular skeletal muscle mass (ASM) of patients with CKD using readily available parameters and Cr/CysC. METHODS: Overall, 573 patients with nondialysis CKD stages 3-5 were included for developing and validating the equations. The participants were randomly divided into development and validation groups in a 2:1 ratio. ASM was measured using the Body Composition Monitor (BCM), a multifrequency bioelectrical impedance spectroscopy device. The height, weight, anthropometric data, and handgrip strength (HGS) of the participants were obtained. Equations were generated using stepwise multiple linear regression models. The prognostic significance of the predicted ASM was evaluated in a CKD registry comprising 1043 patients. RESULTS: The optimal equation without anthropometric data and HGS (Equation 1) was as follows: ASM (kg) = -7.949 - 0.049 × Age (years) - 2.213 × Woman + 0.090 × Height (cm) + 0.210 × Weight (kg) + 1.141 × Cr/CysC. The modified equation (Equation 2) with anthropometric data and HGS was as follows: ASM (kg) = -4.468 - 0.050 × Age (years) - 2.285 × Woman+ 0.079 × Height (cm) + 0.228 × Weight (kg) - 0.127 × Mid-arm muscular circumference (cm) + 1.127 × Cr/CysC. Both equations exhibited strong correlations with the ASM measured via BCM in the validation cohort (r = 0.944 and 0.943 for Equations 1 and 2, respectively) with minimal bias. When Equation 1 was applied to the CKD registry, the estimated ASM index (ASM/Height2) significantly predicted overall mortality over a median of 54 months. CONCLUSIONS: Novel ASM equations offer a simple method for predicting skeletal muscle mass and can provide valuable prognostic information regarding patients with nondialysis CKD.

Resistin: A Potential Indicator of Aortic Stiffness in Non-Dialysis Chronic Kidney Disease Patients.

Background and Objectives: In the progression and development of atherosclerosis, resistin plays a significant role. Chronic kidney disease (CKD), frequently associated with atherosclerosis, exhibits a marked increase in morbidity and mortality rates. This study set out to explore the association between aortic stiffness and serum levels of resistin in non-dialysis-dependent CKD patients ranging from stages 3 to 5. Materials and Methods: We collected fasting blood samples from 240 CKD patients across stages 3 to 5. The concentration of resistin in serum was determined using a commercially available enzyme immunoassay kit. Those patients who exhibited a carotid-femoral pulse wave velocity (cfPWV) greater than 10 m/s were identified as the aortic stiffness group. Results: Out of the 240 CKD patients, 88 (36.7%) were classified within the aortic stiffness group. This group demonstrated higher incidences of diabetes, advanced age, increased body weight, body mass index, body fat mass, systolic and diastolic blood pressure, fasting glucose, and serum resistin levels. Multivariate logistic regression analysis highlighted resistin, diabetes, and body weight as independent predictors of aortic stiffness. Additionally, body fat mass, logarithmically transformed cfPWV (log-cfPWV) values and log-triglyceride levels were independent predictors of log-resistin levels by multivariate stepwise linear regression analysis. Conclusions: In CKD patients from stages 3 to 5, a positive correlation exists between elevated serum resistin levels and cfPWV values, identifying resistin as a potential predictor of aortic stiffness.

M2-like macrophages polarized by Foxp3- Treg-of-B cells ameliorate imiquimod-induced psoriasis.

Our group have demonstrated that splenic B cells contributed to the CD4+ CD25- naive T cells conversion into CD4+ CD25+ Foxp3- regulatory T cells without adding appended cytokines, named Treg-of-B cells which were potent suppressors of adaptive immunity. We like to investigate whether Treg-of-B cells could promote alternatively activated macrophage (M2 macrophages) polarization and alleviate inflammatory disease, psoriasis. In this study, we co-cultured the bone marrow-derived macrophages (BMDMs) with Treg-of-B cells under LPS/IFN-γ stimulation and analyzed the M2-associated gene and protein using qPCR, western blotting, and immunofluorescence staining. We also examined the therapeutic effect of Treg-of-B cell-induced M2 macrophage for skin inflammation using imiquimod (IMQ)-induced psoriatic mouse model. Our results showed that BMDMs co-cultured with Treg-of-B cells upregulated typical M2-associated molecules, including Arg-1, IL-10, Pdcd1lg2, MGL-1, IL-4, YM1/2 and CD206. In an inflammatory environment, TNF-α and IL-6 production by macrophages co-cultured with Treg-of-B cells was decreased significantly. The molecular mechanism revealed that Treg-of-B cells promoted M2 macrophage polarization via STAT6 activation in a cell contact-dependent manner. Moreover, the treatment with Treg-of-B cell-induced M2 macrophages attenuated the clinical manifestations of psoriasis, such as scaling, erythema and thickening in the IMQ-induced psoriatic mouse model. T cell activation in draining lymph nodes was decreased in the Treg-of-B cell-induced M2 macrophage group after IMQ application. In conclusion, our findings suggested that Foxp3- Treg-of-B cells could induce alternatively activated M2 macrophages through STAT6 activation, providing a cell-based therapeutic strategy for psoriasis.

Cisplatin and Albumin-Based Gold-Cisplatin Nanoparticles Enhance Ablative Radiation Therapy-Induced Antitumor Immunity in Local and Distant Tumor Microenvironment.

PURPOSE: Ablative radiation therapy (RT) is an important strategy to eliminate primary tumor and can potentially induce the abscopal effect. Human serum albumin nanoparticle (NP) was used for controlled release of cisplatin to decrease cisplatin's systemic toxicity, and gold (Au) was added to increase RT-induced immunogenic cell death and potentiate the abscopal antitumor immunity. METHODS AND MATERIALS: The designed albumin-based cisplatin-conjugated AuNPs were administered concurrently with ablative RT. C57BL/6 mice implanted with syngeneic murine Lewis lung carcinoma or murine MB49 tumor models were treated with ablative RT (12 Gy per fraction for 2 fractions, total 24 Gy), cisplatin, or Au-cisplatin NPs. RESULTS: Combining ablative RT with cisplatin or Au-cisplatin NPs both destroyed the primary tumor effectively and elicited immunogenic cell death accompanied by release of danger-associated molecular patterns. This enhanced recruitment of effector tumor-infiltrating immune cells, including natural killer T cells and CD8+ T cells, and elicited an increased percentage of professional antigen-presenting CD11c+ dendritic cells. Transient weight loss, accompanying hepatotoxicity, nephrotoxicity, and hematopoietic suppression, was observed as a systemic adverse event in the cisplatin but not the Au-cisplatin NPs group. Cisplatin and Au-cisplatin NPs both showed equivalent ability to reduce metastatic potential when combined with ablative RT, confirmed by suppressed unirradiated flank tumor growth and decreased metastatic lung tumor burden, which translated to improved survival. Mobilization and abundance of effector tumor-infiltrating immune cells including CD8+ T cells and dendritic cells were observed in the distant lung tumor microenvironment after ablative RT with cisplatin or Au-cisplatin NPs, demonstrating increased antitumor immunotherapeutic activity as an abscopal effect. CONCLUSIONS: Compared with cisplatin, the albumin-based Au-cisplatin NPs exhibited equivalent but no superior antitumor immunotherapeutic activity while reducing systemic adverse events and can be safely administered concurrently with ablative RT. Alternative NP formulations may be designed to further improve anticancer outcomes.

Integration of Remote Symptom and Biometric Monitoring Into the Care of Adult Patients With Cancer Receiving Chemotherapy-A Decentralized Feasibility Pilot Study.

PURPOSE: Although electronic patient-reported outcomes (ePROs) are efficacious in symptom management, much is unknown about the utility of vital signs surveillance. We examined the feasibility of a remote patient monitoring platform that integrates ePROs and biometrics into the ambulatory management of symptom burden. METHODS: Using a decentralized workflow, patients with gastrointestinal or thoracic cancer were approached for a 1-month study. Patients reported symptom burden via ePROs and biometrics (blood pressure, oxygen saturation, pulse, weight, and temperature) using bluetooth-enabled devices daily. Alerts on the basis of prespecified thresholds were managed via nurse-led triage. Adherence was defined as the completion of > 70% of daily symptom and biometric reporting requirements. Pilot acceptability, appropriateness, and feasibility were measured using validated instruments. Net promoter score, system usability scale, and emergency department (ED) admission rates were collected. RESULTS: Over 8 months, 36 patients were enrolled and 25 (60% gastrointestinal) completed the study. Participants had a mean age of 58.0 years, mean Eastern Cooperative Oncology Group score of 0.88, were 52% female, and predominantly had stage IV or recurrent disease (72%). Program adherence was 73% and associated with high acceptability (4.63), feasibility (4.56), and appropriateness (4.46). System usability scale and net promoter score scores were 88 and 55, respectively. Seventy percent of alerts were generated by biometrics, 28% for symptoms, and 2% were patient-initiated communication. Finally, the ED visitation rate over the pilot period was 8%. CONCLUSION: Our remote patient monitoring pilot program was highly acceptable, feasible, and appropriate. It had high rates of patient adherence and satisfaction and was associated with low ED visitation rates.

Therapeutic efficacy of cyclin-dependent kinase inhibition in combination with ionizing radiation for lung cancer.

PURPOSE: To evaluate the therapeutic efficacy of cyclin-dependent kinase (CDK) inhibition in combination with ionizing radiation for lung cancer. MATERIALS AND METHODS: Human lung adenocarcinoma (A549) and squamous cell carcinoma (H520) cells were used to evaluate the therapeutic efficacy of CDK inhibition in combination with ionizing radiation in vitro using colony formation assay, γH2AX immunofluorescence staining, western blotting, and cell cycle phase analysis. We also performed in vivo evaluations of ectopic tumor growth. RESULTS: In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner. Although CDK inhibition alone did not increase the intensity of γH2AX foci, its combination with ionizing radiation increased DNA double-strand breaks, as shown by γH2AX immunofluorescence staining and western blotting. The combination of CDK inhibition and ionizing radiation-induced G2/M arrest and increased apoptosis, as evidenced by the increased proportion of cells in G2/M arrest, subG1 apoptotic population, and expression of apoptotic markers (cleaved PARP-1 and cleaved caspase-3). Mechanistic studies showed reduced expression of cyclin A with combined treatment, indicating cell cycle shifting effects. An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone. CONCLUSIONS: We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

Trends in Episode-of-Care Spending for Cancer-Directed Surgery Among US Medicare Beneficiaries From 2011 to 2019.

This cross-sectional study examines trends in the number of cancer-directed surgeries from 2011 to 2019 among US patients aged 65 years or older and in Medicare spending for those surgeries overall and by inpatient vs outpatient sites of care.

Is the Centralization of Complex Surgical Procedures an Unintended Spillover Effect of Global Capitation? - Insights from the Maryland Global Budget Revenue Program.

OBJECTIVE: To determine if global budget revenue (GBR) models incent the centralization of complex surgical care. SUMMARY BACKGROUND: In 2014, Maryland initiated a statewide GBR model. While prior research has shown improvements in cost and outcomes for surgical care post-GBR implementation, the mechanism remains unclear. METHODS: Utilizing state inpatient databases, we compared the proportion of adults undergoing elective complex surgeries (gastrectomy, pneumonectomy/lobectomy, proctectomies, and hip/knee revision) at high-concentration hospitals (HCHs) in Maryland and control states. Annual concentration, per procedure, was defined as hospital volume divided by state volume. HCHs were defined as hospitals with a concentration at least at the 75 th percentile in 2010. We estimated the difference-in-differences (DiD) of the probability of patients undergoing surgery at HCHs before and after GBR implementation. FINDINGS: Our sample included 122,882 surgeries. Following GBR implementation, all procedures were increasingly performed at HCHs in Maryland. States satisfied the parallel trends assumption for the centralization of gastrectomy and pneumonectomy/lobectomy. Post-GBR, patients were more likely to undergo gastrectomy (DiD: 5.5 p.p., 95% CI [2.2, 8.8]) and pneumonectomy/lobectomy (DiD: 12.4 p.p., 95% CI [10.0, 14.8]) at an HCH in Maryland compared with control states. For our hip/knee revision analyses, we assumed persistent counterfactuals and noted a positive DiD post-GBR implementation (DiD: 4.8 p.p., 95% CI [1.3, 8.2]). No conclusion could be drawn for proctectomy due to different pre-GBR trends. CONCLUSIONS: GBR implementation is associated with increased centralization for certain complex surgeries. Future research is needed to explore the impact of centralization on patient experience and access.

Epithelial chemerin-CMKLR1 signaling restricts microbiota-driven colonic neutrophilia and tumorigenesis by up-regulating lactoperoxidase.

Intestinal barrier immunity is essential for controlling gut microbiota without eliciting harmful immune responses, while its defect contributes to the breakdown of intestinal homeostasis and colitis development. Chemerin, which is abundantly expressed in barrier tissues, has been demonstrated to regulate tissue inflammation via CMKLR1, its functional receptor. Several studies have reported the association between increased expression of chemerin-CMKLR1 and disease severity and immunotherapy resistance in inflammatory bowel disease (IBD) patients. However, the pathophysiological role of endogenous chemerin-CMKLR1 signaling in intestinal homeostasis remains elusive. We herein demonstrated that deficiency of chemerin or intestinal epithelial cell (IEC)-specific CMKLR1 conferred high susceptibility to microbiota-driven neutrophilic colon inflammation and subsequent tumorigenesis in mice following epithelial injury. Unexpectedly, we found that lack of chemerin-CMKLR1 signaling specifically reduced expression of lactoperoxidase (LPO), a peroxidase that is predominantly expressed in colonic ECs and utilizes H2O2 to oxidize thiocyanates to the antibiotic compound, thereby leading to the outgrowth and mucosal invasion of gram-negative bacteria and dysregulated CXCL1/2-mediated neutrophilia. Importantly, decreased LPO expression was causally linked to aggravated microbiota-driven colitis and associated tumorigenesis, as LPO supplementation could completely rescue such phenotypes in mice deficient in epithelial chemerin-CMKLR1 signaling. Moreover, epithelial chemerin-CMKLR1 signaling is necessary for early host defense against bacterial infection in an LPO-dependent manner. Collectively, our study reveals that the chemerin-CMKLR1/LPO axis represents an unrecognized immune mechanism that potentiates epithelial antimicrobial defense and restricts harmful colonic neutrophilia and suggests that LPO supplementation may be beneficial for microbiota dysbiosis in IBD patients with a defective innate antimicrobial mechanism.

Biomonitoring of Urinary Nickel Successfully Protects Employees and Introduces Effective Interventions.

Nickel is a heavy metal used in many industries. Nickel exposure can induce respiratory diseases and allergic reactions, and increase cancer risk. This study evaluated the introduction of a grinding and polishing system to prevent injuries from nickel toxicity in workers. We performed a controlled, interventional, before-and-after study from January 2018 to December 2019 at a faucet component industrial manufacturing site. Results from workplace environmental monitoring, questionnaire responses, and biomonitoring were collected before and after the intervention. Thirty-seven workers (100% men) aged 25.0 (interquartile range (IQR): 22.0-33.5) years were categorized into two groups, those with and without nickel exposure. In the exposed group, the median exposure time was 18.0 months (IQR 14.0-20.0 months). Urinary nickel concentration was lower in the exposed group than in the non-exposed group (13.8 (IQR 1.7-20.7); 23.1 (IQR 11.3-32.8) µg/g creatinine, respectively; p = 0.047). The median urinary nickel concentration was lower in the second year than in the first year (17.4 (IQR 2.2-27.4), 7.7 (IQR 4.3-18.5) µg/g creatinine, respectively; p = 0.022). Significant reductions in urinary nickel concentration were observed following the intervention and educational program. Thus, biomonitoring of urinary nickel concentration can successfully reflect the effectiveness of interventions and their relationship to nickel exposure.

Association of Maryland Global Budget Revenue With Spending and Outcomes Related to Surgical Care for Medicare Beneficiaries With Cancer.

Importance: In 2014, Maryland initiated the global budget revenue (GBR) model, placing caps on total hospital expenditures across all care sites. The GBR program aims to reduce unnecessary utilization while maintaining or improving care quality. To date, there has been limited examination of program effects on cancer care. Objective: To compare changes in spending, clinical outcomes, and acute care utilization through 4 years of the GBR program among Medicare beneficiaries who undergo cancer-directed surgery in Maryland vs matched control states. Design, Setting, and Participants: Drawing from a matched pool of hospitals in Maryland (n = 35) and 24 control states with a similar timing of Medicaid expansion (n = 101), we identified Medicare beneficiaries from Maryland and control states who underwent any cancer-directed surgery from 2011 through 2018. Using difference-in-differences analysis, we compared changes in outcomes from before (2011-2013) to after (2015-2018) GBR implementation between patients treated in Maryland and control states. We also performed a subgroup analysis among patients who underwent major surgical procedures that are usually performed in the inpatient setting (cystectomy, esophagectomy, gastrectomy, colorectal resection, nephrectomy, pancreatectomy, and lung resection). Main Outcomes and Measures: Thirty-day episode spending, mortality, readmissions, and emergency department (ED) visits. Results: Relative to Medicare beneficiaries undergoing cancer surgery in control states (n = 4737; 3323 [70.1%] female; 571 [12.1%] dual-eligible; mean [SD] age 74.9 [6.5] years), patients in Maryland (n = 20 320; 14 068 [69.2%] female; 1705 [8.4%] dual-eligible; mean [SD] age 74.9 [6.5] years) had a statistically significant reduction of 2.2 percentage points (95% CI, -4.3 to -0.1) in the 30-day readmission rate. We found no statistically significant changes in 30-day spending, mortality, or ED visits. We report no significant results in the subgroup analysis of patients undergoing major surgical procedures. Conclusions and Relevance: Global budget revenue was not associated with changes in expenditures, ED utilization, or clinical outcomes after cancer-directed surgery through 4 years. There was a modest decline in 30-day readmissions. Specialty-specific definitions of care quality and better alignment across the entire care delivery value chain (ie, physician incentives) may be strategies that could improve delivery of high-value care for beneficiaries undergoing cancer surgery.

KCNJ5 Somatic Mutation Is Associated With Higher Aortic Wall Thickness and Less Calcification in Patients With Aldosterone-Producing Adenoma.

Objective: Primary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status. Methods: We enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed. Results: After propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, P<0.001) than non-carriers. In multivariate analysis, KCNJ5 mutations were independently associated with AAC score (P=0.014) and aortic wall thickness (SMA level: P<0.001; IMA level: P=0.004). After adrenalectomy, mutation carriers had less aortic wall thickness progression than non-carriers (Δthickness SMA: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024; IMA: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.04). Conclusion: KCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.

A Comparison of SARC-F, Calf Circumference, and Their Combination for Sarcopenia Screening among Patients Undergoing Peritoneal Dialysis.

Sarcopenia is frequently encountered in patients undergoing peritoneal dialysis (PD). We evaluated and compared the diagnostic performance of a strength, assistance walking, rise from a chair, climb stairs, and falls (SARC-F) questionnaire, SARC-F combined with calf circumference (SARC-CalF), and calf circumference (CC) for screening sarcopenia among patients undergoing PD. We measured the appendicular skeletal muscle mass, evaluated using a multifrequency bioimpedance spectroscopy device, handgrip strength, and 6-m gait speed. SARC-F, SARC-CalF, and CC were obtained in all participants. Sarcopenia was defined using four different diagnostic criteria, including the Asian Working Group for Sarcopenia (AWGS) 2019, revised European Working Group on Sarcopenia in Older People (EWGSOP2), Foundation for the National Institutes of Health (FNIH), and International Working Group on Sarcopenia (IWGS). Among 186 enrolled patients undergoing PD (mean age 57.5 ± 14.1 years), the sarcopenia prevalence was 25.8-38.2% using the four definitions. The discriminative powers of SARC-CalF (range 0.648-0.748) and CC (range 0.652-0.813) against the four definitions were better than those exhibited by SARC-F (range 0.587-0.625), which achieved significant difference, except when adopting the criteria of the FNIH. After stratification by gender, the superiority of SARC-CalF and CC over SARC-F was maintained when AWGS 2019, EWGSOP2, and IWGS were applied. In conclusion, CC and SARC-CalF outperformed SARC-F in the diagnostic accuracy of sarcopenia among patients undergoing PD.

A Novel Application of Serum Creatinine and Cystatin C to Predict Sarcopenia in Advanced CKD.

Sarcopenia is highly prevalent in patients with advanced chronic kidney disease (CKD), yet a reliable serum index has not been established. The product of serum creatinine and the estimated glomerular filtration rate based on cystatin C (Cr×eGFRcys) was recently proposed as a sarcopenia index (SI), approximately to 24-h filtered creatinine through the glomerulus. We aimed to evaluate the diagnostic validity of the novel SI in advanced CKD. In 297 patients with non-dialysis stage 3b-5 CKD, aged 68.8 ± 12.9 years, the total skeletal muscle mass (SMM), handgrip strength (HGS), and usual gait speed were assessed. Sarcopenia was defined based on the Asian Working Group for Sarcopenia 2019 consensus update. The prevalence of sarcopenia in this cohort was 20.2%. The SI correlated moderately with SMM (r = 0.503, P < 0.001), HGS (r = 0.508, P < 0.001), and gait speed (r = 0.381, P < 0.001); the independency of the SI with three muscle metrics was confirmed after extensive adjustment. For sarcopenia prediction, the SI had acceptable discriminative powers in males [area under the receiver operating characteristic curve (AUC) 0.646, 95% confidence interval (CI) 0.569-0.718] and females (AUC 0.754, 95% CI 0.670-0.826). In males, the best cut-off was 53.9, which provided 71.1% sensitivity, 58.0% specificity, 32.9% positive predictive value (PPV), and 87.4% negative predictive value (NPV); in females, the best cut-off was 45.8, which provided 81.8% sensitivity, 62.3% specificity, 31.0% PPV, and 94.3% NPV. In conclusion, Cr×eGFRcys could be served as a surrogate marker for sarcopenia and may be helpful for sarcopenia screening in advanced CKD. Further studies are needed to expand our investigation.

CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase.

BACKGROUND AND AIMS: We previously demonstrated that cancer-associated fibroblasts (CAFs) promote tumor growth through recruitment of myeloid-derived suppressor cells (MDSCs). 5-lipoxygenase (5-LO) is highly expressed in myeloid cells and is critical for synthesizing leukotriene B4 (LTB4), which is involved in tumor progression by activating its receptor leukotriene B4 receptor type 2 (BLT2). In this study, we investigated whether and how CAFs regulate MDSC function to enhance cancer stemness, the driving force of the cancer aggressiveness and chemotherapy refractoriness, in highly desmoplastic intrahepatic cholangiocarcinoma (ICC). APPROACH AND RESULTS: RNA-sequencing analysis revealed enriched metabolic pathways but decreased inflammatory pathways in cancer MDSCs compared with blood MDSCs from patients with ICC. Co-injection of ICC patient-derived CAFs promoted cancer stemness in an orthotopic ICC model, which was blunted by MDSC depletion. Conditioned media (CM) from CAF-educated MDSCs drastically promoted tumorsphere formation efficiency and stemness marker gene expression in ICC cells. CAF-CM stimulation increased expression and activity of 5-LO in MDSCs, while 5-LO inhibitor impaired the stemness-enhancing capacity of MDSCs in vitro and in vivo. Furthermore, IL-6 and IL-33 primarily expressed by CAFs mediated hyperactivated 5-LO metabolism in MDSCs. We identified the LTB4-BLT2 axis as the critical downstream metabolite signaling of 5-LO in promoting cancer stemness, as treatment with LTB4 was elevated in CAF-educated MDSCs, or blockade of BLT2 (which was preferentially expressed in stem-like ICC cells) significantly reduced stemness-enhancing effects of CAF-educated MDSCs. Finally, BLT2 blockade augmented chemotherapeutic efficacy in ICC patient-derived xenograft models. CONCLUSIONS: Our study reveals a role for CAFs in orchestrating the optimal cancer stemness-enhancing microenvironment by educating MDSCs, and suggests the 5-LO/LTB4-BLT2 axis as promising therapeutic targets for ICC chemoresistance by targeting cancer stemness.

Preclinical evaluation of PEGylated liposomal doxorubicin as an effective radiosensitizer in chemoradiotherapy for lung cancer.

PURPOSE: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. METHODS: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase­3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. RESULTS: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin­V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. CONCLUSIONS: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy.

Serum indices based on creatinine and cystatin C predict mortality in patients with non-dialysis chronic kidney disease.

Serum indices based on creatinine and cystatin C, including creatinine/cystatin C ratio (Cr/CysC), ratio and difference of estimated glomerular filtration rate (eGFR) based on cystatin C and creatinine (eGFRcys/eGFRcre and eGFRDiff), and serum creatinine × eGFRcys, are recently identified serum markers for sarcopenia. We aimed to evaluate the association between these serum indices and mortality in patients with chronic kidney disease (CKD). A single-center retrospective cohort study included 1141 adult patients with stage 1-5 CKD between 2016 and 2018. Basic characteristics, comorbidities, laboratory parameters, and serum creatinine and cystatin C values were obtained. Patients were followed up until death, dialysis, transfer to another hospital, or end of the study. The median age (interquartile range) of our participants was 71 (62-81) years. During a median follow-up of 39 months, 116 (10.2%) patients died. Compared to the survivor group, Cr/CysC, eGFRcys/eGFRcre, eGFRDiff, and Cr × eGFRcys were all lower in the non-survivors (p < 0.001 for all). The receiver operating characteristic curves of serum indices for predicting mortality showed that all four indices had significant discriminative power. Based on the Cox proportional hazard models, lower values of four serum indices, both as continuous and categorical variables, independently predicted mortality. Our findings suggest that low serum indices of Cr/CysC, eGFRcys/eGFRcre, eGFRDiff, and Cr × eGFRcys are independent indicators of mortality in patients with non-dialysis CKD.