Cancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen, we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpain-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T-cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppression in vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1-dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.Colorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of cancer stemness phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in cancer stem cells by establishing embryonic stem-like transcriptional programs, thus impacting the balance between self-renewal and differentiation. We identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, we observed that G9a activity is essential for the maintenance of embryonic-like transcriptional signature promoting self-renewal, tumorigenicity, and undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. Finally, by integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, we identified the canonical Wnt pathway, epithelial-to-mesenchyme transition, and extracellular matrix organization as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Overall, our findings provide novel insights on the role of G9a as a driver of cancer stem cell phenotype, promoting self-renewal, tumorigenicity, and undifferentiated state.
  Cross-sectional study.
 
  To describe the socio-demographics, injury characteristics, prevalence of shoulder and neck symptoms, weekly participation in leisure time physical activity (LTPA) and quality of life (QoL) of individuals with spinal cord injury in Denmark (SCI).
 
  Nation-wide community survey, Denmark.
 
  Individuals with SCI for >2 years were included from three SCI rehabilitation departments. Questionnaire data regarding socio-demographic details, SCI injury characteristics, medical history, shoulder and neck symptoms, LTPA and QoL were collected.
 
  Of 2454 potential participants, 1517 (62%) responded to the survey (mean age = 56.2, SD 16.1, 37% female, 42% tetraplegia, 23% complete SCI, mean time since injury = 16.9, SD 13.5). 75% used some form of assistive mobility device. Responders and non-responders showed no sex or injury type/severity differences. Shoulder and neck symptoms within the past 3 months were reported by 63 and 67% respectively, with 51% reporting shoulder symptoms within theudies using data from this cohort will investigate patterns and associations between shoulder/neck symptoms, use of assistive mobility devices, LTPA and QoL.
  The effect of dietary cholesterol consumption on health effects and serum lipids remains controversial. This study aimed to examine the association of dietary cholesterol trajectories over 14 years in China with the risk of cardio-metabolic diseases and all-cause mortality and serum lipids.
 
  This study used weighted longitudinal data of 8952 adults from the China Health and Nutrition Survey, and subgroup analyses included 5466 adults who provided blood samples. Latent class trajectory modelling was performed to examine cholesterol trajectories. Cox regression models and general linear regressions were performed to examine the association between trajectories and outcomes.
 
  Compared to the participants with persistently low dietary cholesterol intake, participants with gradually increasing cholesterol intake throughout adulthood were more likely to have hypertension (HR = 1.14, 95% CI 1.03, 1.28) and to die due to all causes (HR = 2.19, 95% CI 1.57, 3.05). Moreover, participants with persistently high cholesterol intake were more likely to die due to all causes (HR = 2.26, 95% CI 1.47, 3.47).  https://www.selleckchem.com/products/sb225002.html  The total cholesterol (TC)HDL-cholesterol (HDL-C) ratio and apolipoprotein B (ApoB) in these two groups were also significantly elevated compared to the group with persistently low dietary cholesterol intake (all P < 0.05). An association between trajectories of cholesterol and the incidence of diabetes was also observed; however, such an association became non significant after additional adjustment for other nutrients, food consumption and social environment.
 
  Gradually increasing or persistently high cholesterol consumption throughout adulthood was significantly associated with an increased risk of hypertension and all-cause mortality with elevated serum lipids.
 Gradually increasing or persistently high cholesterol consumption throughout adulthood was significantly associated with an increased risk of hypertension and all-cause mortality with elevated serum lipids.
  Nutrition is associated with frailty, functional impairments, and mortality in elderly people. Only a few studies focused on oldest-old hospitalized patients with worse health and more comorbidities compared with the general older adults in China.
 
  This study aimed to investigate the nutritional risk, malnutrition, and nutritional support status of oldest-old hospitalized patients (≥80 years of age) in China, and to provide a basis for implementing an effective nutritional intervention.
 
  This study involved 358 oldest-old patients of Peking Union Medical College Hospital in China. The Nutrition Risk Screening 2002 scale was used to assess nutritional risk. Malnutrition was defined as body mass index (BMI) < 18.5 kg/m
  ; or unwanted weight loss >10% at any time, or unwanted weight loss >5% in recent 3 months and BMI < 22 kg/m
  . Logistic regression analysis was used to identify factors associated with nutritional risk.
 
  The overall frequency of nutritional risk and malnutrition was 50.3% (180/358) and 36.