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glucocorticoids and overcome corticosteroid insensitivity.The aim of this study was to determine whether endoplasmic reticulum (ER) stress is involved in the apoptosis of granulosa cells in patients with polycystic ovary syndrome (PCOS). A total of 116 patients undergoing in vitro fertilization/intracytoplasmic sperm injection cycles at the Binzhou Medical University Hospital IVF Center between September 2019 and January 2020 were enrolled in the study. Apoptosis of the granulosa cells in each patient was analyzed using flow cytometry, and progesterone and estrogen levels in the cell-culture fluid were measured by enzyme-linked immunosorbent assay. The expressions of X-box-binding protein 1 (XBP1(s)), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), B-cell CLL/lymphoma 2 protein (Bcl-2), and Bcl-2 associated X protein (Bax) at the gene or protein level were analyzed using quantitative real-time polymerase chain reaction and Western blotting, respectively. In patients with PCOS, body mass index and basal serum concentrations of luteinizing h XBP1(s), CHOP, and Bax significantly decreased, while the expression of Bcl-2 and levels of progesterone and estrogen significantly increased (P less then 0.05). We conclude that ER stress could induce the apoptosis of granulosa cells in patients with PCOS. Cell apoptosis may decrease the number of blastocysts formed.Hepatic ischemia and reperfusion (IR) injury is a common complication in clinical practice. Endoplasmic reticulum (ER) stress and autophagy are the key factors in the process of hepatic IR injury. The vitamin D receptor (VDR) can mediate ER stress and autophagy; however, it can also mitigate IR injury. The relationship between VDR, ER stress, and autophagy in hepatic IR injury is unknown. VDR knockout mice and wild-type littermates underwent 70% liver ischemia (90 min) and reperfusion (6 h). To observe the effect of autophagy in the relationship with VDR and ER stress in hepatic IR injury, the autophagy agonist rapamycin and its inhibitor chloroquine were used in the study. Meanwhile, RAW264.7 cells were studied in vitro to verify the relationship between VDR, autophagy, and ER stress. VDR was involved in hepatic IR injury and its activation reduced liver injury and inhibited an inflammatory response. ER stress took part in the liver injury during the process of IR. Meanwhile, VDR activation was found to inhibit inflammation by ER stress, and vice versa. Furthermore, autophagy was the connection between VDR and ER stress. After treatment with rapamycin or chloroquine, the effect of VDR activation or VDR silencing in ER stress was partially reversed. The same tendency was observed in vitro. ER stress and autophagy are important mechanisms of hepatic IR injury. VDR can regulate ER stress through autophagy and then protect the liver from IR injury.Betaine is a biologically active compound exerting beneficial effects in the organism, however, the exact mechanisms underlying its action are not fully elucidated. The present study aimed to explore, whether betaine alleviates disorders induced by feeding rats a high-fat diet (HFD). Rats were divided into 3 groups control, fed an HFD and fed an HFD and receiving betaine (2% water solution for 8 weeks). Betaine improved glucose tolerance, decreased blood levels of non-esterified fatty acids and prevented lipid accumulation in the skeletal muscle of rats on an HFD. Betaine reduced activities of blood alanine aminotransferase, blood levels of bilirubin and hepatic lipid content. Expression of fatty acid synthase in the liver and the skeletal muscle was decreased in response to feeding an HFD, and this effect was deepened by betaine in the muscle tissue. Hepatic and muscular expression of genes related to insulin signaling were unchanged in HFD-fed rats. Lipolysis stimulated by epinephrine (an adrenergic receptos different tissues.Increased peripheral resistance and autonomic nervous system is a key link in pathogenesis of arterial hypertension in diabetic kidney disease. Net effect of glucagon-like peptide 1 receptor (GLP-1R) agonists on blood pressure may result from interplay between vasodilatation, increased natriuresis, heart rate and sympathetic nervous system activity. The aim of study was to compare hemodynamic effect of single subcutaneous dose of 1.2 mg liraglutide to placebo in patients with type 2 diabetes mellitus and impaired renal function. This cross-over study included 17 patients with estimated glomerular filtration rate (eGFR) 60 ml/min/1.73 m2 (p = 0.002), whereas pulse wave velocity increased after liraglutide compared with placebo only in patients with eGFR less then 30 ml/min/1.73 m2 (p = 0.0006). The 24 h mean arterial pressure after liraglutide significantly increased compared to placebo only in latter group. Liraglutide administration in patients with advanced chronic kidney disease (CKD) induces increase of blood pressure due to increase of cardiac output secondary to acceleration of heart rate associated with sympathetic predominance. The vasodilatory effect of liraglutide is preserved only in earlier CKD.Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS treated by diverse disease-modifying therapies that suppress the immune system. Severe acute respiratory syndrome coronavirus 2 mRNA vaccines have been very effective in immunocompetent individuals, but whether MS patients treated with modifying therapies are afforded the same protection is not known. This study determined that dimethyl fumarate caused a momentary reduction in anti-Spike (S)-specific Abs and CD8 T cell response. MS patients treated with B cell-depleting (anti-CD20) or sphingosine 1-phosphate receptor agonist (fingolimod) therapies lack significant S-specific Ab response. Whereas S-specific CD4 and CD8 T cell responses were largely compromised by fingolimod treatment, T cell responses were robustly generated in anti-CD20-treated MS patients, but with a reduced proportion of CD4+CXCR5+ circulating follicular Th cells. These data provide novel information regarding vaccine immune response in patients with autoimmunity useful to help improve vaccine effectiveness in these populations.Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in human asthmatic lungs. In this study, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling, and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, retinoic acid-related orphan receptor γt (RORγt), and Th17 responses, with PRMT5-dependent increases in RORγt's agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.NK cell receptors allow NK cells to recognize targets such as tumor cells. Many of them are expressed on a subset of NK cells, independently of each other, which creates a vast diversity of receptor combinations. Whether these combinations influence NK cell antitumor responses is not well understood. We addressed this question in the C57BL/6 mouse model and analyzed the individual effector response of 444 mouse NK cell subsets, defined by combinations of 12 receptors, against tumor cell lines originating from different tissues and mouse strains. We found a wide range of reactivity among NK subsets, but the same hierarchy of responses was observed for the different tumor types, showing that the repertoire of NK cell receptors does not encode for different tumor specificities but for different intrinsic reactivities. The coexpression of CD27, NKG2A, and DNAM-1 identified subsets with relative cytotoxic specialization, whereas reciprocally, CD11b and KLRG1 defined the best IFN-γ producers. The expression of educating receptors Ly49C, Ly49I, and NKG2A was also strongly correlated with IFN-γ production, but this effect was suppressed by unengaged receptors Ly49A, Ly49F, and Ly49G2. Finally, IL-15 coordinated NK cell effector functions, but education and unbound inhibitory receptors retained some influence on their response. Collectively, these data refine our understanding of the mechanisms governing NK cell reactivity, which could help design new NK cell therapy protocols.

Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. Metabolism activator We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.

In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 21 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations beon with antiangiogenics requires further investigation.

Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor).

Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100-400 mg once a day) plus epacadostat (50-300 mg two times per day; group A), or itacitinib (100-400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3-10 mg once a day; group B).

A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn.