Search

Immune checkpoint blockade (ICB) has demonstrated clinical success in “inflamed” tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell–intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation–mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

The follicular helper T cells are derived from CD4+T cells, promoting the formation of germinal centers and assisting B cells to produce antibodies. This review describes the differentiation process of Tfh cells from the perspectives of the initiation, maturation, migration, efficacy, and subset classification of Tfh cells, and correlates it with autoimmune disease, to provide information for researchers to fully understand Tfh cells and provide further research ideas to manage immune-related diseases. [ABSTRACT FROM AUTHOR]

In this study, we aimed to investigate the molecular pathway(s) underlying the effect of metformin (MET) on the expression of matrix metalloproteinase (MMP)‐2 and MMP‐9. Real‐time polymerase chain reaction, Western blot analysis, and gelatin zymography were used to assay the effects of MET on MMP and AMPK signaling pathways. In addition, HTOG cells were treated with miR‐29b‐3p/a scramble control, H19/a negative control, or MET/PBS to explore possible signaling pathway(s) underlying the inhibitory effect of MET on MMP‐2/MMP‐9. A rat model of polycystic ovary syndrome (PCOS) was also established to validate the molecular mechanism(s) of MET in vivo. The administration of MET suppressed the expression of MMP‐9/MMP‐2 and mTOR while increasing the expression of Akt and AMPK, indicating that MET reduced the expression of MMPs via the AMPK signaling pathway. Meanwhile, the H19/miR‐29b‐3p/MMP‐9 and H19/miR‐29b‐3p/MMP‐2 signaling pathways were implicated in PCOS, in which the interactions between H19/miR‐29b‐3p and MMP‐9/MMP‐2/miR‐29b‐3p were confirmed. Furthermore, the administration of MET suppressed the expression of H19 while elevating the expression of miR‐29b‐3p. And the role of MET in PCOS was also confirmed in vivo via examining the activity of H19 and AMPK signaling pathways in cell or serum samples collected from PCOS rats. MET exhibits a therapeutic effect in the treatment of PCOS by reducing the expression of MMPs. [ABSTRACT FROM AUTHOR]

The authors discuss the four programmed death receptor-1/programmed death-ligand 1 (PD-L1) targeted immunotherapies approved by the U.S. Food and Drug Administration for the treatment of patients with locally-advanced or metastatic urothelial cancer. Topics mentioned include the estimated number of patients who die from urothelial cancer annually in the U.S., ineligibility of patients for cisplatin-based therapy, and PD-L1 assays included in the labels of three products for second-line use.

Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1. This accelerated approval was based on results of a single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum-containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow-up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1,19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for ≥ 6 months. The most common adverse reactions (≥20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune-related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit-risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s). [ABSTRACT FROM AUTHOR]

Scutellarin is a flavonoid isolated from a medicinal herb Scutellaria barbata D. Don and exerts therapeutic effects on cardiovascular diseases. However, it remains unclear whether Scutellarin exhibits anti-tumor actions on human colon cancer. The current study aimed to investigate whether Scutellarin produces antiproliferative and pro-apoptotic effects on HCT-116 human colon cancer cells and to elucidate the mechanisms involved. Human colon cancer cells were exposed to different concentrations of Scutellarin, and cellular growth and apoptosis were evaluated by MTT assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, western blot analysis and other assays. A cell viability assay demonstrated that Scutellarin treatment reduced the viability of HCT-116 cells in a dose- and time-dependent manner. TUNEL staining demonstrated that Scutellarin also induced apoptotic changes in HCT-116 cells. The expression level of the anti-apoptotic protein, Bcl-2 apoptosis regulator (Bcl-2), was reduced by Scutellarin in HCT-116 cells, whereas the expression Bcl-2 associated X apoptosis regulator (Bax) and the activation of caspase-3 protein were increased by Scutellarin treatment. Further investigation revealed that Scutellarin significantly increased the phosphorylation of p53 protein in HCT-116 cells. Additionally, suppression of p53 using a specific inhibitor, pifithrin-a, abrogated the pro-apoptotic effects of Scutellarin in HCT-116 cells. Collectively, Scutellarin reduced the viability and induced apoptosis of human colon carcinoma cells, potentially by regulating p53 and Bcl-2/Bax expression. These data suggested that Scutellarin may be useful as a promising anti-tumor drug for treating colon cancer. [ABSTRACT FROM AUTHOR]

Background: Detecting epidermal growth factor receptor (EGFR) activating mutations in plasma could guide EGFRtyrosine kinase inhibitor (EGFR-TKI) treatment for advanced non-small cell lung cancer (NSCLC). However, dynamic quantitative changes of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. The aim of this study was to measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment and to determine its correlation with the response and resistance to EGFR-TKI. Methods: This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Totally, 256 patients were enrolled in CTONG0901 and randomized to receive erlotinib or gefitinib. One hundred and eight patients harbored L858R mutation in their tumors and 80 patients provided serial blood samples as pre-planned scheduled. Serial plasma L858R was detected using quantitative polymerase chain reaction. Dynamic types of plasma L858R were analyzed using Ward's hierarchical clustering method. Progression-free survival (PFS) and overall survival (OS) were compared between different types. Results: As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. After the analysis of Ward's hierarchical clustering method, two dynamic types were found. In 61 patients, L858R increased to its highest level when disease progressed (ascend type), while in 19 patients, L858R maintained a stable level when disease progressed (stable type). Median PFS was 11.1 months (95% CI, 6.6-15.6) and 7.5 months (95% CI, 1.4-13.6) in patients with ascend and stable types, respectively (P = 0.023). Median OS was 19.7 months (95% CI, 16.5-22.9) and 16.0 months (95% CI, 13.4-18.5), respectively (P = 0.050). Conclusions: This is the first report finding two different dynamic types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different dynamic types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration. [ABSTRACT FROM AUTHOR]

Background: The risk of cardiovascular events remains high in patients with coronary heart disease (CHD) after successful percutaneous coronary intervention (PCI). Panax quinquefolius saponin, a major component of Xinyue capsule, has been used to treat patients with CHD. The aim of this study is to evaluate the efficacy and safety of Xinyue capsules in patients with CHD after PCI.Methods/design: This study is a multicenter, placebo-controlled, double-blind, randomized controlled clinical trial. A total of 1100 participants are randomly allocated to two groups: the intervention group and a placebo group. The intervention group receives Xinyue capsules plus conventional treatment, and the placebo group receives placebo capsules plus conventional treatment. The patients receive either Xinyue or placebo capsules three times daily (1.8 g/day) for up to 24 weeks. The primary outcome measure is the time from randomization to the first occurrence of major adverse cardiovascular events. The secondary outcome measure is the time from randomization to the first occurrence of stroke, pulmonary embolism, and peripheral vascular events, as well as death due to any cause. All outcome measures will be assessed at 12, 24, 36, and 48 weeks after randomization. Adverse events will be monitored during the trial.Discussion: The aim of this study is to evaluate the effects of Xinyue capsules on patients with CHD after interventional treatment. The results of this trial will provide critical evidence regarding Chinese herbal medicine treatment for CHD.Trial Registration: Chinese Clinical Trials Registry identifier ChiCTR-IPR-14005475. Registered on 10 November 2014. [ABSTRACT FROM AUTHOR]

Regulatory advice and assessment play an important role in the successful development of new drugs and radiopharmaceuticals for the treatment of urologic malignancies. Cooperation between the US Food and Drug Administration (FDA) and the pharmaceutical industry has led to the approval of more than 20 new urologic oncology products in the last 2 decades. Despite these advances, more effective treatments need to be developed and approved for the treatment of urologic malignancies. This review provides general information about the FDA׳s role in the development of investigational new drugs, with an emphasis on the regulatory process and the requirements for marketing approval. In addition, this review summarizes the products for the treatment of urologic malignancies that were approved by the FDA in the last 30 years and the key issues concerning urologic oncology products that were discussed publicly at Oncologic Drug Advisory Committee meetings in the past 10 years. [ABSTRACT FROM AUTHOR]

Objective: Although chondroprotective activities have been documented for polysaccharides, the potential target of different polysaccharide may differ. The study was aimed to explore the effect of glucan HBP-A in chondrocyte monolayer culture and chondrocytes-alginate hydrogel constructs in vivo, especially on the expression of type II collagen. Methods: Chondrocytes isolated from rabbit articular cartilage were cultured and verified by immunocytochemical staining of type II collagen. Chondrocyte viability was assessed after being treated with HBP-A in different concentrations. Morphological status of chondrocytes-alginate hydrogel constructs in vitro was observed by scanning electron microscope (SEM). The constructs were treated with HBP-A and then injected to nude mice subcutaneously. Six weeks after transplantation, the specimens were observed through transmission electron microscopy (TEM). The mRNA expressions of disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTs-5), aggrecan and type II collagen in both monolayer culture and constructs were determined by real time polymerase chain reaction (PCR). The expression of type II collagen and matrix metalloproteinases-3 (MMP-3) in chondrocyte monolayer culture was also tested through Western blot and enzyme linked immunosorbent assay (ELISA), respectively. Results: MMP-3 secretion and ADAMTs-5 mRNA expression in vitro were inhibited by HBP-A at 0.3 mg/mL concentration. In morphological study, there were significant appearance of collagen in those constructs treated by HBP-A. Accordingly, in both chondrocyte monolayer culture and chondrocytes-alginate hydrogel constructs, the expression of type II collagen was increased significantly in HBP-A group when compared with control group ( P<0.001). Conclusions: The study documented that the potential pharmacological target of glucan HBP-A in chondrocytes monolayer culture and tissue engineered cartilage in vivo may be concerned with the inhibition of catabolic enzymes MMP-3, ADAMTs-5, and increasing of type II collagen expression. [ABSTRACT FROM AUTHOR]

Background. Acupuncture is frequently advocated as an adjunct treatment for essential hypertension. The aim of this review was to assess its adjunct effectiveness in treating hypertension. Methods. We searched PubMed, the Cochrane Library, EMBASE, and the Chinese databases Sino-Med, CNKI, WanFang, and VIP through November, 2012, for eligible randomized controlled trials that compared acupuncture with sham acupuncture. Outcome measures were changes in diastolic (DBP) and systolic blood pressure (SBP). Results. A total of 4 randomized controlled trials were included. We found no evidence of an improvement with the fact that acupuncture relative to sham acupuncture in SBP change (n = 386; mean difference = -3.80 mmHg, 95% CI = -10.03- 2.44 mmHg; I2 = 99%), and an insignificant improvement in DBP change (n = 386; mean difference = -2.82 mmHg, 95% CI = -5.22-(-0.43) mmHg; I2 = 97%). In subgroup analyses, acupuncture significantly improved both SBP and DBP in patients taking antihypertensive medications. Only minor acupuncture-related adverse events were reported. Conclusions. Our results are consistent with acupuncture significantly lowers blood pressure in patients taking antihypertensive medications. We did not find that acupuncture without antihypertensive medications significantly improves blood pressure in those hypertensive patients. [ABSTRACT FROM AUTHOR]

It has been reported that lactoferrin (LF) participates in the host immune response against Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) invasion by enhancing NK cell activity and stimulating neutrophil aggregation and adhesion. We further investigated the role of LF in the entry of SARS pseudovirus into HEK293E/ACE2-Myc cells. Our results reveal that LF inhibits SARS pseudovirus infection in a dose-dependent manner. Further analysis suggested that LF was able to block the binding of spike protein to host cells at 4°C, indicating that LF exerted its inhibitory function at the viral attachment stage. However, LF did not disrupt the interaction of spike protein with angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV. Previous studies have shown that LF colocalizes with the widely distributed cell-surface heparan sulfate proteoglycans (HSPGs). Our experiments have also confirmed this conclusion. Treatment of the cells with heparinase or exogenous heparin prevented binding of spike protein to host cells and inhibited SARS pseudovirus infection, demonstrating that HSPGs provide the binding sites for SARS-CoV invasion at the early attachment phase. Taken together, our results suggest that, in addition to ACE2, HSPGs are essential cell-surface molecules involved in SARS-CoV cell entry. LF may play a protective role in host defense against SARS-CoV infection through binding to HSPGs and blocking the preliminary interaction between SARS-CoV and host cells. Our findings may provide further understanding of SARS-CoV pathogenesis and aid in treatment of this deadly disease. [ABSTRACT FROM AUTHOR]

Background and Aim: To profile changes of coagulation, anticoagulation and fibrolytic factors associated with liver function failure and portal vein thrombosis (PVT) formation in chronic liver cirrhosis patients. Methods: A total of 116 cirrhotic patients admitted to our hospital from June 2006 to October 2008 were included in our study. All patients were classified into two groups: PVT group (31 patients), composed of patients with PVT and a control group (85 patients), including patients without PVT. Platelet, prothrombin time (PT), activated partial prothrombin time (APTT) and fibrinogen were measured. Also, plasma samples from the patients were analyzed for the levels of antithrombin III (AT-III), protein C (PC), protein S (PS), D-dimer, tissue-type plasminogen activator as well as plasminogen activator inhibitor-1. Statistical analyses were carried out to evaluate the correlation of specific variations with the disease status. Results: In general, the higher Child-Pugh scores, indicating the aggravation of hepatic impairment of the patients, correlated well with the prolonged PT/APTT and increased D-dimer, as well as decreased platelet, fibrinogen, PC and AT-III levels in the serum. Furthermore, we found that the PC, PS and D-dimer levels in PVT patients were 2.32 ± 0.72 mg/L, 17.14 ± 3.62 mg/L and 0.99 ± 0.36 mg/L, respectively, both representing a significant difference compared with those in the control group without PVT. Logistic regression model shows that the odds ratio value of one unit of increase of PC and D-dimer were 0.48 and 15.57. Conclusions: Cirrhotic patients displayed dysfunctions in the coagulation, anti-coagulation and fibrolytic systems. The development of PVT in these patients may be independently associated with the decrease of PC, PS and D-dimer. Furthermore, decreasing PC and increasing D-dimer may be risk factors inducing PVT in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Taxane resistance is a common clinical problem in the treatment of many metastatic malignancies. Observational clues or evidence of overcoming such resistance is important for developing treatments that can extend taxane activity. We report a case of the reversal of docetaxel resistance with the addition of antiangiogenic agents bevacizumab and thalidomide to docetaxel and prednisone in a patient with metastatic castration-resistant prostate cancer after PSAWG progression on docetaxel and prednisone. The patient then responded for an additional 7 months. The addition of bevacizumab and thalidomide after progression on docetaxel/prednisone might reverse docetaxel resistance. These or other antiangiogenic agents for overcoming clinical taxane resistance are candidates for further study. [ABSTRACT FROM AUTHOR]

Marek's disease (MD) is lymphoproliferative neoplastic disease in chickens, which is caused by Marek's disease virus (MDV). Our previous study profiled microRNA (miRNA) transcriptome in MD lymphoma, and found that gga-miR-199-3p, gga-miR- 140-3p, and gga-miR-221-5p were down-regulated in MD lymphoma. In this study, we further investigated their differential expression between MDV-infected spleens and noninfected spleens at 4, 7, 14, 21, and 28 d postinfection (dpi) to elucidate whether deregulation of them was specific to late tumor transformation phase or not. The results showed that ggamiR- 199-3p was down-regulated at 14 and 28 dpi, and the expression of gga-miR-140-3p was decreased at 14 dpi, which indicated that deregulation of these miRNAs appeared since early stage of MD tumor transformation. Additionally, the inhibitory effects of gga-miR-199-3p, gga-miR-140-3p, and gga-miR-221- 5p on MDV-transformed lymphoid cell line (MSB1) cells proliferation were observed, which suggested that these miRNAs acted as MD tumor suppressors. Their aberrant expression at early tumor transformation phase and suppressive role in cell proliferation indicated that they were involved in MD lymphoma transformation, and might play crucial roles in MD tumorigenesis. [ABSTRACT FROM AUTHOR]