Purpose: Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.Experimental Design: The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.Results: We showed that JQ1 induced marked G 1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21 CIP1/WAF1 , hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21 CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest.Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors. Conclusion: Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors.

To determine whether Bmi-1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3-week-old Bmi-1-/- mice were treated with the antioxidant N-acetylcysteine (NAC, 1 mg mL−1) in their drinking water, or pyrro-quinoline quinone (PQQ, 4 mg kg−1 diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle-treated Bmi1-/- and wild-type mice. Bmi-1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five-week-old vehicle-treated Bmi-1-/- mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi-1-/- mice; subsequently, this caused DNA damage, the activation of TGF-β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress-induced epithelial-to-mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi-1 knocked down HK2 cells. All phenotypic alterations caused by Bmi-1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury.

FGF23 may also contribute to CVD. Prevention of Klotho decline, reactivation of endogenous Klotho production, or supplementation of exogenous Klotho attenuate renal fibrosis, retard CKD progression, improve mineral metabolism, ameliorate cardiomyopathy, and alleviate vascular calcification in CKD. However, the poor CVD outcome after depletion of FGF23 with FGF23 antibody stimulates the generation of a more specific inhibitor of FGF23 for CKD treatment. Key Message: Klotho/FGF23 may not only be diagnostic and/or prognostic biomarkers for CKD and CVD, but are also pathogenic contributors to CKD progression and CVD development. The Klotho/FGF23 axis should be a novel target for renal clinics.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

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Sarcopenia is an age-related geriatric syndrome that is characterized by a progressive loss of muscle mass, strength and function. Chronic heart failure (CHF), the final stage of various cardiovascular diseases, may be closely correlated with the occurrence of sarcopenia. Accumulating evidence has demonstrated that CHF can promote the development of sarcopenia through multiple pathophysiological mechanisms, including malnutrition, inflammation, hormonal changes, oxidative stress, autophagy, and apoptosis. Additionally, CHF can aggravate the adverse outcomes associated with sarcopenia, including falls, osteoporosis, frailty, cachexia, hospitalization, and mortality. Sarcopenia and CHF are mutually interacting clinical syndromes. Patients with these two syndromes seem to endure a double burden, with no particularly effective way to hinder their progression. However, the combination of physical exercise, nutritional supplements, and drug therapy may counteract the development of these maladies. In this review, we will summarize the latest progress in the pathogenesis and treatment of sarcopenia in patients with CHF.

BackgroundEnhanced motility of cancer cells is a critical step in promoting tumor metastasis. Lysophosphatidic acid (LPA), representing the major mitogenic activity in serum, stimulates migration in various types of cancer cells. However, the underlying signaling mechanisms for LPA-induced motility of cancer cells remain to be elucidated.Methodology/Principal FindingsIn this study, we found that LPA dose-dependently stimulated migration of MDA-MB-231 breast cancer cells, with 10 µM being the most effective. LPA also increased ERK activity and the MEK inhibitor U0126 could block LPA-induced ERK activity and cell migration. In addition, LPA induced PAK1 activation while ERK activation and cell migration were inhibited by ectopic expression of an inactive mutant form of PAK1 in MDA-MB-231 cells. Furthermore, LPA increased PI3K activity, and the PI3K inhibitor LY294002 inhibited both LPA-induced PAK1/ERK activation and cell migration. Moreover, in the breast cancer cell, LPA treatment resulted in remarkable production of reactive oxygen species (ROS), while LPA-induced ROS generation, PI3K/PAK1/ERK activation and cell migration could be inhibited by N-acetyl-L-Cysteine, a scavenger of ROS.Conclusions/SignificanceTaken together, this study identifies a PI3K/PAK1/ERK signaling pathway for LPA-stimulated breast cancer cell migration. These data also suggest that ROS generation plays an essential role in the activation of LPA-stimulated PI3K/PAK1/ERK signaling and breast cancer cell migration. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis.

BackgroundThe goal of this study was to assess the association between endometrial thickness on the chorionic gonadotropin (hCG) day and in vitro fertilization and embryo transfer (IVF-ET) outcome in normal responders after GnRH antagonist administration.MethodsA retrospective cohort study was performed in normal responders with GnRH antagonist administration from January 2011–December 2013. Patients were divided into four groups according to endometrial thickness, as follows: <7 mm (group 1), > = 7- < 8 mm (group 2), > = 8- < 14 mm (group 3), and > =14 mm (group 4).ResultsA total of 2106 embryo transfer cycles were analyzed. The pregnancy rate (PR) was 44.87%.The clinical pregnancy rate, ongoing pregnancy rate and the implantation rate (17.28%, 13.79%, 10.17%, respectively) were significantly lower in group 1 compared to the other three groups (p < 0.05). The miscarriage rate was higher in patients with endometrial thickness less than 7 mm. The clinical pregnancy rate, ongoing pregnancy rate and implantation rate were highest in patients with endometrial thickness higher than 14 mm, but showed no difference in patients with those of endometrial thickness between 8-14 mm.ConclusionsThere is a correlation between endometrial thickness measured on hCG day and clinical outcome in normal responders with GnRH antagonist administration. The pregnancy rate was lower in patients with endometrial thickness less than 7 mm compared with patients with endometrial thickness more than 7 mm.