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Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro , and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.

Guangzhou, one of China's megacities, is beset with frequent occurrence of high-concentration ozone events. In this study, online instruments were used to simultaneously monitor ozone, nitrogen oxides (NOx) and volatile organic compounds (VOCs) at GPACS (the Guangzhou Panyu Atmospheric Composition Station) of the China Meteorological Administration, from June 2011 to May 2012, in order to determine their characteristics, the effect of VOCs on ozone photochemical production and the relationship between VOC / NOx ratio and ozone formation. The results showed that during the observation period, the seasonal variation of ozone concentration was lower in spring and winter compared to summer and autumn, which is opposite that for VOCs and NOx. In terms of VOCs, aromatics had the largest ozone formation potential, among which toluene, xylenes, ethylbenzene, 1,2,4-trimethylbenzene and 1,3,5-trimethylbenzene were the most important species, with a total contribution of about 44%. As the VOC / NOx ratios were very high during high-concentration ozone events that occur all year round, we speculate ozone production was likely to be NOx-limited regime (12:00-16:00 LT) in Guangzhou. Further investigation based on numerical models is needed in the future to obtain more detailed and robust conclusions.

Background Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients’ treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. Methods Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. Results Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. Conclusions This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

Prostate cancer cells escape growth inhibition from transforming growth factor β (TGFβ) by downregulating TGFβ receptors. However, the mechanism by which cancer cells downregulate TGFβ receptors in prostate is not clear. Here, we showed that coordinated action of miR-21 and androgen receptor (AR) signaling had a critical role in inhibiting TGFβ receptor II (TGFBR2) expression in prostate cancer cells. Our results revealed that miR-21 suppresses TGFBR2 levels by binding to its 3′-UTR and AR signaling further potentiates this effect in both untransformed and transformed human prostate epithelial cells as well as in human prostate cancers. Analysis of primary prostate cancers showed that increased miR-21/AR expression parallel a significantly reduced expression of TGFBR2. Manipulation of androgen signaling or the expression levels of AR or miR-21 negatively altered TGFBR2 expression in untransformed and transformed human prostate epithelial cells, human prostate cancer xenografts and mouse prostate glands. Importantly, we demonstrated that miR-21 and AR regulated each other’s expression resulting in a positive feedback loop. Our results indicated that miR-21/AR mediate its tumor-promoting function by attenuating TGFβ-mediated Smad2/3 activation, cell growth inhibition, cell migration and apoptosis. Together, these results suggest that the AR and miR-21 axis exerts its oncogenic effects in prostate tumors by downregulating TGFBR2, hence inhibiting the tumor-suppressive activity of TGFβ pathway. Targeting miR-21 alone or in combination with AR may restore the tumor inhibitory activity of TGFβ in prostate cancer.

The chemical composition, size, shape and surface characteristics of nanoparticles affect the way proteins bind to these particles, and this in turn influences the way in which nanoparticles interact with cells and tissues 1 , 2 , 3 , 4 , 5 . Nanomaterials bound with proteins can result in physiological and pathological changes, including macrophage uptake 1 , 6 , blood coagulation 7 , protein aggregation 8 and complement activation 7 , 9 , but the mechanisms that lead to these changes remain poorly understood. Here, we show that negatively charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen, which promotes interaction with the integrin receptor, Mac-1. Activation of this receptor increases the NF-κB signalling pathway, resulting in the release of inflammatory cytokines. However, not all nanoparticles that bind to fibrinogen demonstrated this effect. Our results show that the binding of certain nanoparticles to fibrinogen in plasma offers an alternative mechanism to the more commonly described role of oxidative stress in the inflammatory response to nanomaterials. Polymer-coated nanoparticles of a certain size can unfold fibrinogen and induce the binding of an integrin receptor that triggers the release of inflammatory signals.

Purpose: Biopiezoelectric materials have good biocompatibility and excellent piezoelectric properties, and they can generate local currents in vivo to restore the physiological electrical microenvironment of the defect and promote bone regeneration. Previous studies of guided bone regeneration membranes have rarely addressed the point of restoring it, so this study prepared a Barium titanate/ Polylactic acid (BT/PLA) piezoelectric composite membrane and investigated its bone-formation, with a view to providing an experimental basis for clinical studies of guided bone tissue regeneration membranes. Methods: BT/PLA composite membranes with different BT ratio were prepared by solution casting method, and piezoelectric properties were performed after corona polarization treatment. The optimal BT ratio was selected and then subjected to in vitro cytological experiments and in vivo osteogenic studies in rats. The effects on adhesion, proliferation and osteogenic differentiation of the pre-osteoblastic cell line (MC3T3-E1) were investigated. The effect of composite membranes on bone repair of cranial defects in rats was investigated after 4 and 12 weeks. Results: The highest piezoelectric coefficient d33 were obtained when the BT content was 20%, reaching (7.03 [+ or -] 0.26) pC/N. The value could still be maintained at (4.47 [+ or -] 0.17) pC/N after 12 weeks, meeting the piezoelectric constant range of bone. In vitro, the MC3T3-E1 cells showed better adhesion and proliferative activity in the group of polarized 20%BT. The highest alkaline phosphatase (ALP) content was observed in cells of this group. In vivo, it promoted rapid bone regeneration. At 4 weeks postoperatively, new bone formation was evident at the edges of the defect, with extensive marrow cavity formation; after 12 weeks, the defect was essentially completely closed, with density approximating normal bone tissue and significant mineralization. Conclusion: The BT/PLA piezoelectric composite membrane has good osteogenic properties and provides a new idea for guiding the research of membrane materials for bone tissue regeneration. Keywords: barium titanate, polylactic acid, bio-piezoelectric materials, polarization, osteogenic differentiation, bone regeneration

Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure ( p O 2 ) and decreased O 2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine–threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis -acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3′-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR’s regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

Tetracycline antibiotics (TCs) are a broad-spectrum antibiotic, widely used in livestock and poultry breeding. Residue of tetracycline antibiotics in animal manure may cause changes in vegetable TCs content and soil microbial community. On the basis of the investigation and analysis of TCs pollution in the soil of main vegetable bases and the livestock manure of major large-scale farms in Chongqing, China, field experiment was conducted to study the residues of tetracycline antibiotics in Brassica juncea var. gemmifera and soil under different kinds and different dosages of livestock manures. Effects of tetracycline antibiotics on the structure and diversity of soil microbial community were also investigated by high-throughput sequencing. TCs content in soil was increased by applying livestock manure. The contents of tetracycline, oxytetracycline (OTC) and chlortetracycline (CTC) in the soil under pig manure treatment were 171.07–660.20 μg kg−1, 25.38–345.78 μg kg−1 and 170.77–707.47 μg kg−1, respectively. The contents of TC, OTC and CTC in the soil under the treatment of chicken manure were 166.62–353.61 μg kg−1, 122.25–251.23 μg kg−1 and 15.12–80.91 μg kg−1, respectively. TCs in edible parts of Brassica juncea var. gemmifera was increased after livestock manure treatment Proteobacteria, Acidobacteria, Actinobacteria, Chioroflexi and Bacteroidetes under livestock manure treatment were the dominant phyla, accounting for 85.2–92.4% of the total abundance of soil bacteria. The soil OTUs under the treatment of pig manure was higher than that under the treatment of chicken manure. Biogas residue (Livestock manure after fermentation treatment) can effectively reduce the environmental and ecological risks caused by antibiotic residues.

Context: Zinc-α2-glycoprotein (ZAG) was found to influence lipolysis in adipose tissue and has recently been proposed as a candidate factor in the regulation of body weight. Objective: To elucidate the association of serum ZAG level with body weight and percentage of body fat in normal, obese subjects and high-fat diet (HFD)-induced obese mice. Design: The relationship between serum ZAG and obesity-related parameters was studied in 44 human subjects and 36 mice fed standard food and HFD. Furthermore, the effects of ZAG overexpression on adipose tissue of mice was also evaluated by using a liposome transfection method. Results: Serum ZAG level was significantly lower in obese patients and obese mice in comparison to that in people and mice with normal weight. The further statistical analysis demonstrated that ZAG level was negatively correlated with body weight (r=-0.62, P<0.001), body mass index (r=-0.64, P<0.001), waist circumference(r=-0.68, P<0.001), hip circumference (r=-0.60, P<0.001), percentage of body fat (r=-0.52, P=0.03) and fat mass(r=-0.59, P=0.01) in human subjects after adjustment for age and sex. Furthermore, ZAG overexpression in mice reduced body weight and the percentage of epididymal fat. The decreased FAS, ACC1 and DGAT mRNA and the increased HSL mRNA were also observed in epididymal adipose tissue in ZAG overexpression mice. Conclusion: ZAG is closely linked to obesity. Serum ZAG level is inversely associated with body weight and percentage of body fat. The action of ZAG is associated with downregulated lipogenic enzymes and upregulated lipolytic enzyme expressions in adipose tissue of mice.