Summary Accumulating evidence suggests that co-deletion of tumor suppressor genes Pten and p53 plays a crucial role in the development of castration-resistant prostate cancer in vivo. However, the molecular mechanism underlying Pten/p53-deficiency driven prostate tumorigenesis remains incompletely understood. Building upon insights gained from our studies with Pten/p53-deficient mouse embryonic fibroblasts (MEFs), we report here that hexokinase 2 (HK2) is selectively upregulated by the combined loss of Pten and p53 in prostate cancer cells. Mechanistically, Pten deletion increases HK2 mRNA translation through activation of the AKT-mTORC1-4EBP1 axis and p53 loss enhances HK2 mRNA stability through inhibition of miR143 biogenesis. Genetic studies demonstrate that HK2-mediated aerobic glycolysis, known as the Warburg effect, is required for Pten/p53-deficiency driven tumor growth in xenograft mouse models of prostate cancer. Our findings suggest that HK2 might be a therapeutic target for prostate cancer patients carrying Pten and p53 mutations.

Nitrogen, phosphorus and oxygen tri-doped porous graphite carbon@oxidized carbon cloth electrodes exhibit excellent activity and durability for full water splitting at all pH values.

It suggests that TLR4 negatively regulates paclitaxel chemotherapy and MyD88 is an essential downstream factor to TLR4 signalling for this resistance. Knockdown of TLR4 induces paclitaxel chemosensitivity which might depress the Akt pathway. The TLR4-MyD88 signalling represents an important source to promote tumour growth.

Endoscopy is a clinical gold standard to exam the interior of a hollow organ or body cavity. For the first of time, this study presents the design and construction of a fluorescent endoscopic system that harnesses the power of the second near‐infrared window II (NIR‐II) fluorescence imaging. An NIR‐II fluorescent molecular probe, indocyanine green (ICG) conjugated bevacizumab (Bev‐ICG) that targets vascular endothelial growth factor (VEGF), is successfully synthesized and evaluated along with the NIR‐II endoscopy imaging system. Simultaneous NIR‐II fluorescence and white‐light (WL) imaging of VEGF is validated in an orthotopic rat colorectal cancer model. This NIR‐II endoscopy system is a generalizable design, and it is compatible with the most of current clinic endoscopies. Similar hardware upgrades are expected to greatly promote the application of NIR‐II fluorescent imaging in the clinic.

Metal surfaces with intrinsic chirality play an irreplaceable role in many significant enantioselective chemical processes such as enantioselective catalysis, sensing, and separation. Nonetheless, current methods for the precise preparation of such chiral surfaces suffer with issues of unscalable production and low surface areas. Herein, we report the synthesis of chiral Au nanoparticles with precisely determined homochiral facets. Though a scalable wet chemical method, {125̅8}R and {85̅12}S high-Miller-index facets are obtained with the l- and d-chiral Au nanocrystals, respectively. The growth process of these homochiral facets is investigated, and a new nanocrystal growth pathway is revealed. More importantly, the remarkable enantioselective recognition properties of these homochiral surfaces are demonstrated and enable an efficient electrochemical method for chiral discrimination of l-/d -tryptophan. These results provide a foundation of fundamental studies of heterogeneous enantioselective processes and may pave way for the development of nanocatalysts for enantioselective chemistry.

Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC) patients who have developed resistance to the second generation anti-androgen receptor (AR) axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT) in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten −/p53-deficiency-driven CRPC mouse model. Mechanistically, 2-DG causes AMPK phosphorylation, which in turn inhibits mTORC1-S6K1 translation signaling to preferentially block anti-apoptotic protein MCL-l synthesis to prime mitochondria-dependent apoptosis while simultaneously activates ULK1-driven autophagy for cell survival to counteract the apoptotic action of anti-Warburg effect. Accordingly, inhibition of autophagy with CQ sensitizes cancer cells to apoptosis upon 2-DG challenge. Given that 2-DG is recommended for phase II clinical trials for prostate cancer and CQ has been clinically used as an anti-malaria drug for many decades, the preclinical results from our proof-of-principle studies in vivo are imminently translatable to clinical trials to evaluate the therapeutic efficacy by the combination modality for a subset of currently incurable CRPC harboring PTEN and TP53 mutations.

Background. Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined. Methods. Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies. Results. Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (all P < 0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (all P < 0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies. Conclusion. It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.

In ovarian cancer patients, chemotherapy resistance is the principal factor restricting long-term treatment. Paclitaxel (Pac) has been previously reported to be a ligand to Toll-like receptor 4 (TLR4). It was determined that TLR4 signaling is divided into the following two pathways: Myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent. The present study investigated the effect of TLR4 ligation by Pac in MyD88-positive (MyD88+) and MyD88-negative (MyD88−) human ovarian cancer cell lines. An RNA interference expression vector was specifically constructed to target TLR4 mRNA, which was stably transfected into the human ovarian cancer cell lines (SKOV3, OVCAR3, A2780 and 3AO). Cytokines, including interleukin (IL)-6 and IL-8, were detected. Cell proliferation and apoptosis were assessed in the cells transfected with scramble control and TLR4 shRNA to explore the possible functions of TLR4 in ovarian cancer cell growth. It was found that lipopolysaccharide and Pac significantly increase the secretion of IL-6 and IL-8 in the SKOV3 cell line. Similarly, Pac resulted in a significant upregulation of IL-6 and IL-8 in OVCAR3 cells, but not in A2780 and 3AO cells. These results suggested that in MyD88+ ovarian cancer cell lines, TLR4 depletion shows increased sensitivity to Pac treatment in inhibiting cell proliferation compared with in cells without TLR4 knockdown. On the contrary, such changes were not found in MyD88− cells (A2780 and 3AO). TLR4 negatively regulates Pac chemotherapy, particularly in terms of cell proliferation, and TLR4 may be a novel treatment target in Pac-resistant ovarian cancer.