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Background Triple-negative breast cancer (TNBC) is often aggressive and associated with a poor prognosis. Due to the lack of available targeted therapies and to problems of resistance with conventional chemotherapeutic agents, finding new treatments for TNBC remains a challenge and a better therapeutic strategy is urgently required. Methods TNBC cells and xenograft mice were treated with a combination of chloroquine (CQ) and isorhamnetin (IH). Mitochondrial fission, apoptosis, and related signaling pathways were determined by flow cytometry, immunofluorescence, and related molecular biological techniques. Results The inhibition of autophagy/mitophagy by CQ selectively enhances IH-induced mitochondrial fission and apoptosis in TNBC cells but not in estrogen-dependent breast cancer cells. These events were accompanied by mitochondrial translocation of Bax and the release of cytochrome c. Mechanistically, these effects were associated with oxidative stress-mediated phosphorylation of CaMKII (Thr286) and Drp1 (S616), and subsequent mitochondrial translocation of CaMKII and Drp1. The interruption of the CaMKII pathway by genetic approaches (e.g. CaMKII mutant or siRNA) attenuated combination-mediated mitochondrial fission and apoptosis. The combination of CQ/IH was a marked inhibitor tumor growth, inducing apoptosis in the TNBC xenograft mouse model in association with the activation of CaMKII and Drp1 (S616). Conclusions Our study highlights the critical role of ROS-mediating CaMKII/Drp1 signaling in the regulation of mitochondrial fission and apoptosis induced by combination of CQ/IH. These findings also suggest that IH could potentially be further developed as a novel chemotherapeutic agent. Furthermore, a combination of IH with classic autophagy/mitophagy inhibitor could represent a novel therapeutic strategy for the treatment of TNBC.

Objective To investigate the association of long-term changes in body mass index, waist circumference, and waist-to-height ratio with the risk of type 2 diabetes mellitus in the older population. Methods We conducted a prospective cohort study in Jiangsu Province, China. Data from 593 participants who were aged ≥60 years were analyzed. The hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model. Results Over a median follow-up period of 5.08 years, 70 participants (11.80%) developed type 2 diabetes mellitus. Compared with participants with persistently normal body mass index, waist circumference, and waist-to-height ratio, those in whom these parameters changed from normal to abnormal and those in whom these parameters were persistently abnormal had a significantly higher risk of type 2 diabetes mellitus, with adjusted hazard ratios of 2.11 (95% confidence interval: 1.05–4.26) and 2.37 (95% confidence interval: 1.21–4.63) for body mass index, 2.75 (95% confidence interval: 1.16–6.51) and 2.32 (95% confidence interval: 1.29–4.16) for waist circumference, and 2.24 (95% confidence interval: 1.14–5.91) and 4.11 (95% confidence interval: 2.21–7.68) for waist-to-height ratio, respectively. Conclusion Long-term changes in obesity-related anthropometric indicators are strongly associated with the risk of type 2 diabetes mellitus in the older population.

Background Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular mechanism for lysosomal degradation of damaged cellular components. The specific degradation of nuclear components by the autophagy pathway is called nucleophagy. Most studies have focused on autophagic turnover of cytoplasmic materials, and little is known about the role of autophagy in the degradation of nuclear components. Methods Human MDA-MB-231 and MCF-7 breast cancer cell lines were used as model systems in vitro. Induction of nucleophagy by nuclear DNA leakage was determined by western blot and immunofluorescence analyses. The interaction and colocalization of LC3 and lamin A/C was determined by immunoprecipitation and immunofluorescence. The role of the SUMO E2 ligase, UBC9, on the regulation of SUMOylation of lamin A/C and nucleophagy was determined by siRNA silencing of UBC9, and analyzed by immunoprecipitation and immunofluorescence. Results DNA damage induced nuclear accumulation of UBC9 ligase which resulted in SUMOylation of lamin A/C and that SUMOylation of this protein was required for the interaction between the autophagy protein LC3 and lamin A/C, which was required for nucleophagy. Knockdown of UBC9 prevented SUMOylation of lamin A/C and LC3-lamin A/C interaction. This attenuated nucleophagy which degraded nuclear components lamin A/C and leaked nuclear DNA mediated by DNA damage. Conclusions Our findings suggest that nuclear DNA leakage activates nucleophagy through UBC9-mediated SUMOylation of lamin A/C, leading to degradation of nuclear components including lamin A/C and leaked nuclear DNA.

Binarization plays an important role in document analysis and recognition (DAR) systems. In this paper, we present our winning algorithm in ICFHR 2018 competition on handwritten document image binarization (H-DIBCO 2018), which is based on background estimation and energy minimization. First, we adopt mathematical morphological operations to estimate and compensate the document background. It uses a disk-shaped structuring element, whose radius is computed by the minimum entropy-based stroke width transform (SWT). Second, we perform Laplacian energy-based segmentation on the compensated document images. Finally, we implement post-processing to preserve text stroke connectivity and eliminate isolated noise. Experimental results indicate that the proposed method outperforms other state-of-the-art techniques on several public available benchmark datasets.

A number of research have proven that antimicrobial peptides are of greatest potential as a new class of antibiotics. Antimicrobial peptides and cell-penetrating peptides share some similar structure characteristics. In our study, a new peptide analog, APP (GLARALTRLLRQLTRQLTRA) from the cell-penetrating peptide ppTG20 (GLFRALLRLLRSLWRLLLRA), was identified simultaneously with the antibacterial mechanism of APP against Salmonella typhimurium and Streptococcus pyogenes . APP displayed potent antibacterial activity against Gram-negative and Gram-positive strains. The minimum inhibitory concentration was in the range of 2 to 4 μM. APP displayed higher cell selectivity (about 42-fold increase) as compared to the parent peptide for it decreased hemolytic activity and increased antimicrobial activity. The calcein leakage from egg yolk l -α-phosphatidylcholine (EYPC)/egg yolk l -α-phosphatidyl- dl -glycerol and EYPC/cholesterol vesicles demonstrated that APP exhibited high selectivity. The antibacterial mechanism analysis indicated that APP induced membrane permeabilization in a kinetic manner for membrane lesions allowing O -nitrophenyl-β- d -galactoside uptake into cells and potassium release from APP-treated cells. Flow cytometry analysis demonstrated that APP induced bacterial live cell membrane damage. Circular dichroism, fluorescence spectra, and gel retardation analysis confirmed that APP interacted with DNA and intercalated into the DNA base pairs after penetrating the cell membrane. Cell cycle assay showed that APP affected DNA synthesis in the cell. Our results suggested that peptides derived from the cell-penetrating peptide have the potential for antimicrobial agent development, and APP exerts its antibacterial activity by damaging bacterial cell membranes and binding to bacterial DNA to inhibit cellular functions, ultimately leading to cell death.

Background While the phenotypic link between body mass index (BMI) and some female reproductive disorders is well established, the genetic architecture and causal relationships have not been systematically studied. We aimed to create an atlas of the shared genetic associations of BMI and 16 female reproductive disorders and to identify their common risk loci, biological pathways, and potential mechanisms. Methods We assessed the genetic correlations between BMI and 16 reproductive disorders using summary data from large-scale genome-wide association studies. Cross-trait pleiotropic analysis identified shared loci and genes, while functional annotation and tissue-specific analysis revealed relevant biological pathways and tissues. Multi-trait colocalization analysis examined the role of hormones and metabolites in these traits. Additionally, bidirectional Mendelian randomization (MR) analysis was employed to assess causal relationships between BMI and reproductive outcomes. We also conducted summary data-based MR (SMR) analysis to identify potential drug targets. Results Our results revealed a significant genetic correlation between BMI and eight female reproductive diseases. Furthermore, we identified 50 shared pleiotropic loci between BMI and these traits, with 21 of them showing significant colocalization, suggesting a complex shared genetic architecture across the genome. In addition, the top biological pathways and tissues enriched with these pleiotropic loci were associated with RNA metabolism, macromolecule biosynthesis, type B pancreatic cell apoptosis, various brain regions, and the pituitary. Moreover, multi-trait colocalization indicated that insulin, lipid metabolites, glucose, glycine, and glutamine mediate shared mechanisms between BMI, gestational diabetes mellitus (GDM), and endometrial cancer. MR analysis suggested BMI may cause several reproductive diseases, with only GDM affecting BMI reversely. Finally, SMR analysis revealed EIF2S2P3 and MCM6 , which may have a causative effect on both BMI & GDM and BMI & gestational hypertension. Conclusion Our results suggest a significant genetic link between BMI and eight female reproductive diseases, highlighting a shared and causal genetic basis. Reducing BMI in women may serve as an effective strategy to lower the risk of female reproductive disorders. The identified pleiotropic loci, genes, and shared pathways could provide new therapeutic targets for both obesity and reproductive diseases, along with their comorbidities. Clinical trial number Not applicable.

The regiospecific distribution of fatty acids (FAs) and composition of triglyceride (TAG) molecular species of fishes were analyzed and calculated by pancreatic lipase (PL) hydrolysis and Visual Basic (VB) program. DHA was preferentially located at sn-2 position in TAG molecule, whereas EPA was almost equally distributed in each position of glycerol backbone. DOP, DPP, EPP, PoPP, PPO, and PPP were the predominant TAG species. MPP in anchovy, DDP, DOP, DPP in tuna, and EOO and OOO in salmon were the characteristic TAG molecules, which were meaningful to differentiate marine fish oils. Furthermore, the data management, according to TCN and ECN, was firstly applied to classify the TAG molecular species. The ECN42, ECN46, and ECN48 groups were rich in TAGs. The lower ECN values, compared to the higher TCN values, indicated that the most abundant TAGs exhibited a higher unsaturated degree. Therefore, our study not only offered a simple and feasible approach for the analysis of TAG composition but also firstly summarized the information by data management within ECN and TCN.

Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m2 (day 1), gemcitabine 1 g/m2 (days 1 and 8) and oxaliplatin 130 mg/m2 (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

Structural fractures generally develop in the upper crust strata and are usually distributed in a convergent pattern, forming structural fracture zones with a specific strike. Fracture zones control the reservoir seepage system and seriously affect the migration and accumulation of oil and gas in tight sandstone reservoirs. Therefore, characterizing the characteristics of the fracture zones for tight oil exploration and development effectively is essential. In this paper, the variable scale fractal method is introduced to calculate the petrophysical log, and a new curve H is built. An intensity log is to characterize the intensity of structural fracture development. The H curve is in a good linear relationship with the intensity curve after the comparison of the H curve and intensity curve in 32 wells. A quantitative relationship between H and the intensity curve is established. Based on the parameters obtained from the core and image logs, the discrete fracture network model was established using H curves from more than 300 wells, and the structural fracture zone was analyzed. The model shows that the fracture zones formed by structural fractures are in S-N and NW-SE directions in the study area. The orientation of the structural fracture zone is consistent with that of the fractured fault zone and fault, and the development of the fractured zone is consistent with the regional tectonic evolution characteristics. The characteristics of the fracture zone explain the distribution law of oil accumulation and groundwater salinity in the study area.

Increasing evidences reveal that autophagy inhibitor could enhance the effect of chemotherapy to cancer. However, few autophagy inhibitors are currently approved for clinical application in humans. Berbamine (BBM) is a natural compound extracted from traditional Chinese medicine that is widely used for treatment of a variety of diseases without any obvious side effects. Here we found that BBM is a novel auophagy inhibitor, which potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human breast cancer cells. Mechanistically, we found that BBM blocked autophagosome-lysosome fusion by inhibiting the interaction of SNAP29 and VAMP8. Furthermore, BBM induced upregulation of BNIP3 and the interaction between SNAP29 and BNIP3. BNIP3 depletion or SNAP29 overexpression abrogated BBM-mediated blockade of autophagosome-lysosome fusion through the interaction between SNAP29 and VAMP8, whereas BNIP3 overexpression blocked autophagosome-lysosome fusion through inhibition of the interaction between SNAP29 and VAMP8. These findings suggest that upregulation of BNIP3 and interaction between BNIP3 and SNAP29 could be involved in BBM-mediated blockade of autophagosome-lysosome fusion through inhibition of the interaction between SNAP29 and VAMP8. Our findings identify the critical role of BNIP3 in blockade of autophagosome-lysosome fusion mediated by BBM, and suggest that BBM could potentially be further developed as a novel autophagy inhibitor, which could enhance the effect of chemotherapy to cancer.