Explore the vast range of titles available.

تلقي الرواية الضوء على منطقة مجهولة جغرافيا وتاريخيا من الصين، وهي منطقة غير مألوفة للقارئ العربي، وتثير داخله شعورا مبهما بالسحر والغموض، ويتوازى بالرواية مساران سرديان، يروي المسار الرئيسي التغيرات التاريخية للتبت على مدار الخمسين عاما الماضية، وتحول بطل الرواية (جين مي وانغ تشا) من شخصية الراهب إلى العلماني، ويصف التمرد المسلح للمتشددين، والإصلاح الديمقراطي، ونشوب الحرب بين الصين والهند، وغيرها من الأحداث التاريخية الكبرى لتاريخ التبت، ومع الصعود والهبوط في مصير العديد من الشخصيات الصغيرة، تعرض الرواية النظرة التبتية حول مفهوم الموت والحياة وفهم وتجاوز المعاناة المتعلقة بحياة المعلم البوذي.‪‪‪‪‪‪‪‪‪‪

Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18–70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0–1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4–26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7–25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523–0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16–9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76–7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1–4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1–4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer. Shanghai Natural Science Foundation.

ObjectiveAutophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis.DesignGain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.ResultsThe expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.ConclusionsDysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients’ responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

Background Recent studies have shown that the presence of systemic inflammation correlates with poor survival in various cancers. The aim of this study was to determinate the prognostic value of the neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) in patients with esophageal squamous cell carcinoma (ESCC). Methods Preoperative NLR and PLR were evaluated in 483 patients undergoing esophagectomy for ESCC from January 2005 to December 2008. The prognostic significance of both markers was then determined by both uni- and multivariate analytical methods. Receiver operating characteristic (ROC) curves were also plotted to verify the accuracy of NLR and PLR for survival prediction. Results High preoperative NLR (≥3.5 versus  < 3.5, P  = 0.039) and PLR (≥150 versus  < 150, P  < 0.001) were significantly associated with poor overall survival in multivariate analysis. However, our study demonstrated a better discrimination for the PLR in terms of hazard ratio(HR) than the NLR (HR = 1.840 versus HR = 1.339). Patients with NLR ≥3.5 had significantly poorer overall survival compared to NLR <3.5 (35.4% versus 57.7%, P  < 0.001). Patients with PLR ≥150 also had significantly poorer overall survival compared to patients with PLR <150 (32.7% versus 63.5%, P  < 0.001). The area under the curve (AUC) was 0.658 (95% confidence interval (CI): 0.610 to 0.706, P  < 0.001) for NLR and 0.708 (95% CI: 0.662 to 0.754, P  < 0.001) for PLR, indicating that PLR was superior to NLR as a predictive factor in ESCC. Conclusions Preoperative NLR and PLR were significant predictors of overall survival in patients with ESCC. However, PLR is superior to NLR as a predictive factor in patients with ESCC.

The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19. •Molecular docking has been used for the search of possible medications that fall under the approved bioactive that may inhibit the SARS-CoV-2 spike protein and the 3CLPRO protease.•Several exciting hits on the 3CLPRO main proteinase are Zanamivir, Indinavir, Remdesivir, and Saquinavir.•Flavin Adenine Dinucleotide (FAD) Adeflavin, a B2 Deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of COVID-19.

Silicon (Si) alleviates cadmium (Cd) toxicity and accumulation in a number of plant species, but the exact molecular mechanisms responsible for this effect are still poorly understood. Here, we investigated the effect of Si on Cd toxicity and accumulation in rice (Oryza sativa) by using two mutants (lsi1 and lsi2) defective in Si uptake and their wild types (WTs). Root elongation was decreased with increasing external Cd concentrations in both WTs and mutants, but Si did not show an alleviative effect on Cd toxicity in all lines. By contrast, the Cd concentration in both the shoots and roots was decreased by Si in the WTs, but not in the mutants. Furthermore, Si supply resulted in a decreased Cd concentration in the root cell sap and xylem sap in the WTs, but not in the mutants. Pre-treatment with Si also decreased Cd accumulation in the WTs, but not in the mutants. Silicon slightly decreased Cd accumulation in the cell wall of the roots. The expression level of OsNramp5 and OsHMA2 was down-regulated by Si in the WTs, but not in the mutants. These results indicate that the Si-decreased Cd accumulation was caused by down-regulating transporter genes involved in Cd uptake and translocation in rice.

The physiological role of microRNAs (miRNAs) in osteoblast differentiation remains elusive. Exosomal miRNAs isolated from human bone marrow-derived mesenchymal stem cells (BMSCs) culture were profiled using miRNA arrays containing probes for 894 human matured miRNAs. Seventy-nine miRNAs (∼8.84%) could be detected in exosomes isolated from BMSC culture supernatants when normalized to endogenous control genes RNU44. Among them, nine exosomal miRNAs were up regulated and 4 miRNAs were under regulated significantly (Relative fold>2, p<0.05) when compared with the values at 0 day with maximum changes at 1 to 7 days. Five miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) were further validated and differentially expressed in the individual exosomal samples from hBMSCs cultured at different time points. Bioinformatic analysis by DIANA-mirPath demonstrated that RNA degradation, mRNA surveillance pathway, Wnt signaling pathway, RNA transport were the most prominent pathways enriched in quantiles with differential exosomal miRNA patterns related to osteogenic differentiation. These data demonstrated exosomal miRNA is a regulator of osteoblast differentiation.

: The Gustave Roussy Immune Score (GRIm-Score) was initially reported to select patients for immunotherapy. Therefore, the purpose of the current retrospective study was to determine whether GRIm-Score, a novel nutritional and inflammatory-based prognostic score, is a useful prognostic marker in patients with esophageal squamous cell carcinoma (ESCC) undergoing surgical resection. : A retrospective single institutional study including 372 ESCC patients undergoing surgical resection was performed. The GRIm-Score was simply calculated by lactate dehydrogenase (LDH), neutrophil lymphocyte ratio (NLR) and albumin (ALB). The cancer-specific survival (CSS) was analyzed for the current study with Cox regression analyses with forward stepwise and Kaplan-Meier methods. : There were 284 (76.3%) men and 88 (23.7%) women with the mean age of 59.3 ± 8.0 years (range: 36-80 years). Patient with a high GRIm-Score had poor CSS (10.3% vs. 35.0%, < 0.001). The GRIm-Score, in multivariate analyses, instead of NLR, LDH or ALB, was an independent prognostic factor for CSS ( = 0.004). : The GRIm-Score was an independent prognostic marker in patients with ESCC undergoing surgical resection. Our study is also the first study to discuss the prognostic value of GRIm-Score in patients with resectable ESCC.

Background Many applications of CRISPR/Cas9-mediated genome editing require Cas9-induced non-homologous end joining (NHEJ), which was thought to be error prone. However, with directly ligatable ends, Cas9-induced DNA double strand breaks may be repaired preferentially by accurate NHEJ. Results In the repair of two adjacent double strand breaks induced by paired Cas9-gRNAs at 71 genome sites, accurate NHEJ accounts for about 50% of NHEJ events. This paired Cas9-gRNA approach underestimates the level of accurate NHEJ due to frequent + 1 templated insertions, which can be avoided by the predefined Watson/Crick orientation of protospacer adjacent motifs (PAMs). The paired Cas9-gRNA strategy also provides a flexible, reporter-less approach for analyzing both accurate and mutagenic NHEJ in cells and in vivo, and it has been validated in cells deficient for XRCC4 and in mouse liver. Due to high frequencies of precise deletions of defined “3n”-, “3n + 1”-, or “3n + 2”-bp length, accurate NHEJ is used to improve the efficiency and homogeneity of gene knockouts and targeted in-frame deletions. Compared to “3n + 1”-bp, “3n + 2”-bp can overcome + 1 templated insertions to increase the frequency of out-of-frame mutations. By applying paired Cas9-gRNAs to edit MDC1 and key 53BP1 domains, we are able to generate predicted, precise deletions for functional analysis. Lastly, a Plk3 inhibitor promotes NHEJ with bias towards accurate NHEJ, providing a chemical approach to improve genome editing requiring precise deletions. Conclusions NHEJ is inherently accurate in repair of Cas9-induced DNA double strand breaks and can be harnessed to improve CRISPR/Cas9 genome editing requiring precise deletion of a defined length.

Background It has been well documented that long non-coding RNAs (lncRNAs) regulate numerous characteristics of cancer, including proliferation, migration, metastasis, apoptosis, and even metabolism. LncRNA BCYRN1 (BCYRN1) is a newly identified brain cytoplasmic lncRNA with 200 nucleotides that was discovered to be highly expressed in tumour tissues, including those of hepatocellular carcinoma, gastric cancer and lung cancer. However, the roles of BCYRN1 in colorectal cancer (CRC) remain obscure. This study was designed to reveal the role of BCYRN1 in the occurrence and progression of CRC. Methods RT-PCR was used to detect the expression level of BCYRN1 in tumour tissues and CRC cell lines. BCYRN1 was knocked down in CRC cells, and cell proliferation changes were evaluated by cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), and Ki-67 and proliferating cell nuclear antigen (PCNA) expression assays. Cell migration and invasion changes were evaluated by wound healing, Transwell and invasion-related protein expression assays. Flow cytometry analysis was used to assess whether BCYRN1 regulates the apoptosis of CRC cells. The dual luciferase reporter gene detects the competitive binding of BCYRN1 to miR-204-3p. In vivo experiments were performed to evaluate the effect of BCYRN1 on tumour development. TargetScan analysis and dual luciferase reporter gene assays were applied to detect the target gene of miR-204-3p. Rescue experiments verified that BCYRN1 affects CRC by regulating the effect of miR-204-3p on KRAS. Results We found that compared with normal tissues and human intestinal epithelial cells (HIECs), CRC tumour tissues and cell lines had significantly increased BCYRN1 levels. We further determined that knockdown of BCYRN1 inhibited the proliferation, migration, and invasion and promoted the apoptosis of CRC cells. In addition, bioinformatics analysis and dual luciferase reporter assay showed that BCYRN1 served as a competitive endogenous RNA (ceRNA) to regulate the development of CRC through competitively binding to miR-204-3p. Further studies proved that overexpression of miR-204-3p reversed the effects of BCYRN1 on CRC. Next, TargetScan analysis and dual luciferase reporter assay indicated that KRAS is a target gene of miR-204-3p and is negatively regulated by miR-204-3p. A series of rescue experiments showed that BCYRN1 affected the occurrence and development of CRC by regulating the effects of miR-204-3p on KRAS. In addition, tumorigenesis experiments in a CRC mouse model confirmed that BCYRN1 downregulation effectively inhibited tumour growth. Conclusions Our findings suggest that BCYRN1 plays a carcinogenic role in CRC by regulating the miR-204-3p/KRAS axis.