A genome wide analysis of the response to uncapped telomeres in budding yeast reveals a novel role for the NAD+ biosynthetic gene BNA2 in chromosome end protection

NAD+ metabolism may be linked to telomere end protection in yeast

Chemotherapy-Induced Neoantigen Nanovaccines Enhance Checkpoint Blockade Cancer Immunotherapy

Chemotherapeutics have the potential to increase the efficacy of cancer immunotherapies by stimulating the production of damage-associated molecular patterns (DAMPs) and eliciting mutations that result in the production of neoantigens, thereby increasing the immunogenicity of cancerous lesions. However, the dose-limiting toxicity and limited immunogenicity of chemotherapeutics are not sufficient to induce a robust antitumor response. We hypothesized that cancer cells treated with ultrahigh doses of various chemotherapeutics artificially increased the abundance, variety, and specificity of DAMPs and neoantigens, thereby improving chemoimmunotherapy. The chemotherapy-induced (IVCI) nanovaccines manufactured from cell lysates comprised multiple neoantigens and DAMPs, thereby exhibiting comprehensive antigenicity and adjuvanticity. Our IVCI nanovaccines exhibited enhanced immune responses in CT26 tumor-bearing mice, with a significant increase in CD4/CD8 T cells in tumors in combination with immune checkpoint inhibitors. The concept of IVCI nanovaccines provides an idea for manufacturing and artificial enhancement of immunogenicity vaccines to improve chemoimmunotherapy

Promoter methylation inhibits BRD7 expression in human nasopharyngeal carcinoma cells

Abstract Background Nasopharyngeal carcinoma (NPC) is a head and neck malignancy with high occurrence in South-East Asia and Southern China. Recent findings suggest that epigenetic inactivation of multiple tumor suppressor genes plays an important role in the tumourigenesis of NPC. BRD7 is a NPC-associated bromodomain gene that exhibits a much higher-level of mRNA expression in normal than in NPC biopsies and cell lines. In this study, we explored the role of DNA methylation in regulation of BRD7 transcription. Methods The presence of CpG islands within BRD7 promoter was predicted by EMBOSS CpGplot and Softberry CpGFinder, respectively. Nested methylation-specific PCR and RT-PCR were employed to detect the methylation status of BRD7 promoter and the mRNA expression of BRD7 gene in tumor cell lines as well as clinical samples. Electrophoretic mobility shift assays (EMSA) and luciferase assay were used to detect the effects of cytosine methylation on the nuclear protein binding to BRD7 promoter. Results We found that DNA methylation suppresses BRD7 expression in NPC cells. In vitro DNA methylation in NPC cells silenced BRD7 promoter activity and inhibited the binding of the nuclear protein (possibly Sp1) to Sp1 binding sites in the BRD7 promoter. In contrast, inhibition of DNA methylation augments induction of endogenous BRD7 mRNA in NPC cells. We also found that methylation frequency of BRD7 promoter is much higher in the tumor and matched blood samples from NPC patients than in the blood samples from normal individuals. Conclusion BRD7 promoter demethylation is a prerequisite for high level induction of BRD7 gene expression. DNA methylation of BRD7 promoter might serve as a diagnostic marker in NPC.</p

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma:results of the GAUDI study (BO21000)

The safety and activity of obinutuzumab (GA101) plus chemotherapy in relapsed/refractory follicular lymphoma was explored in 56 patients. Participants received obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks for 6 to 8 cycles) or obinutuzumab plus fludarabine and cyclophosphamide (G-FC; every 4 weeks for 4 to 6 cycles). Patients were randomly assigned to either obinutuzumab 1600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses. Treatment responders were eligible for obinutuzumab maintenance every 3 months for up to 2 years. Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68%; G-FC, 82%). Grade 3/4 IRRs were rare (7%) and restricted to the first infusion. All patients received the planned obinutuzumab dose. Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43%) and G-FC (50%). At induction end, 96% (27/28) of patients receiving G-CHOP (complete response [CR], 39% [11/28]) and 93% (26/28) receiving G-FC (CR, 50% [14 of 28]) achieved responses. G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. Obinutuzumab plus chemotherapy resulted in 93% to 96% response rates, supporting phase 3 investigation. This trial was registered at www.clinicaltrials.gov as #NCT00825149

Activation of Akt/mTOR pathway is associated with poor prognosis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck region, which frequently occurs in Southeast Asia, especially in the south of China. It is known that the mammalian target of rapamycin (mTOR) pathway plays a central role in regulating cellular functions, including proliferation, growth, survival, mobility, and angiogenesis. Aberrant expression of the mTOR signaling pathway molecules has been found in many types of cancer. However, whether the alterations of p-Akt, p-p70S6K and p-4EBP1 protein expression are associated with clinicopathological features and prognostic implications in NPC have not been reported. The purposes of the present study are to investigate the association between the expression of p-Akt, p-p70S6K and p-4EBP1 proteins and clinicopathological features in NPC by immunohistochemistry. The results showed that the positive percentage of p-Akt, p-p70S6K and p-4EBP1 proteins expression in NPC (47.2%, 73.0% and 61.7%, respectively) was significantly higher than that in the non-cancerous nasopharyngeal control tissue (33.3%, 59.1% and 47.0%, respectively). There was a significantly higher positive expression of p-Akt in undifferentiated non-keratinizing nasopharyngeal carcinoma than that in differentiated non-keratinizing nasopharyngeal carcinoma (P = 0.014). Additionally, positive expression of p-p70S6K and p-4EBP1 proteins, and positive expression of either of p-Akt, p-p70S6K and p-4EBP1 were significantly correlated inversely with overall survival rates of NPC patients (P = 0.023, P = 0.033, P = 0.008, respectively). Spearman's rank correlation test showed that expression of p-Akt in NPC was significantly associated with expression of p-p70S6K (r = 0.263, P<0.001) and p-4EBP1(r = 0.284, P<0.001). Also there was an obviously positive association between expression of p-p70S6K and p-4EBP1 proteins in NPC (r = 0.286, P<0.001). Multivariate Cox regression analysis further identified positive expression of p-4EBP1 and p-p70S6K proteins were the independent poor prognostic factors for NPC (P = 0.043, P = 0.027, respectively). Taken together, high expression of p-p70S6K and p-4EBP1 proteins may act as valuable independent biomarkers to predict a poor prognosis of NPC

Increased expression of flotillin-2 protein as a novel biomarker for lymph node metastasis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot-2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC

Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis

Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients. To carry out a meta-analysis of trials from the rituximab RA clinical programme to investigate this relationship further. This was a meta-analysis of four placebo-controlled, phase II or III clinical trials. The efficacy end point in all analyses was change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 24 weeks. Assay of serotype and missing data imputation methods were consistent across all studies. The population analysed comprised 2177 patients (rituximab, n=1416; placebo, n=761). Demographics and baseline disease characteristics were well balanced. When a fixed-effects meta-analysis approach was used, the overall-effect model indicated evidence of additional treatment benefit with rituximab in seropositive patients: reduction in DAS28-ESR at week 24 was on average 0.35 units (95% CI 0.12 to 0.84; n=1394) greater than in seronegative patients; this effect was not seen in placebo patients. Heterogeneity indices indicated significant uncertainty in the overall-effect model (Q=8.8, I=0.77; p=0.03 (χ(2) test)). Baseline Health Assessment Questionnaire score, pain visual analogue scale, swollen joint counts of 28 joints and race were significant contributors to this heterogeneity, with additional analysis indicating that these effects may predominate in early RA (methotrexate-naïve) populations. A dominant effect was seen in patients for whom one or more tumour necrosis factor inhibitors had failed. Although the difference was modest, the overall-effect model indicates that seropositive patients respond better to rituximab than seronegative patient

Geological conditions and the main controlling factors for the tight oil accumulation in Liushagang Formation of Fushan Depression, Beibuwan Basin

Unravelling the accumulation conditions and their controlling factors for the tight oil in the Liushagang Formation, Fushan Depression, Beibuwan Basin, is critical for the further evaluation of the tight oil distribution and the favorable exploration area.Based on comprehensive analysis of seismic, well logging, core and lab tests in this study, the effective source rocks, favorable reservoir, and the source-reservoir matching relations were investigated.It can be proposed that the high-quality source rocks were formed in Huangtong, Bailian two sub-sags during the maximum lake flooding periods in Liushagang depositional stage and were characterized as high organic content and moderate degree of thermal evolution, and thus they provide the material basis for the formation of tight oil; due to the influence of multi-source supply, tight sandstones penetrated into these two sub-sags and they were widely distributed with superimposed source-reservoir assemblages. The development of dissolution pores and structural fractures was favorable for the migration and enrichment of tight oil; the tectonic conditions of the sag were relatively stable and no major fault system was active when the main sources entered peak oil window, and thus the relatively stable tectonic environment enabled the formation and preservation of tight oil accumulations.Therefore, the Liushagang Formation of the Fushan Depression have favorable geological conditions for the formation of tight oil, which mainly distribute in the lower L1 submember and L2 member vertically and Huangtong and Bailian sub-sags horizontally.The distribution of high-quality source rocks, the distribution of "sweet point" reservoirs being rich in dissolution pores and favorable superimposed source-reservoir assemblages are the three main controlling factors for the formation and distribution of tight oil in Liushagang Formation of Fushan Depression, Beibuwan Basin