Epstein-Barr virus deubiquitinating enzyme BPLF1 is involved in EBV carcinogenesis by affecting cellular genomic stability.

Increased mutational burden and EBV load have been revealed from normal tissues to Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs). BPLF1, encoded by EBV, is a lytic cycle protein with deubiquitinating activity has been found to participate in disrupting repair of DNA damage. We first confirmed that BPLF1 gene in gastric cancer (GC) significantly increased the DNA double strand breaks (DSBs). Ubiquitination mass spectrometry identified histones as BPLF1 interactors and potential substrates, and co-immunoprecipitation and in vitro experiments verified that BPLF1 regulates H2Bub by targeting Rad6. Over-expressing Rad6 restored H2Bub but partially reduced γ-H2AX, suggesting that other downstream DNA repair processes were affected. mRNA expression of BRCA2 were significantly down-regulated by next-generation sequencing after over-expression of BPLF1, and over-expression of p65 facilitated the repair of DSBs. We demonstrated BPLF1 may lead to the accumulation of DSBs by two pathways, reducing H2B ubiquitination (H2Bub) and blocking homologous recombination which may provide new ideas for the treatment of gastric cancer.

Comprehensive Characterization of Metabolism-Associated Subtypes of Renal Cell Carcinoma to Aid Clinical Therapy.

Renal cell carcinoma (RCC) is a disease characterized by excessive administration complexity because it exhibits extraordinary nonuniformity among distinct molecular subtypes. We herein intended to delineate the metabolic aspects of clear cell RCC (ccRCC) in terms of the gene expression profile. Recent studies have revealed that metabolic variations within tumors are related to the responsiveness to immune checkpoint inhibitor (ICI) therapy and patient prognosis. We used 100 previously reported metabolic (MTB) pathways to quantify the metabolic landscape of the 729 ccRCC patients. Three MTB subtypes were established, and the MTB scores were calculated using principal component analysis (PCA). The high MTB score group had better overall survival (OS) and was associated with higher expression of immune-checkpoint and immune-activity signatures. The opposite was true of the low MTB score group, which may explain the poor prognosis of these patients. Three ICI-treated cohorts or tyrosine kinase inhibitor (TKI) treated cohort proved that patients with higher MTB scores exhibited notable therapeutic benefits and clinical gains. This research explained that the MTB score could be applied as a powerful prognostic indicator and predictive of ICI or TKI therapy. Assessing the MTB scores in a more extended group will facilitate our perception of tumor metabolism and provide guidance for studies on targeted approaches for ccRCC patients.

Health Shocks and Unbalanced Growth of Medical Resources: Evidence From the SARS Epidemic in China.

Since the outbreak of the SARS epidemic in 2003, the Chinese government has increased inputs to bolster the health care system. However, the COVID-19 pandemic has exposed the geographic maldistribution of health resources in China. We examine the spatial and temporal variation of the SARS epidemic using a difference-in-differences strategy. Our empirical results show that, compared with cities without SARS case reports, exogenous health shocks significantly increased the affected cities' medical resources supply. We provide multiple robustness tests to examine the validity of the main findings. Further study shows that the mechanism is because the SARS event increased the financial autonomy of the epidemic-affected cities, thus providing an incentive for local governments to increase health resources. Meanwhile, health shocks have little influence on the regions with only imported cases than the infected area. These findings provide a possible explanation for the inequality in the distribution of health resources.

Triglyceride-glucose index and estimated 10-year risk of a first hard cardiovascular event.

Background: Whether Triglyceride-glucose (TyG) index is associated with 10-year risk of a first hard atherosclerotic cardiovascular disease (ASCVD) event in the United States remains unclear. Methods: In this cross-sectional study, the participants, ranged from 40 to 79 years old, were from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. TyG index was the independent variable and 10-year risk of a first hard ASCVD was the dependent variable. The other variables, such as age, gender, race, body mass index (BMI), hypertension treatment states, smoking states and low-density lipoprotein cholesterol (LDL-C) et al. were considered as the potential confounding factors. Multivariate linear regression models and smooth curve fittings were used to evaluate the association between TyG index and 10-year risk of a first hard ASCVD event. Results: A total of 2,142 participants were included in the analysis. The results showed that TyG index was associated with an increased 10-year risk of a first hard ASCVD event [ß = 2.208, 95% (1.716, 2.700), P < 0.00001]. The association had statistical significance in both men [ß = 3.862 95% CI (3.274, 4.450), P < 0.00001] and women [ß = 1.067, 95% CI (0.286, 1.849), P = 0.00756)] according to subgroup analysis. Smooth curve fittings revealed that TyG index was linearly associated with 10-year risk of ASCVD in both male and female. Conclusion: Triglyceride-glucose index was associated with an increased 10-year risk of a first hard ASCVD event in the United States, suggesting it is necessary to monitor and control an appropriate range of TyG index.

Hyperprogressive disease in patients with advanced renal cell carcinoma: a new pattern of post-treatment cancer behavior.

Renal cell carcinoma (RCC) is among the most common cancers of the genitourinary system. Once RCC has progressed to a high tumor stage, surgery is no longer the optimal option, and treatment with drugs is more suitable. However, a proportion of patients with advanced RCC (aRCC) experience accelerated progression following targeted therapy or immunotherapy, a condition known as hyperprogressive disease (HPD). There is a growing body of literature that recognizes the importance of HPD. In the present review, thousands of studies that describe a variety of treatments for aRCC were identified in PubMed, Web of Science, and Cochrane Library and analyzed to establish the severity of clinical outcomes. Therefore, we managed to perform a review related to HPD of aRCC in these databases. It was found that 7~74% of patients advanced into progressive disease, 0~45% of patients died during post-treatment assessment, possibly due to fatal HPD. However, risk factors, mechanisms, and predictive factors are still not entirely clear. It is suggested that combination therapies might play a pivotal role in preventing HPD. Additional light needs to be shed on customization of therapies for aRCC after more data is collected and analyzed for HPD.

Development of a high-throughput and sensitive assay of fusion genes in lung cancer by array-based MALDI-TOFMS.

ALK (anaplastic lymphoma kinase gene), ROS1 (ros proto-oncogene 1) and RET (ret proto-oncogene) fusions are oncogenic drivers in non-small cell lung cancer (NSCLC). Methods like fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are highly sensitive but subjectively analyzed, labor intensive, expensive and unsuitable for multiple fusion gene screening. This study aimed to establish a high-throughput, sensitive and cost-effective screening method (array-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, array-based MALDI-TOFMS) for ALK, ROS1 and RET fusion detection. This method was established with three fusion gene positive cell lines (H2228, ALK positive; HCC78, ROS1 positive; LC-2/AD, RET positive) and negative samples. Then, 34 clinical samples were selected and detected by Sanger sequencing, next generation sequencing (NGS) and array-based MALDI-TOFMS. The results were compared and analyzed and Sanger sequencing was considered the standard. 7 cases showed ALK fusions, 1 case showed ROS1 fusions, no case showed RET fusions and 4 cases were both ALK and ROS1 fusions. Results showed that array-based MALDI-TOFMS was 100% concordant with Sanger sequencing and NGS 82.3%. In this study, we reported the utility of array-based MALDI-TOFMS in the assessment of ALK, ROS1 and RET fusions in routine lung biopsies of FFPE and fresh tissue specimens. Besides, this method may also be applied to the diagnosis, monitoring and prognosis of illness.