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ObjectiveThe effectiveness of sugemalimab vs. placebo in post-chemoradiotherapy patients with locally advanced, unresectable stage III NSCLC has been demonstrated and approved by China National Medical Products Administration. The purpose of this study was to assess the cost-effectiveness of sugemalimab vs. placebo for consolidation treatment of stage III NSCLC from the perspective of the Chinese healthcare system.MethodsA 3-state Markov model with a 3-week cycle length was performed to appraise the incremental cost-utility ratio (ICUR) of sugemalimab consolidation therapy based on the GEMSTONE-301 clinical trial over a 10-year time horizon. Only direct medical costs, including costs of drug (maintenance and subsequent treatment), routine follow-up, best supportive care, and terminal care in end of life were considered in this model. Costs and health utilities were obtained from local databases and published articles. Sensitivity and scenario analyses were adopted to evaluate the model uncertainty. Internal and external data sources were used to justify the plausibility of the extrapolated portion of the survival model chosen.ResultsIn comparison with the placebo, sugemalimab consolidation therapy was not cost-effective as it yielded an ICUR value of $90,277 and $49,692 for the concurrent chemoradiotherapy (cCRT) and the sequential chemoradiotherapy (sCRT) population at the willingness-to-pay (WTP) threshold of $37,663/QALYs, respectively. When taking the sugemalimab patient assistance program (PAP) into consideration, sugemalimab consolidation therapy was cost-effective with an ICUR dramatic decreases below the WTP. Sensitivity analyses demonstrated that the ICUR was most sensitive to the discount rate and subsequent treatment. However, none of the sensitive parameters could affect the cost-effective conclusions without or with PAP. Scenario analyses revealed that the model was particularly affected by assumptions regarding discount in sugemalimab, time horizon, mean duration of sugemalimab maintenance treatment.ConclusionsFrom the perspective of Chinese healthcare system, sugemalimab consolidation therapy was not a cost-effective strategy in cCRT and sCRT patients with unresectable stage III NSCLC. Given that the sugemalimab PAP was available, sugemalimab consolidation therapy became a cost-effective option.

Aspirin is a prototypic cyclooxygenase inhibitor with a variety of beneficial effects on human health. It prevents age-related diseases and delays the aging process. Previous research has shown that aspirin might act through a dietary restriction-like mechanism to extend lifespan. To explore the mechanism of action of aspirin on aging, we determined the whole-genome expression profile of Caenorhabditis elegans treated with aspirin. Transcriptome analysis revealed the RNA levels of genes involved in metabolism were primarily increased. Reproduction has been reported to be associated with metabolism. We found that aspirin did not extend the lifespan or improve the heat stress resistance of germline mutants of glp-1. Furthermore, Oil Red O staining showed that aspirin treatment decreased lipid deposition and increased expression of lipid hydrolysis and fatty acid β-oxidation-related genes. The effect of germline ablation on lifespan was mainly mediated by DAF-12 and DAF-16. Next, we performed genetic analysis with a series of worm mutants and found that aspirin did not further extend the lifespans of daf-12 and daf-16 single mutants, glp-1;daf-12 and glp-1;daf-16 double mutants, or glp-1;daf-12;daf-16 triple mutants. The results suggest that aspirin increase metabolism and regulate germline signalling to activate downstream DAF-12 and DAF-16 to extend lifespan.

Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemotherapy drug resistance. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes an lncRNA, and decreased MEG3 expression plays an important role in multiple cancers. However, its biological role in the development of the chemoresistance phenotype of human lung adenocarcinoma (LAD) is unknown. This study aimed to observe the expression of MEG3 in LAD and to evaluate its biological role and clinical significance in the resistance of LAD cells to cisplatin. MEG3 expression was markedly decreased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by an lncRNA microarray. MEG3 overexpression in A549/DDP cells increased their chemosensitivity to cisplatin both in vitro and in vivo by inhibiting cell proliferation and inducing apoptosis. By contrast, MEG3 knockdown in A549 cells decreased the chemosensitivity. Moreover, MEG3 was decreased in cisplatin-insensitive LAD tissues while p53 protein levels were decreased and Bcl-xl protein levels increased. Furthermore, patients with lower levels of MEG3 expression showed worse responses to cisplatin-based chemotherapy. These findings demonstrate that MEG3 is significantly downregulated in LAD and partially regulates the cisplatin resistance of LAD cells through the control of p53 and Bcl-xl expression. Thus, MEG3 may represent a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy.

CDT-1 and CDT-2 are two cellodextrin transporters discovered in the filamentous fungus Neurospora crassa. Previous studies focused on characterizing the role of these transporters in only a few conditions, including cellulose degradation, and the function of these two transporters is not yet completely understood. In this study, we show that deletion of cdt-2, but not cdt-1, results in growth defects not only on Avicel but also on xylan. cdt-2 can be highly induced by xylan, and this mutant has a xylodextrin consumption defect. Transcriptomic analysis of the cdt-2 deletion strain on Avicel and xylan showed that major cellulase and hemicellulase genes were significantly down-regulated in the cdt-2 deletion strain and artificial over expression of cdt-2 in N. crassa increased cellulase and hemicellulase production. Together, these data clearly show that CDT-2 plays a critical role in hemicellulose sensing and utilization. This is the first time a sugar transporter has been assigned a function in the hemicellulose degradation pathway. Furthermore, we found that the transcription factor XLR-1 is the major regulator of cdt-2, while cdt-1 is primarily regulated by CLR-1. These results deepen our understanding of the functions of both cellodextrin transporters, particularly for CDT-2. Our study also provides novel insight into the mechanisms for hemicellulose sensing and utilization in N. crassa, and may be applicable to other cellulolytic filamentous fungi.

BACKGROUND: Although the Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) has been available for more than 75 years, one third of the world's population is still infected with Mycobacterium tuberculosis and approximately 2 million people die of TB every year. To reduce this immense TB burden, a clearer understanding of the functional genes underlying the action of BCG and the development of new vaccines are urgently needed. METHODS AND FINDINGS: Comparative genomic analysis of 19 M. tuberculosis complex strains showed that BCG strains underwent repeated human manipulation, had higher region of deletion rates than those of natural M. tuberculosis strains, and lost several essential components such as T-cell epitopes. A total of 188 BCG strain T-cell epitopes were lost to various degrees. The non-virulent BCG Tokyo strain, which has the largest number of T-cell epitopes (359), lost 124. Here we propose that BCG strain protection variability results from different epitopes. This study is the first to present BCG as a model organism for genetics research. BCG strains have a very well-documented history and now detailed genome information. Genome comparison revealed the selection process of BCG strains under human manipulation (1908-1966). CONCLUSIONS: Our results revealed the cause of BCG vaccine strain protection variability at the genome level and supported the hypothesis that the restoration of lost BCG Tokyo epitopes is a useful future vaccine development strategy. Furthermore, these detailed BCG vaccine genome investigation results will be useful in microbial genetics, microbial engineering and other research fields.

In this study, 24 standard nontuberculous mycobacteria (NTM) species strains including 12 slowly growing mycobacteria strains and 12 rapidly growing mycobacteria strains were subjected to drug susceptibility testing using microplate Alamar Blue assay-based 7H9 broth. The most active antimicrobial agents against the 24 NTM strains were streptomycin, amikacin, the fluoroquinolones, and the tetracyclines. Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium bolletii, and Mycobacterium simiae are resistant to most antimicrobial agents. The susceptibility results of this study from 24 NTM standard strains can be referenced by clinicians before susceptibility testing for clinical isolates is performed or when conditions do not allow for susceptibility testing. The application of broth-based methods is recommended by the Clinical and Laboratory Standards Institute, and the documentation of the susceptibility patterns of standard strains of mycobacteria can improve the international standardization of susceptibility testing methods.

BACKGROUND: Tuberculosis (TB) is a disease caused by the chronic and continuous infection of the pathogen Mycobacterium tuberculosis (M. tuberculosis). M. tuberculosis is an intracellular bacterial pathogen and is eliminated mainly through CD4(+) effector Th cells. M. tuberculosis induces regulatory T lymphocytes (Tregs) that mediate immune suppression by cell-to-cell contact or by secreting cytokines such as transforming growth factor-β (TGF-β). To understand the role of regulatory T-cells in the pathogenesis of TB, we have measured the in vivo frequency of regulatory T-cells and associated in vivo cytokine production in pulmonary tuberculosis patients. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed blood samples from 3 different populations (Group 1: patients with active TB, Group 2: patients recovered from TB and Group 3: healthy controls). We measured natural regulatory T-cell expression in peripheral blood using flow cytometry, and levels of blood serum IFN-γ and TGF-β1 using ELISA. The in vivo function of inductive regulatory T cells was mainly indicated by the expression of IFN-γ, TGF-β1, etc. Frequencyof natural regulatory T cells and inductive regulatory T cells in the peripheral blood samples from Group 1 patients were all significantly higher (P

BackgroundSarcopenia, the presence of skeletal muscle mass depletion, can be objectively quantified, whereas subjective global assessment (SGA) is a widely utilized subjective instrument to assess nutritional status. Both the presence of sarcopenia and SGA-assessed malnutrition, in isolation, have been shown to be associated with worse overall survival in a wide range of cancers. However, there is no research evaluating the independent prognostic significance of both the presence of sarcopenia and malnutrition as part of the same analysis. We investigated the impact of sarcopenia on overall survival in colorectal cancer specifically controlling for malnutrition.MethodsWe examined a consecutive case series of 112 patients with colorectal cancer first seen at our institution between August 2012 and October 2017. Using computed tomography (CT) imaging, the cross-sectional area of muscles at the L3 vertebral level was measured and then divided by height squared to calculate skeletal muscle index (SMI). Sarcopenia was defined as SMI ≤38.5 cm2/m2 for women and ≤52.4 cm2/m2 for men. SGA assessments were completed within 2 weeks of CT imaging. The association of sarcopenia and malnutrition with overall survival was assessed using univariate and multivariate Cox regression analysis.ResultsMedian age at presentation was 53.3 years. Sixty-six (58.9%) patients had metastatic disease at diagnosis. Using SMI, 46 (41.1%) patients were sarcopenic, while 66 (58.9%) were non-sarcopenic. Using SGA, 69 (61.6%) patients were assessed as well-nourished, while 43 (38.4%) were malnourished. Of 69 patients classified as well-nourished by SGA, 22 (31.9%) were sarcopenic. Similarly, of 43 patients categorized as malnourished by SGA, 19 (44.2%) were non-sarcopenic. On multivariate analysis, after adjusting for age, gender, tumor stage, BMI, treatment history and SGA, patients with sarcopenia had 3 times greater risk of mortality compared to those without sarcopenia (p = 0.001). The median survival of patients with both sarcopenia and malnutrition (n = 24) was 14.6 months (95% CI: 10.5 to 18.6) compared to the median survival of 25.9 months (95% CI: 7.8 to 44.0) in patients who were either sarcopenic or malnourished but not both (n = 41; p = 0.001). The median survival of patients who were non-sarcopenic and well nourished (n = 48; p = 0.001) was 38.6 months (95% CI: 25.6 to 51.6).ConclusionsThe exploratory study suggests that presence of sarcopenia supersedes the presence of malnutrition as a predictor of survival in colorectal cancer. Co-existence of sarcopenia and malnutrition is associated with worse survival in colorectal cancer compared to just one of those conditions being present. Prospective studies with large sample sizes are needed to confirm these findings.

OBJECTIVE:Surgery remains the primary form of treatment for infective endocarditis (IE). However, it is not clear what type of prosthetic valve provides a better prognosis. We conducted a meta-analysis to compare the prognosis of infective endocarditis treated with biological valves to cases treated with mechanical valves. METHODS:Pubmed, Embase and Cochrane databases were searched from January 1960 to November 2016.Randomized controlled trials, retrospective cohorts and prospective studies comparing outcomes between biological valve and mechanical valve management for infective endocarditis were analyzed. The Newcastle-Ottawa Scale(NOS) was used to evaluate the quality of the literature and extracted data, and Stata 12.0 software was used for the meta-analysis. RESULTS:A total of 11 publications were included; 10,754 cases were selected, involving 6776 cases of biological valves and 3,978 cases of mechanical valves. The all-cause mortality risk of the biological valve group was higher than that of the mechanical valve group (HR = 1.22, 95% CI 1.03 to 1.44, P = 0.023), as was early mortality (RR = 1.21, 95% CI 1.02 to 1.43, P = 0.033). The recurrence of endocarditis (HR = 1.75, 95% CI 1.26 to 2.42, P = 0.001), as well as the risk of reoperation (HR = 1.79, 95% CI 1.15 to 2.80, P = 0.010) were more likely to occur in the biological valve group. The incidence of postoperative embolism was less in the biological valve group than in the mechanical valve group, but this difference was not statistically significant (RR = 0.90, 95% CI 0.76 to 1.07, P = 0.245). For patients with prosthetic valve endocarditis (PVE), there was no significant difference in survival rates between the biological valve group and the mechanical valve group (HR = 0.91, 95% CI 0.68 to 1.21, P = 0.520). CONCLUSION:The results of our meta-analysis suggest that mechanical valves can provide a significantly better prognosis in patients with infective endocarditis. There were significant differences in the clinical features of patients receiving a biological valve compared to patients receiving a mechanical valve. A large, multicenter retrospective study included in our meta-analysis suggested that any mortality risk of the biological valve group was significant higher than that of the mechanical valve group. However, the risk was no different after risk was adjusted. So, we thought the reason for this result may be related to the characteristics of the patient rather than valve dysfunction. It is still necessary to future randomized studies to verify this conclusion.

Plant temperature (Tp) is an important indicator of plant health. To determine the dynamics of plant temperature and self-cooling ability of the plant, we measured Tp in Artemisia ordosica in July, in the Mu Us Desert of Northwest China. Related factors were also monitored to investigate their effects on Tp, including environmental factors, such as air temperature (Ta), relative humidity, wind speed; and physiological factors, such as leaf water potential, sap flow, and water content. The results indicate that: 1) Tp generally changes in conjunction with Ta mainly, and varies with height and among the plant organs. Tp in the young branches is most constant, while it is the most sensitive in the leaves. 2) Correlations between Tp and environmental factors show that Tp is affected mainly by Ta. 3) The self-cooling ability of the plant was effective by midday, with Tp being lower than Ta. 4) Increasing sap flow and leaf water potential showed that transpiration formed part of the mechanism that supported self-cooling. Increased in water conductance and specific heat at midday may be additional factors that contribute to plant cooling ability. Therefore, our results confirmed plant self-cooling ability. The response to high temperatures is regulated by both transpiration speed and an increase in stem water conductance. This study provides quantitative data for plant management in terms of temperature control. Moreover, our findings will assist species selection with taking plant temperature as an index.

BackgroundBiological soil crusts are common components of desert ecosystem; they cover ground surface and interact with topsoil that contribute to desertification control and degraded land restoration in arid and semiarid regions.Methodology/principal findingsTo distinguish the changes in topsoil affected by biological soil crusts, we compared topsoil properties across three types of successional biological soil crusts (algae, lichens, and mosses crust), as well as the referenced sandland in the Mu Us Desert, Northern China. Relationships between fractal dimensions of soil particle size distribution and selected soil properties were discussed as well. The results indicated that biological soil crusts had significant positive effects on soil physical structure (PConclusions/significanceBiological soil crusts cause an important increase in soil fertility, and are beneficial to sand fixation, although the process is rather slow. Fractal dimension proves to be a sensitive and useful index for quantifying changes in soil properties that additionally implies desertification. This study will be essential to provide a firm basis for future policy-making on optimal solutions regarding desertification control and assessment, as well as degraded ecosystem restoration in arid and semiarid regions.

BACKGROUND: Tuberculosis (TB) is a serious public health problem in China, and within China, Inner Mongolia has a high prevalence area of TB. Though studies on the genetic diversity of Mycobacterium tuberculosis (MTB) have been reported in many provinces, there are no such studies to date in Inner Mongolia. In this study, we investigated the genetic diversity of MTB in Inner Mongolia. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed 372 clinical MTB isolates with 22-loci mycobacterial interspersed repetitive unit and variable-number tandem repeats (MIRU-VNTR), spoligotyping, large sequence polymorphism (LSP), and NTF region analysis to understand the TB genotypes prevalent in Inner Mongolia. We found that the Beijing family was the most prevalent genotype (85.48%, 318/372), and the "modern" sublineage accounted for 76.73% (244/318) of the isolates. Our data also showed that there was no statistically significant association between the two major nationalities and the Beijing genotype (χ(2) = 3.612, P = 0.057; P>0.05). CONCLUSION/SIGNIFICANCE: The Beijing genotype is the most prevalent family of M. tuberculosis in Inner Mongolia, and we do not find any correlation between the Beijing genotype and the major nationalities.