Real-world cost- effectiveness analysis: Tumor Treating Fields for newly diagnosed glioblastoma in China.

BACKGROUND: Glioblastoma (GBM) stands as the most aggressive and prevalent primary brain malignancy. Tumor Treating Fields (TTFields), an innovative therapy complementing chemotherapy for GBM treatment, which can significantly enhance overall survival, disease progression-free survival, and patient's quality of life. However, there is a dearth of health economics evaluation on TTFields therapy both domestically and internationally. OBJECTIVE: The study aims to assess the cost-effectiveness of TTFields + temozolomide (TMZ) in comparison to TMZ alone for newly diagnosed GBM patients. The intent is to provide robust economic evidence to serve as a foundation for policymaking and decision-making processes in GBM treatment. METHODS: We estimated outcomes for newly diagnosed GBM patients over a lifetime horizon using a partitioned survival model with three states: Progression-Free Survival, Progression Disease, and Death. The survival model was derived from a real-world study in China, with long-term survival data drawn from GBM epidemiology literature. Adverse event rates were sourced from the EF-14 trial data. Cost data, validated by expert consultation, was obtained from public literature and databases. Utility values were extracted from published literature. Using Microsoft Excel, we calculated expected costs and quality-adjusted life years (QALYs) over 15 years from a health system perspective. The willingness-to-pay threshold was set at three times the Chinese per capita Gross Domestic Product (GDP) in 2022, amounting to CN¥242,928 (US$37,655) /QALY. A 5% discount rate was applied to costs and utilities. Results underwent analysis through single factor and probability sensitivity analyses. RESULTS: TTFields + TMZ demonstrated a mean increase in cost by CN¥389,326 (US$57,859) and an increase of 2.46 QALYs compared to TMZ alone. The incremental cost-effectiveness ratio (ICER) was CN¥157,979 (US$23,474) per QALY gained. The model exhibited heightened sensitivity to changes in the discount rate. Probability sensitivity analysis indicates that, under the existing threshold, the probability of TTFields + TMZ being economical is 95.60%. CONCLUSIONS: This cost-effectiveness analysis affirms that incorporating TTFields into TMZ treatment proves to be cost-effective, given a threshold three times the Chinese per capita GDP.

Optimizing Trilobatin Production via Screening and Modification of Glycosyltransferases.

Trilobatin (TBL) is a key sweet compound from the traditional Chinese sweet tea plant (Rubus suavissimus S. Lee). Because of its intense sweetness, superior taste profile, and minimal caloric value, it serves as an exemplary natural dihydrochalcone sweetener. It also has various health benefits, including anti-inflammatory and glucose-lowering effects. It is primarily produced through botanical extraction, which impedes its scalability and cost-effectiveness. In a novel biotechnological approach, phloretin is used as a precursor that is transformed into TBL by the glycosyltransferase enzyme ph-4'-OGT. However, this enzyme's low catalytic efficiency and by-product formation limit the large-scale synthesis of TBL. In our study, the enzyme Mdph-4'-OGT was used to screen 17 sequences across species for TBL synthesis, of which seven exhibited catalytic activity. Notably, PT577 exhibited an unparalleled 97.3% conversion yield within 3 h. We then optimized the reaction conditions of PT577, attaining a peak TBL bioproduction of 163.3 mg/L. By employing virtual screening, we identified 25 mutation sites for PT577, thereby creating mutant strains that reduced by-products by up to 50%. This research enhances the enzymatic precision for TBL biosynthesis and offers a robust foundation for its industrial-scale production, with broader implications for the engineering and in silico analysis of glycosyltransferases.

Identification and Validation of Magnolol Biosynthesis Genes in Magnolia officinalis.

Bacterial infections pose a significant risk to human health. Magnolol, derived from Magnolia officinalis, exhibits potent antibacterial properties. Synthetic biology offers a promising approach to manufacture such natural compounds. However, the plant-based biosynthesis of magnolol remains obscure, and the lack of identification of critical genes hampers its synthetic production. In this study, we have proposed a one-step conversion of magnolol from chavicol using laccase. After leveraging 20 transcriptomes from diverse parts of M. officinalis, transcripts were assembled, enriching genome annotation. Upon integrating this dataset with current genomic information, we could identify 30 laccase enzymes. From two potential gene clusters associated with magnolol production, highly expressed genes were subjected to functional analysis. In vitro experiments confirmed MoLAC14 as a pivotal enzyme in magnolol synthesis. Improvements in the thermal stability of MoLAC14 were achieved through selective mutations, where E345P, G377P, H347F, E346C, and E346F notably enhanced stability. By conducting alanine scanning, the essential residues in MoLAC14 were identified, and the L532A mutation further boosted magnolol production to an unprecedented level of 148.83 mg/L. Our findings not only elucidated the key enzymes for chavicol to magnolol conversion, but also laid the groundwork for synthetic biology-driven magnolol production, thereby providing valuable insights into M. officinalis biology and comparative plant science.

Embodied mathematical pedagogy to liberate racialized and multilingual bodies.

When language is defined narrowly in mathematics classrooms, racially and linguistically minoritized students in classrooms could be systematically positioned as "learners of deficiency." Recent scholarship calls for expanding the notion of language to emphasize embodied expression of mathematical ideas. Taking a critical perspective to understand racialized experiences of using languages in disciplinary learning spaces, this article proposes the reconceptualization of embodiment as a language for racialized multilingual learners. This study was conducted in a Grade 1 classroom in a linguistically and racially diverse school in Canada. Through a series of professional development sessions, we worked with an experienced teacher to redesign the normalized and institutionalized pedagogy toward greater mobility of racialized multilingual learners' bodies, which was intertwined with their intellectual liberation. Focusing on the spatiality of pedagogy, the previously restrictive areas in the school were transformed into a place that augments embodied expression of mathematical ideas and agentive participation of minoritized learners. The analysis focused on the embodied discourse that participating racialized multilingual students used to actively engage in mathematical discussion. Our findings show that the designed pedagogy, characterized by the spatial and temporal expansion of the learning environment, offered more spaces for uncertainty and spontaneity with the decreased control of the teacher as an explicator. Our article furthers anti-colonial approaches to understand the intersection of racialized bodies and language in mathematics education.

Structural characterization of an L-fuculose-1-phosphate aldolase from Klebsiella pneumoniae.

Fuculose phosphate aldolases play an important role in glycolysis and gluconeogenesis pathways. L-fuculose 1-phosphate aldolase catalyzes the reversible cleavage of L-fuculose 1-phosphate to DHAP and L-lactaldehyde. Class II aldolases found in bacteria are linked to pathogenesis of human pathogens, and have potential applications in the biosynthesis of carbohydrates and other chiral compounds. Here we report the structure of a putative L-fuculose 1-phosphate aldolase (KpFucA) from the nosocomial pathogen Klebsiella pneumoniae to 1.85 Å resolution. The enzyme crystallizes in space group P422 with one monomer per asymmetric unit. Analytical ultracentrifugation analysis confirms that KpFucA is a tetramer in solution. A magnesium ion cofactor and sulfate ion were identified in the active pocket. Enzyme activity assays confirmed that KpFcuA has a strong preference for L-fuculose 1-phosphate as a substrate, but can also catalyze the cleavage of fructose-1,6-bisphosphate and glucose-6-phosphate. This work should provide a starting point for further investigation of the role of KpFucA in K. pneumoniae pathogenesis or in industrial applications.

Tackling brain drain at Chinese CDCs: understanding job preferences of public health doctoral students using a discrete choice experiment survey.

BACKGROUND: Given the demands for public health and infectious disease management skills during COVID-19, a shortage of the public health workforce, particularly with skills and competencies in epidemiology and biostatistics, has emerged at the Centers for Disease Controls (CDCs) in China. This study aims to investigate the employment preferences of doctoral students majoring in epidemiology and biostatistics, to inform policy-makers and future employers to address recruitment and retention requirements at CDCs across China. METHODS: A convenience sampling approach for recruitment, and an online discrete choice experiment (DCE) survey instrument to elicit future employee profiles, and self-report of their employment and aspirational preferences during October 20 and November 12, 2020. Attributes included monthly income, employment location, housing benefits, children's education opportunities, working environment, career promotion speed and bianzhi (formally established post). RESULTS: A total of 106 doctoral epidemiology and biostatistics students from 28 universities completed the online survey. Monthly income, employment location and bianzhi was of highest concern in the seven attributes measured, though all attributes were statistically significant and presented in the expected direction, demonstrating preference heterogeneity. Work environment was of least concern. For the subgroup analysis, employment located in a first-tier city was more likely to lead to a higher utility value for PhD students who were women, married, from an urban area and had a high annual family income. Unsurprisingly, when compared to single students, married students were willing to forgo more for good educational opportunities for their children. The simulation results suggest that, given our base case, increasing only monthly income from 10,000 ($ 1449.1) to 25,000 CNY ($ 3622.7) the probability of choosing the job in the third-tier city would increase from 18.1 to 53.8% (i.e., the location choice is changed). CONCLUSION: Monthly income and employment location were the preferred attributes across the cohort, with other attributes then clearly ranked and delineated. A wider use of DCEs could inform both recruitment and retention of a public health workforce, especially for CDCs in third-tier cities where resource constraints preclude all the strategies discussed here.

Were economic evaluations well reported for the newly listed oncology drugs in China's national reimbursement drug list.

PURPOSE: To assess the reporting quality of published economic evaluations of the negotiated oncology drugs listed for China's 2020 National Reimbursement Drug List (NRDL). METHODS: A comprehensive search was conducted to identify economic evaluation studies of negotiated oncology drugs listed in China's 2020 NRDL using the PubMed/MEDLINE, Embase, Web of Science, CNKI, SinoMed, and WanFang Database up to March 31, 2021. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist scored the reporting quality between 0 and 100. A linear regression analysis was employed to examine the influence of various characteristics on the reporting quality scores. RESULTS: Eighty papers were included in the study, with the majority published during the past decade. Furthermore, more than half of the articles (57.5%, or 46 out of 80) were written in English. The average CHEERS score was 74.63 ± 12.75 and ranged from 43.48 to 93.75. The most inadequately reported items included choice of model, characterization of heterogeneity, and discussion, as well as currency, price date and conversion. Higher scores were associated with articles published from 2019 to 2021 and English publications. CONCLUSION: The economic evaluation studies of negotiated oncology drugs listed in 2020 NRDL had moderate reporting quality. The Chinese economic evaluation publications could improve the reporting quality if the CHEERS checklist is consistently implemented. Also, the Chinese journals maybe explore introducing a reporting standard for economic evaluations.

STAT3 Promotes Schistosome-Induced Liver Injury by Inflammation, Oxidative Stress, Proliferation, and Apoptosis Signal Pathway.

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms responsible for the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and Stat3flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum Liver injury, effector molecule levels, and RNA transcriptome resequencing of liver tissue were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 (signal transducer and activator of transcription 3) in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there was obvious liver fibrosis. A sustained pathological process (inflammation, oxidative stress, proliferation, and apoptosis) occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we observed activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver deficiency of phospho-STAT3 alleviated infection-induced liver dysfunction, hepatic granuloma formation, and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress, and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation, and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.

Job preferences of undergraduate pharmacy students in China: a discrete choice experiment.

BACKGROUND: Pharmacists are a crucial part of the health workforce and play an important role in achieving universal health coverage. In China, pharmaceutical human resources are in short supply, and the distribution is unequal. This study aimed to identify the key job characteristics that influence the job preferences of undergraduate pharmacy students and to elicit the relative importance of different job characteristics to shed light on future policy interventions. METHODS: A discrete choice experiment was conducted to assess the job preferences of undergraduate pharmacy students from 6 provinces in mainland China. A face-to-face interview was used to collect data. Conditional logit and mixed logit models were used to analyse data, and the final model was chosen according to the model fit statistics. A series of policy simulations was also conducted. RESULTS: In total, 581 respondents completed the questionnaire, and 500 respondents who passed the internal consistency test were analysed. All attributes were statistically significant except for open management. Monthly income and work location were most important to respondents, followed by work unit (which refers to the nature of the workplace) and years to promotion. There was preference heterogeneity among respondents, e.g., male students preferred open management, and female students preferred jobs in public institutions. Furthermore, students with an urban background or from a single-child family placed higher value on a job in the city compared to their counterparts. CONCLUSION: The heterogeneity of attributes showed the complexity of job preferences. Both monetary and nonmonetary job characteristics significantly influenced the job preferences of pharmacy students in China. A more effective policy intervention to attract graduates to work in rural areas should consider both incentives on the job itself and the background of pharmacy school graduates.

Plasma Level of Elabela in Patients with Coronary Heart Disease and Its Correlation with the Disease Classification.

This study aimed to evaluate the concentration of plasma elabela (ELA) in patients with coronary heart disease (CHD) and its correlation with the disease classification.We enrolled 238 patients diagnosed by coronary angiography as CHD and 86 controls. The CHD group was divided into three subgroups: stable angina (SA), unstable angina (UAP), and acute myocardial infarction (AMI). The plasma levels of ELA were measured in all participants and compared among different groups. The relationship between ELA and CHD classification was analyzed.ELA levels were markedly higher by 10.71% in patients with CHD than in controls (P < 0.05). The concentration of ELA in UAP and AMI subgroups were higher than in controls and SA subgroup. The former difference was significant (P < 0.05), but the latter was not. In addition, the ELA concentration was not correlated with SYNTAX score, left ventricular ejection fraction, and other biochemical variables.The newfound hormone, ELA, significantly increased in patients with UAP and AMI. There is a tendency that ELA levels might be correlated with CHD classification, but not with lesion severity. ELA may play a role in acute coronary syndrome.

Language disparity is not a significant barrier for time-sensitive care of acute ischemic stroke.

BACKGROUND: Language barriers were reported to affect timely access to health care and outcome. The aim of this study was to investigate the effect of language disparity on quality benchmarks of acute ischemic stroke therapy. METHODS: Consecutive patients with acute ischemic stroke at the University of California Irvine Medical Center from 2013 to 2016 were studied. Patients were categorized into 3 groups according to their preferred language: English, Spanish, and other languages. Quality benchmarks and outcomes of the 3 language groups were analyzed. RESULTS: Of the 928 admissions, 69.7% patients recorded English as preferred language, as compared to 17.3% Spanish and 13.0% other languages. There was no significant difference in the rate of receiving intravenous thrombolysis (24.3, 22.1 and 21.0%), last-known-well to door time, door-to-imaging time, door-to-needle time, and hospital length of stay among the 3 language groups. In univariate analysis, the other languages group had lower chance of favorable outcomes than the English-speaking group (26.3% vs 40.4, p < 0.05) while the Spanish-speaking group had lower mortality rate than English-speaking group (3.1% vs 7.7%, p = 0.05). After adjusting for age and initial NIHSS scores, multivariate regression models showed no significant difference in favorable outcomes and mortality between different language groups. CONCLUSION: We demonstrate no significant difference in quality benchmarks and outcome of acute ischemic stroke among 3 different language groups. Our results suggest that limited English proficiency is not a significant barrier for time-sensitive stroke care at Comprehensive Stroke Center.

Analysing the preferences for family doctor contract services in rural China: a study using a discrete choice experiment.

BACKGROUND: Preliminary evaluations have found that family doctor contract services (FDCSs) have significantly controlled medical expenses, better managed chronic diseases, and increased patient satisfaction and service compliance. In 2016, China proposed the establishment of a family doctor system to carry out contract services, but studies have found the uptake and utilization of these services to be limited. This study aimed to investigate rural residents' preferences for FDCSs from the perspective of the Chinese public. METHODS: A discrete choice experiment (DCE) was performed to elicit the preferences for FDCSs among rural residents in China. Attributes and levels were established based on a literature review and qualitative methods. Five attributes, i.e., cost, medicine availability, the reimbursement rate, family doctor competence, and family doctor attitude, were evaluated using a mixed logit model. RESULTS: A total of 609 residents were included in the main DCE analysis. The respondents valued the high competence (coefficient 2.44, [SE 0.13]) and the good attitude (coefficient 1.42, [SE 0.09]) of family doctors the most. Cost was negatively valued (coefficient - 0.01, [SE 0.01]), as expected. Preference heterogeneity analysis was conducted after adjusting the interaction terms, and we found that rural residents with higher educational attainment prefer a good attitude more than their counterparts with lower educational attainment. The estimated willingness to pay (WTP) for "high" relative to "low" competence was 441.13 RMB/year, and the WTP for a provider with a "good" attitude relative to a "poor" attitude was 255.77 RMB/year. CONCLUSION: The present study suggests that strengthening and improving the quality of primary health care, including the competence and attitudes of family doctors, should be prioritized to increase the uptake of FDCSs. The contract service package, including the annual cost, the insurance reimbursement rate and individualized services, should be redesigned to be congruent with residents having different health statuses and their stated preferences.

Job preferences of undergraduate nursing students in eastern China: a discrete choice experiment.

BACKGROUND: Shortage and mal-distribution of nursing human resources is an intractable problem in China. There is an urgent need to explore the job preferences of undergraduate nursing students. The main aim of this study is to investigate the stated preferences of nursing students when choosing a job. METHODS: A discrete choice experiment (DCE) was conducted to assess job preferences of the final year undergraduate nursing students from four medical universities/colleges in Shandong Province, China. Job attributes include location, monthly income, bianzhi (which refers to the established posts and can be loosely regarded as state administrative staffing), career development and training opportunity, work environment and working strength. Mixed logit models were used to analyze the DCE data. RESULTS: A total of 445 undergraduate nursing students were included in the main DCE analysis. They demonstrated higher preference for a job with higher monthly income, and the probability of choosing a rural job would increase to 92.8% if monthly income increased from RMB 2000 (US$ 296) to RMB 8000 (US$ 1183). They expressed higher stated preferences for a job which required light working strength and with excellent work environment over other non-economic attributes. Among all attributes, location was the least important attribute. Subgroup analysis showed that students who came from city or county and whose family income was more than RMB 50 000 (US$ 7396) were significantly willing to pay more monthly income for a job in city. CONCLUSIONS: This study confirmed that economic and non-economic factors both affected the job choices of the students. These results may be more effective for policymakers to perfect the employment policies and design strategies to attract more nursing students taking jobs in rural areas.

Small interfering RNA targeting of peroxiredoxinâ ¡ gene enhances formaldehyde-induced toxicity in bone marrow cells isolated from BALB/c mice.

BACKGROUDS: Formaldehyde (FA) is an important chemicals that can induce sick house syndrome and may be an incentive of childhood leukemia, however the exact mechanism is unclear. Oxidative stress may be an underlying reason of cancer occurring, while diverse antioxidants can protect the bone marrow cells (BMCs) from damaged. PeroxiredoxinⅡ (PrxⅡ) is an important member of the peroxiredoxin family, can remove reactive oxygen species (ROS), and is closely related with the occurrence of tumor. The present study aimed to detect a possible relationship between PrxⅡ gene and FA-induced bone marrow toxicity. METHODS: The BMCs were taken out from BALB/c mice, then exposed to control and different doses of FA (50, 100, 200 µmol/L). The cell viability, ROS level and expressions of PrxⅡ gene were examined. Afterwards, we used a small interfering RNA (siRNA) to inhibit the expression of PrxⅡ gene, and chose 100 µmol/L FA for exposure dose, to examine the cell viability, ROS level, cell cycle, apoptotic rate, expressions of PrxⅡ gene in BMCs. RESULTS: After a 24 h exposure to different doses of FA, the cell viability, expressions of PrxⅡ gene were decreased with the increasing of FA concentration, while the ROS level was increased. Inhibiting PrxⅡ gene's expression could enhance above FA-induced events. Additionally, siRNA targeting of PrxⅡcould aggravate cell cycle arrest to inhibit cell's growth and development, as well as increase apoptotic rates induced by FA. CONCLUSION: These results demonstrated that PrxⅡ gene was involved in FA-induced bone marrow toxicity, and siRNA targeting of PrxⅡcould enhance this toxic process.

Colorimetric determination of lead(II) or mercury(II) based on target induced switching of the enzyme-like activity of metallothionein-stabilized copper nanoclusters.

It is shown that metallothionein-stabilized copper nanoclusters (MT-CuNCs) display catalase-like activity. In the presence of either lead(II) or mercury(II), the catalase-like activity is converted to a peroxidase-like activity. On addition of Pb(II) or Hg(II), the inhibitory effect of MT-CuNCs on the chromogenic reaction of 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2 is weakened. On the other hand, the catalytic effect of the nanoclusters on the chromogenic reaction is increased. The system MT-CuNCs-Pb(II)/Hg(II) exhibits high affinity for the substrates TMB and H2O2. Their catalytic behavior follows Michaelis-Menten kinetics. Based on these findings, a method was developed for visual detection (via the blue coloration formed) and spectrophotometric determination (at 450 nm) of Pb(II) and Hg(II). The linear range for Pb(II) extends from 0.7 to 96 µM, and the linear ranges for Hg(II) from 97 nM to 2.3 µM and from 3.1 µM to 15.6 µM. The detection limits are 142 nM for Pb(II) and 43.8 nM for Hg(II). Graphical abstract Metallothionein-stabilized copper nanoclusters (MT-CuNCs) display catalase-like activity. On addition of Pb(II) or Hg(II), the catalase-like activity is converted to a peroxidase-like activity. The latter catalyzes the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2.

MeDEStrand: an improved method to infer genome-wide absolute methylation levels from DNA enrichment data.

BACKGROUND: DNA methylation of CpG dinucleotides is an essential epigenetic modification that plays a key role in transcription. Widely used DNA enrichment-based methods offer high coverage for measuring methylated CpG dinucleotides, with the lowest cost per CpG covered genome-wide. However, these methods measure the DNA enrichment of methyl-CpG binding, and thus do not provide information on absolute methylation levels. Further, the enrichment is influenced by various confounding factors in addition to methylation status, for example, CpG density. Computational models that can accurately derive absolute methylation levels from DNA enrichment data are needed. RESULTS: We developed "MeDEStrand," a method that uses a sigmoid function to estimate and correct the CpG bias from enrichment results to infer absolute DNA methylation levels. Unlike previous methods, which estimate CpG bias based on reads mapped at the same genomic loci, MeDEStrand processes the reads for the positive and negative DNA strands separately. We compared the performance of MeDEStrand to that of three other state-of-the-art methods "MEDIPS," "BayMeth," and "QSEA" on four independent datasets generated using immortalized cell lines (GM12878 and K562) and human primary cells (foreskin fibroblasts and mammary epithelial cells). Based on the comparison of the inferred absolute methylation levels from MeDIP-seq data and the corresponding reduced-representation bisulfite sequencing data from each method, MeDEStrand showed the best performance at high resolution of 25, 50, and 100 base pairs. CONCLUSIONS: The MeDEStrand tool can be used to infer whole-genome absolute DNA methylation levels at the same cost of enrichment-based methods with adequate accuracy and resolution. R package MeDEStrand and its tutorial is freely available for download at https://github.com/jxu1234/MeDEStrand.git .

Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer.

Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+ T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.

TRIM38 inhibits TNFα- and IL-1ß-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3.

TNFα and IL-1ß are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNFα- and IL-1ß-mediated signaling is finely tuned is not fully elucidated. Here, we identify tripartite-motif protein 38 (TRIM38) as a critical negative regulator of TNFα- and IL-1ß-triggered signaling. Overexpression of TRIM38 inhibited activation of NF-κB and induction of downstream cytokines following TNFα and IL-1ß stimulation, whereas knockdown or knockout of TRIM38 had the opposite effects. TRIM38 constitutively interacted with critical components TGF-ß-activated kinase 1 (TAK1)-binding protein 2/3 (TAB2/3) and promoted lysosome-dependent degradation of TAB2/3 independent of its E3 ubiquitin ligase activity. Consistently, deficiency of TRIM38 resulted in abolished translocation of TAB2 to the lysosome, increased level of TAB2 in cells, and enhanced activation of TAK1 after TNFα and IL-1ß stimulation. We conclude that TRIM38 negatively regulates TNFα- and IL-1ß-induced signaling by mediating lysosome-dependent degradation of TAB2/3, two critical components in TNFα- and IL-1ß-induced signaling pathways. Our findings reveal a previously undiscovered mechanism by which cells keep the inflammatory response in check to avoid excessive harmful immune response triggered by TNFα and IL-1ß.

Neurological manifestations, laboratory and neuroimaging features in HIV-infected patients.

OBJECTIVE: To present detailed information regarding these aspects in Human Immunodeficiency Virus (HIV)-infected patients making an effort to improve the recognition of neurological complications of HIV infection. METHODS: This retrospective study analyzed the clinical manifestations, laboratory and neuroimaging results of HIV-infected patients with neurological complications at Xuanwu hospital, Beijing, China from January 2011 to December 2014, one of top-rated hospitals in Beijing, China. RESULTS: A diverse range of clinical diagnoses was identified, including encephalopathy, meningoencephalitis, peripheral neuropathy, multiple sclerosis, cerebral infarction and lymphoma associated with HIV infection. The mostly observed neurological disorders were motor/sensory deficits in the limbs (75%), cognitive impairments (42%) and fever (33%). Non-specific results of laboratory tests, including elevated erythrocyte sedimentation rate (ESR), cerebrospinal fluid (CSF) protein concentration and IgG, were found. Brain Magnetic Resonance Imaging (MRI) abnormalities displayed a variety of patterns and distributions due to diverse clinical profiles. CONCLUSION: The clinical scenarios of HIV-infected patients are remarkably diverse and complex. Etiological tests would be cardinal to make more definitive diagnosis for HIV-infected patients. Prospective studies with follow-up were needed to bring more accurate information.

Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway.

The lack of the neuropeptide orexin, also known as hypocretin, results in narcolepsy, a chronic sleep disorder characterized by frequent sleep/cataplexy attacks and rapid eye movement sleep abnormalities. However, the downstream pathways of orexin signaling are not clearly understood. Here, we show that orexin activates the mTOR pathway, a central regulator of cell growth and metabolism, in the mouse brain and multiple recombinant cell lines that express the G protein-coupled receptors (GPCRs), orexin 1 receptor (OX1R) or orexin 2 receptor (OX2R). This orexin/GPCR-stimulated mTOR activation is sensitive to rapamycin, an inhibitor of mTOR complex 1 (mTORC1) but is independent of two well known mTORC1 activators, Erk and Akt. Rather, our studies indicate that orexin activates mTORC1 via extracellular calcium influx and the lysosome pathway involving v-ATPase and Rag GTPases. Moreover, a cytoplasmic calcium transient is sufficient to mimic orexin/GPCR signaling to mTORC1 activation in a v-ATPase-dependent manner. Together, our studies suggest that the mTORC1 pathway functions downstream of orexin/GPCR signaling, which plays a crucial role in many physiological and metabolic processes.