Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi-center, single-arm, open-label, phase 2 study.

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single-arm, multi-center, open-label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression-free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3-month median follow-up, the median progression-free survival had not been achieved, while the 30-month progression-free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5-79.6) and 81.3% (95% CI, 70.8-88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Pharmacokinetics, pharmacodynamics and tolerability of single and multiple doses of janagliflozin, a sodium-glucose co-transporter-2 inhibitor, in Chinese people with type 2 diabetes mellitus.

AIMS: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and tolerability of janagliflozin, a novel sodium-glucose co-transporter-2 inhibitor, in Chinese people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this study, 36 people with T2DM were randomly assigned in a 1:1:1:1 ratio to receive janagliflozin 25 mg, janagliflozin 50 mg, dapagliflozin 10 mg or placebo. Participants received a single dose on day 1, and were treated once daily from day 4 to day 17. RESULTS: Following oral administration, janagliflozin was rapidly absorbed, reaching Cmax at 2 hours. The mean half-life (t1/2 ) at steady state was approximately 21 to 23 hours. There was no significant accumulation with multiple doses (accumulation factor < 2). In participants treated with janagliflozin 25 mg, janagliflozin 50 mg, dapagliflozin 10 mg or placebo, change in mean 24-hour urinary glucose excretion from baseline was 92.35, 94.17, 87.61 and 6.26 g after multiple doses, and change in mean fasting plasma glucose level from baseline to day 17 was -2.18, -2.66, -2.79 and 1.70%, respectively. Most adverse events (AEs) were mild or moderate with no deaths, serious AEs, or discontinuations due to AEs. CONCLUSIONS: Single and multiple oral administration (14 days) of janagliflozin 25 mg and 50 mg exhibited favourable PK, PD and tolerability profiles in Chinese people with T2DM, which were comparable to those of dapagliflozin 10 mg. Janagliflozin 25 mg and 50 mg are recommended for further clinical investigation.

Endovascular hypothermia improves post-resuscitation myocardial dysfunction by increasing mitochondrial biogenesis in a pig model of cardiac arrest.

The aim of the study was to investigate the effects of endovascular hypothermia on mitochondrial biogenesis in a pig model of prolonged cardiac arrest (CA). Ventricular fibrillation was electrically induced, and animals were left untreated for 10 min; then after 6min of cardiopulmonary resuscitation (CPR), defibrillation was attempted. 25 animals that were successfully resuscitated were randomized into three groups: Sham group (SG, 5, no CA), normal temperature group (NTG, 5 for 12 h observation and 5 for 24 h observation), and endovascular hypothermia group (EHG, 5 for 12 h observation and 5 for 24 h observation). The core temperatures (Tc) in the EHG were maintained at 34 ±â€¯0.5 °C for 6 h by an endovascular hypothermia device (Coolgard 3000), then actively increased at the speed of 0.5 °C per hour during the next 6 h to achieve a normal body temperature, while Tc were maintained at 37.5 ±â€¯0.5 °C in the NTG. Cardiac and mitochondrial functions, the quantification of myocardial mitochondrial DNA (mtDNA), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factor (NRF)-1, and NRF-2 were examined. Results showed that myocardial and mitochondrial injury and dysfunction increased significantly at 12 h and 24 h after CA. Endovascular hypothermia offered a method to rapidly achieve the target temperature and provide stable target temperature management (TTM). Cardiac outcomes were improved and myocardial injuries were alleviated with endovascular hypothermia. Compared with NTG, endovascular hypothermia significantly increased mitochondrial activity and biogenesis by amplifying mitochondrial biogenesis factors' expressions, including PGC-1α, NRF-1, and NRF-2. In conclusions, endovascular hypothermia after CA alleviated myocardial and mitochondrial dysfunction, and was associated with increasing mitochondrial biogenesis.

Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma.

The therapeutic strategy for advanced nasopharyngeal carcinoma (NPC) is still challenging. It is an urgent need to uncover novel treatment targets for NPC. Therefore, understanding the mechanisms underlying NPC tumorigenesis and progression is essential for the development of new therapeutic strategies. Here, we showed that TP53-regulated inhibitor of apoptosis (TRIAP1) was aberrantly overexpressed and associated with poor survival in NPC patients. TRIAP1 overexpression promoted NPC cell proliferation and suppressed cell death in vitro and in vivo, whereas TRIAP1 knockdown inhibited cell tumorigenesis and enhanced apoptosis through the induction of mitochondrial fragmentation, membrane potential alteration and release of cytochrome c from mitochondria into the cytosol. Intersecting with our previous miRNA data and available bioinformatic algorithms, miR-320b was identified and validated as a negative regulator of TRIAP1. Further studies showed that overexpression of miR-320b suppressed NPC cell proliferation and enhanced mitochondrial fragmentation and apoptosis both in vitro and in vivo, while silencing of miR-320b promoted tumor growth and suppressed apoptosis. Additionally, TRIAP1 restoration abrogated the proliferation inhibition and apoptosis induced by miR-320b. Moreover, the loss of miR-320b expression was inversely correlated with TRIAP1 overexpression in NPC patients. This newly identified miR-320b/TRIAP1 pathway provides insights into the mechanisms leading to NPC tumorigenesis and unfavorable clinical outcomes, which may represent prognostic markers and potential therapeutic targets for NPC treatment.

Therapeutic effect of human umbilical cord mesenchymal stem cells on tubal factor infertility using a chronic salpingitis murine model.

BACKGROUND: The study was conducted to evaluate the application of human umbilical cord mesenchymal stem cells (hUCMSCs) in the treatment of tubal factor infertility (TFI) caused by Chlamydia trachomatis, and investigate their effect on fertility in animal models of chronic salpingitis. METHODS: In this study, we investigated the therapy effects of the transplantation of hUCMSCs in tubal factor infertility using a chronic salpingitis murine model which induced Chlamydia trachomatis. Twenty rats were divided into two groups: control group (n = 10) and treatment group (n = 10). hUCMSCs were given to mice after exposure to C. trachomatis for 4 weeks. After treatment for 4 weeks, five mice were randomly selected from each of the two groups to sacrifice and we examined the organ morphology and pathology, inflammatory cytokines, proliferation, and apoptosis in fallopian tube (FT).The remaining five mice from each group were caged 2:1 with male mice for another 4 weeks, the numbers of pregnant mice and the mean number of pups in the different groups were enumerated and calculated. RESULTS: Intravaginal inoculation of hUCMSCs alleviated hydrosalpinx of the oviduct. EdU-labeled hUCMSCs are located at the interstitial site of the fallopian tube. Macrophage (F4/80) infiltration was significantly reduced in the treatment group compared with the control group and expression levels of the anti-inflammatory cytokine IL10 were increased after hUCMSCs treatment. Furthermore, mRNA and protein expression levels of PCNA and Caspase-3 were increased and decreased, respectively, in the hUCMSCs' treatment group compared with the control. Moreover, hUCMSCs' transplantation improved murine fertility. CONCLUSIONS: Anti-inflammatory and anti-apoptotic effects of hUCMSCs may play an important role in TFI. Our data suggest that hUCMSCs' transplantation contributed to the repair of tubal injury and improvement of fertility, providing a basis for assessing the contribution of stem cells in the oviduct for direct repair of the tube to assist reproduction.

A Flexible and Highly Sensitive Inductive Pressure Sensor Array Based on Ferrite Films.

There is a rapid growing demand for highly sensitive, easy adaptive and low-cost pressure sensing solutions in the fields of health monitoring, wearable electronics and home care. Here, we report a novel flexible inductive pressure sensor array with ultrahigh sensitivity and a simple construction, for large-area contact pressure measurements. In general, the device consists of three layers: a planar spiral inductor layer and ferrite film units attached on a polyethylene terephthalate (PET) membrane, which are separated by an array of elastic pillars. Importantly, by introducing the ferrite film with an excellent magnetic permeability, the effective permeability around the inductor is greatly influenced by the separation distance between the inductor and the ferrite film. As a result, the value of the inductance changes largely as the separation distance varies as an external load applies. Our device has achieved an ultrahigh sensitivity of 1.60 kPa-1 with a resolution of 13.61 Pa in the pressure range of 0-0.18 kPa, which is comparable to the current state-of-the-art flexible pressure sensors. More remarkably, our device shows an outstanding stability when exposed to environmental interferences, e.g., electrical noises from skin surfaces (within 0.08% variations) and a constant pressure load for more than 32 h (within 0.3% variations). In addition, the device exhibits a fast response time of 111 ms and a good repeatability under cyclic pressures varying from 38.45 to 177.82 Pa. To demonstrate its practical usage, we have successfully developed a 4 × 4 inductive pressure sensor array into a wearable keyboard for a smart electronic calendar application.

Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study.

BACKGROUND: Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma. METHODS: In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival. FINDINGS: We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p<0·0001), disease-free survival (HR 3·51, 2·43-5·07; p<0·0001), and overall survival (HR 3·22, 2·18-4·76; p<0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status. INTERPRETATION: The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis. FUNDING: The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities.

Prognostic significance of tumor-infiltrating lymphocytes in nondisseminated nasopharyngeal carcinoma: A large-scale cohort study.

The American Joint Committee on Cancer (AJCC) staging system is inadequate for an accurate prognosis in nasopharyngeal carcinoma (NPC). Thus, new biomarkers are under intense investigation. Here, we investigated whether the density of TILs could predict prognosis in NPC. First, we used 1490 cases of nasopharyngeal carcinoma samples from two independent cohorts to evaluate the density and distribution of tumor-infiltrating lymphocytes (TILs). Second, in one cohort, we assessed associations between TILs and clinical outcomes in 593 randomly selected samples (defined as the training set) and validated findings in the remaining 593 samples (defined as the validation set). Furthermore, we confirmed the prognostic value of TILs in a second independent cohort of 304 cases (defined as the independent set). Based on multivariable Cox regression analysis, we also established an effective prognostic nomogram including TILs to improve accuracy in predicting disease-free survival (DFS) for patients with nondisseminated NPC. We found that high TILs in the training set were significantly associated with favorable DFS [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.58, p < 0.001], overall survival (OS, HR 0.42, 95% CI 0.27-0.64, p < 0.001), distant metastasis-free survival (DMFS, HR 0.37, 95% CI 0.23-0.58, p < 0.001) and local-regional recurrent free survival (LRRFS, HR 0.43, 95% CI 0.25-0.73, p = 0.002). Multivariate analysis showed that TILs are an independent prognostic indicator for DFS in all cohorts. In summary, this study indicated that TILs may reflect the immunological heterogeneity of NPC and could represent a new prognostic biomarker.

Differential genome-wide profiling of alternative polyadenylation sites in nasopharyngeal carcinoma by high-throughput sequencing.

BACKGROUND: Alternative polyadenylation (APA) is a widespread phenomenon in the posttranscriptional regulation of gene expression that generates mRNAs with alternative 3'-untranslated regions (3'UTRs). APA contributes to the pathogenesis of various diseases, including cancer. However, the potential role of APA in the development of nasopharyngeal carcinoma (NPC) remains largely unknown. METHODS: A strategy of sequencing APA sites (SAPAS) based on second-generation sequencing technology was carried out to explore the global patterns of APA sites and identify genes with tandem 3'UTRs in samples from 6 NPC and 6 normal nasopharyngeal epithelial tissue (NNET). Sequencing results were then validated using quantitative RT-PCR in a larger cohort of 16 NPC and 16 NNET samples. RESULTS: The sequencing data showed that the use of tandem APA sites was prevalent in NPC, and numerous genes with APA-switching events were discovered. In total, we identified 195 genes with significant differences in the tandem 3'UTR length between NPC and NNET; including 119 genes switching to distal poly (A) sites and 76 genes switching to proximal poly (A) sites. Several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of cell migration, macromolecule catabolic process, protein catabolic process, proteolysis, small conjugating protein ligase activity, and ubiquitin-protein ligase activity. CONCLUSIONS: APA site-switching events are prevalent in NPC. APA-mediated regulation of gene expression may play an important role in the development of NPC, and more detailed studies targeting genes with APA-switching events may contribute to the development of novel future therapeutic strategies for NPC.

Transradial Versus Transfemoral Approach for Percutaneous Coronary Intervention in Elderly Patients in China: A Retrospective Analysis.

Objective To compare hospital costs and clinical outcomes between transradial intervention (TRI) and transfemoral intervention (TFI) in elderly patients aged over 65 years. Methods We identified 1229 patients aged over 65 years who underwent percutaneous coronary intervention (PCI) in Fuwai Hospital, Beijing, China, between January 1 and December 31, 2010. Total hospital costs and in-hospital outcomes were compared between TRI and TFI. An inverse probability weighting (IPW) model was introduced to control potential biases. Results Patients who underwent TRI were younger, less often female, more likely to receive PCI for single-vessel lesions, and less likely to undergo the procedure for ostial lesions. TRI was associated with a cost saving of CNY7495 (95%CI: CNY4419-10 420). Such differences were mainly driven by lower PCI-related costs. TRI patients had shorter length of stay (1.9 days, 95%CI: 1.1-2.7 days), shorter post-procedural stay (0.7 days, 95%CI: 0.3-1.1 days), and fewer major adverse cardiac events (adjusted odds ratio = 0.47, 95%CI: 0.31-0.73). There was no statistical significance in the incidence of post-PCI bleeding between TRI and TFI (P>0.05). Such differences remained consistent in clinically relevant subgroups of acute myocardial infarction, acute coronary syndrome, and stable angina. Conclusion The use of TRI in patients aged over 65 years was associated with significantly reduced hospital costs and more favorable clinical outcomes.

The China Acute Myocardial Infarction (CAMI) Registry: A national long-term registry-research-education integrated platform for exploring acute myocardial infarction in China.

BACKGROUND: Acute myocardial infarction (AMI) has become a major cause of hospitalization and mortality in China. There has been limited data to date available to characterize AMI presentation, contemporary patterns of medical care, and outcomes in China. AIMS: The CAMI Registry is a national project with the objectives to timely obtain real-world knowledge about AMI patients and to provide the platform for clinical research, guide preventive measures and care quality improvement efforts in China. METHODS AND PROGRESS: The CAMI registry is a prospective, nationwide, multicenter observational study for AMI patients. The registry includes three levels of hospitals (representing typical Chinese governmental and administrative models) from all provinces and municipalities throughout Mainland China except Hong Kong and Macau. Sites were instructed to enroll consecutive patients with a primary diagnosis of AMI. Clinical data, treatments, outcomes and cost are collected by local investigators and captured electronically, with a standardized set of variables and standard definitions, and rigorous data quality control. Post-discharge patient follow-up to 2 years is planned. The CAMI Registry was launched in January 2013. A total of 108 hospitals have participated in the registry so far. As of September 2014, 26,103 patients with AMI were registered. CONCLUSIONS: The CAMI registry represents a well-supported and the largest national long-term registry-research-education platform for surveillance, research, prevention and care improvement for AMI in China, the world's most populous nation. The broad representation of all provinces and different-level hospitals will allow for the exploration of AMI across diverse geographic regions and economic circumstances.

Microarray Expression Profiling of Long Non-Coding RNAs Involved in Nasopharyngeal Carcinoma Metastasis.

Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18 vs. S26) was constructed to determine the expression profile of lncRNAs using the microarray analysis, and we found 167 lncRNAs and 209 mRNAs were differentially expressed. Bioinformatic analysis indicated that the dysregulated mRNAs participated in important biological regulatory functions in NPC. Validation of 26 significantly dysregulated lncRNAs by qRT-PCR showed the expression patterns of 22 lncRNAs were in accordance with the microarray data. Furthermore, the expression level of ENST00000470135, which was the most upregulated lncRNA in high metastatic cell lines, was significantly higher in NPC cell lines and tissues with lymph node metastasis (LNM) and knocking down ENST00000470135 suppressed the migration, invasion and proliferation of NPC cells in vitro. In conclusion, our study revealed expression patterns of lncRNAs in NPC metastasis. The dysregulated lncRNAs may act as novel biomarkers and therapeutic targets for NPC.

High expression of Talin-1 is associated with poor prognosis in patients with nasopharyngeal carcinoma.

BACKGROUND: Talin-1 is a cytoskeletal protein that plays an important role in tumourgenesis, migration and metastasis in several malignant tumors. The aim of this study was to evaluate the expression and prognostic value of Talin-1 in nasopharyngeal carcinoma (NPC). METHODS: Talin-1 mRNA and protein expression were examined in NPC cell lines and clinical nasopharyngeal tissues by quantitative RT-PCR, agarose gel electrophoresis and western blotting. The expression of Talin-1 was analyzed by immunohistochemical staining in 233 paraffin-embedded NPC specimens with clinical follow-up data and cox regression analysis was used to identify independent prognostic factors. The functional role of Talin-1 in NPC cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by the wound healing and transwell invasion assays. RESULTS: The expression of Talin-1 was significantly upregulated in most NPC cell lines and clinical tissues at both the mRNA and protein levels. High expression of Talin-1 was significantly associated with distant metastasis (P = 0.001) and patient death (P = 0.001). In addition, high expression of Talin-1 was associated with significantly poorer overall survival (OS: HR, 2.15; 95% CI, 1.28-3.63; P = 0.003) and poorer distant metastasis-free survival (DMFS: HR, 2.39; 95% CI, 1.38-4.15; P = 0.001). Cox regression analysis indicated that high expression of Talin-1 and TNM stage were independent prognostic indicators (both P < 0.05). Stratified analysis demonstrated that high expression of Talin-1 was associated with significantly poorer survival in patients with advanced stage disease (stage III-IV, HR, 1.91; 95% CI, 1.09-3.35; P = 0.02 for OS and HR, 2.22; 95% CI, 1.24-3.99; P = 0.006 for DMFS). Furthermore, the depletion of Talin-1 suppressed the migratory and invasive ability of NPC cells in vitro. CONCLUSIONS: Our data demonstrate that high expression of Talin-1 is associated with significantly poorer OS and poorer DMFS in NPC and depletion of Talin-1 expression inhibited NPC cell migration and invasion. Talin-1 may serve as novel prognostic biomarker in NPC.

[Effect of lifestyle interventions on reduction of cardiovascular disease events and its mortality in pre-diabetic patients:long-term follow-up of Da Qing Diabetes Prevention Study].

OBJECTIVE: To investigate if a six-year intensive lifestyle intervention in people with pre-diabetes lead to reduction of cardiovascular events and cardiovascular disease (CVD) mortality in subsequent 23 years. METHODS: Five hundreds and nineteen subjects with normal glucose tolerance (NGT) and 577 subjects with impaired glucose tolerance (IGT) in Da Qing city were recruited in the study in 1986. The IGT subjects randomly assigned to either the no-intervention group or one of three lifestyle intervention groups (diet, exercise, or diet plus exercise) to receive a 6-year lifestyle intervention. In 2009, the participants were followed up to assess the primary outcomes of cardiovascular events and CVD mortality by a questionnaire and medical records. RESULTS: Subjects in IGT no-intervention group had the highest incidences of cardiovascular events (44.44%) and CVD mortality (20.00%), while those in NGT group had the lowest incidences of cardiovascular events (29.59%) and CVD mortality (7.52%) after 23-year follow-up. The incidences of cardiovascular events and CVD mortality in IGT intervention subjects were 37.84% and 12.53%, respectively. The multivariable analyses showed that, after controlling of age, gender, BMI smoking, blood pressure and cardiovascular event at baseline, the CVD mortality and incidence of cardiovascular events in IGT no-intervention group was 1.89 (HR = 1.89, 95%CI 1.11-3.22, P = 0.02) and 1.38 (HR = 1.38, 95%CI 1.01-1.90, P = 0.04) times of those in NGT group. However, the CVD mortality and incidence of cardiovascular events were not different in the IGT intervention group compared with those in the NGT group (HR = 1.39, 95%CI 0.89-2.18, P = 0.15 and HR = 1.25, 95%CI 0.98-1.59, P = 0.07, respectively). CONCLUSIONS: Subjects with IGT were at high risk for cardiovascular events and mortality. A six-year lifestyle intervention in this population can reduce both the incidence of cardiovascular event and CVD mortality.

Geniposide ameliorates psoriatic skin inflammation by inhibiting the TLR4/MyD88/NF-κB p65 signaling pathway and MMP9.

Psoriasis is an incurable immune-mediated disease affecting the skin or the joints. There are continuing studies on drugs for psoriasis prevention and treatment. This research found that Geniposide (GE) significantly thinned IMQ mice's skin lesions, reduced the scales, and lowered the presence of inflammatory cells in the pathology in a dose-dependent manner. GE inhibited IL-23, IL-22, IL-17A, IL-12, IL-6, and TNF-α levels in psoriatic mice serum. AKT1, TNF, TLR4, MMP9, MAPK3, and EGFR were selected as the top 6 targets of GE against psoriasis via network pharmacology, and GE-TLR4 has the most robust docking score value by molecular docking. Taken together, GE significantly inhibited TLR4 and MMP9 protein expression and influenced MyD88/NF-κB p65 signaling pathway. Finally, TLR4 was verified as the critical target of GE, which engaged in immunomodulatory activities and reduced MMP9 production in LPS and TAK-242-induced HaCaT cells. GE had a medium affinity for TLR4, and the KD value was 1.06 × 10-5 M. GE is an effective treatment and preventative strategy for psoriasis since it impacts TLR4.

DNA-methylome-derived epigenetic fingerprint as an immunophenotype indicator of durable clinical immunotherapeutic benefits in head and neck squamous cell carcinoma.

BACKGROUND: Cancer immunotherapy provides durable response and improves survival in a subset of head and neck squamous cell carcinoma (HNSC) patients, which may due to discriminative tumor microenvironment (TME). Epigenetic regulations play critical roles in HNSC tumorigenesis, progression, and activation of functional immune cells. This study aims to identify an epigenetic signature as an immunophenotype indicator of durable clinical immunotherapeutic benefits in HNSC patients. METHODS: Unsupervised consensus clustering approach was applied to distinguish immunophenotypes based on five immune signatures in The Cancer Genome Atlas (TCGA) HNSC cohort. Two immunophenotypes (immune 'Hot' and immune 'Cold') that had different TME features, diverse prognosis, and distinct DNA methylation patterns were recognized. Immunophenotype-related methylated signatures (IPMS) were identified by the least absolute shrinkage and selector operation algorithm. Additionally, the IPMS score by deconvolution algorithm was constructed as an immunophenotype classifier to predict clinical outcomes and immunotherapeutic response. RESULTS: The 'Hot' HNSC immunophenotype had higher immunoactivity and better overall survival (p = 0.00055) compared to the 'Cold' tumors. The immunophenotypes had distinct DNA methylation patterns, which was closely associated with HNSC tumorigenesis and functional immune cell infiltration. 311 immunophenotype-related methylated CpG sites (IRMCs) was identified from TCGA-HNSC dataset. IPMS score model achieved a strong clinical predictive performance for classifying immunophenotypes. The area under the curve value (AUC) of the IPMS score model reached 85.9% and 89.8% in TCGA train and test datasets, respectively, and robustness was verified in five HNSC validation datasets. It was also validated as an immunophenotype classifier for predicting durable clinical benefits (DCB) in lung cancer patients who received anti-PD-1/PD-L1 immunotherapy (p = 0.017) and TCGA-SKCM patients who received distinct immunotherapy (p = 0.033). CONCLUSIONS: This study systematically analyzed DNA methylation patterns in distinct immunophenotypes to identify IPMS with clinical prognostic potential for personalized epigenetic anticancer approaches in HNSC patients. The IPMS score model may serve as a reliable epigenome prognostic tool for clinical immunophenotyping to guide immunotherapeutic strategies in HNSC.

Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC.

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine-glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

A novel EIF3C-related CD8+ T-cell signature in predicting prognosis and immunotherapy response of nasopharyngeal carcinoma.

PURPOSE: At present, dysfunctional CD8+ T-cells in the nasopharyngeal carcinoma (NPC) tumor immune microenvironment (TIME) have caused unsatisfactory immunotherapeutic effects, such as a low response rate of anti-PD-L1 therapy. Therefore, there is an urgent need to identify reliable markers capable of accurately predicting immunotherapy efficacy. METHODS: Utilizing various algorithms for immune-infiltration evaluation, we explored the role of EIF3C in the TIME. We next found the influence of EIF3C expression on NPC based on functional analyses and RNA sequencing. By performing correlation and univariate Cox analyses of CD8+ Tcell markers from scRNA-seq data, we identified four signatures, which were then used in conjunction with the lasso algorithm to determine corresponding coefficients in the resulting EIF3C-related CD8+ T-cell signature (ETS). We subsequently evaluated the prognostic value of ETS using univariate and multivariate Cox regression analyses, Kaplan-Meier curves, and the area under the receiver operating characteristic curve (AUROC). RESULTS: Our results demonstrate a significant relationship between low expression of EIF3C and high levels of CD8+ T-cell infiltration in the TIME, as well as a correlation between EIF3C expression and progression of NPC. Based on the expression levels of four EIF3C-related CD8+ T-cell marker genes, we constructed the ETS predictive model for NPC prognosis, which demonstrated success in validation. Notably, our model can also serve as an accurate indicator for detecting immunotherapy response. CONCLUSION: Our findings suggest that EIF3C plays a significant role in NPC progression and immune modulation, particularly in CD8+ T-cell infiltration. Furthermore, the ETS model holds promise as both a prognostic predictor for NPC patients and a tool for adjusting individualized immunotherapy strategies.

CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.