Cardiac tumour necrosis factor receptor-associated factor 7 mediates the ubiquitination of apoptosis signal-regulating kinase 1 and aggravates cardiac hypertrophy.

AIMS: Cardiac remodelling is a common pathophysiological process in the development of various cardiovascular diseases, but there is still a lack of effective interventions. Tumour necrosis receptor-associated factor 7 (TRAF7) belongs to the tumour necrosis factor receptor-associated factor family and plays an important role in biological processes. Previous studies have shown that TRAF7 mutations lead to congenital defects and malformations of the heart. However, the molecular mechanisms of TRAF7 in the underlying pathogenesis of pathological cardiac hypertrophy remain unknown. We aim to study the molecular mechanisms and effects of TRAF7 in cardiac remodelling and whether it has the potential to become a therapeutic target for cardiac remodelling. METHODS AND RESULTS: The pressure overload-induced cardiac hypertrophy model in mice was established via transverse aortic constriction (TAC) surgery, and cardiomyocytes were treated with phenylephrine (PE) to induce hypertrophic phenotype. Levels of cardiac dysfunction and remodelling were measured with echocardiography and tissue or cell staining. RNA sequencing, western blot, qRT-PCR, co-immunoprecipitation, and in vivo ubiquitination assays were used to explore the molecular mechanisms. The results showed that the expression of TRAF7 increased gradually during the development of hypertrophy. Accordingly, TRAF7 significantly exacerbated the PE-induced enlargement of primary neonatal Sprague-Dawley rat cardiomyocytes, whereas TRAF7 knockdown alleviated the hypertrophic phenotype in primary cardiomyocytes. Cardiac-specific overexpression of TRAF7 accelerated hypertrophic phenotype in mice and cardiac-specific Traf7 conditional knockout mice improved hypertrophic phenotype induced by TAC. Mechanistically, TRAF7 directly interacted with apoptosis signal-regulating kinase-1 (ASK1) and promoted ASK1 phosphorylation by mediating the K63-linked ubiquitination of ASK1 in response to PE stimulation, which then promoted ASK1 activation and downstream signalling during cardiac hypertrophy. Notably, the pro-hypertrophic effect of TRAF7 was largely blocked by GS4997 in vitro and cardiac-specific Ask1 conditional knockout in vivo. CONCLUSION: In summary, we identified TRAF7 as an essential regulator during cardiac hypertrophy, and modulation of the regulatory axis between TRAF7 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.

Irinotecan plus raltitrexed as second-line treatment in locally advanced or metastatic colorectal cancer patients: a prospective open-label, single-arm, multi-center, phase II study.

BACKGROUND: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. METHODS: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. RESULTS: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. CONCLUSIONS: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.

Medical Malpractice in Otolaryngology within the United States: A LexisNexis-Based Demographic Analysis.

OBJECTIVE: Otolaryngologists are at a significantly greater risk of being sued than most other physicians. To date, there is a lack of studies characterizing trends in otolaryngology malpractice claims. To assess these trends and risk variables, this study examined malpractice claims against otolaryngologists. STUDY DESIGN: Retrospective database review. SETTING: LexisNexis Jury Verdicts and Settlements. METHODS: The LexisNexis legal database was used to locate jury verdicts and settlements related to medical malpractice in otolaryngology, from 2018 to 2024. The study did not include any claims covered by the Social Security Disability Insurance, Workers' Compensation, Healthcare Law, or Criminal Law and Procedure categories. Temporal trends were evaluated, and logistic regression was used to identify independent risk factors. RESULTS: Out of 903 items, 79 reported malpractice cases were included (mean age 44.5; 60.3% female). The most sued subspecialty was head and neck oncology (32.5%). Negligence (93.7%) was the primary cause of action. Of cases sent to the jury, 87.7% of them resulted in a verdict in favor of the defendant. The mean plaintiff verdict payout was $7,432,508.06 and the mean identified settlement amount was $1,562,500.00. Physical injury (62.0%) was the highest type of harm. Regional analysis indicated a higher percentage of cases from New York favored the defendant (21.1% vs 13.6%; P = .034). CONCLUSION: This study highlights key trends in otolaryngology malpractice claims, emphasizing the prevalence in cases of head and neck surgery, primarily attributed to negligence. By identifying trends and risk factors, otolaryngologists can get a better understanding of the dynamics surrounding malpractice.

Development of Chinese college students' perception teacher differential behavior scale and its reliability and validity test.

OBJECTIVE: To compile a scale of Chinese college students' perception of teachers' differential behavior and to provide a reference for college students to establish correct life values, promote college students' physical and mental health, and reduce teachers' differential treatment. METHODS: Open-ended questionnaires and expert interviews were used to conduct interviews and correspondence with 58 college students, ten psychologists, and six psychologists to form an initial questionnaire. Then, the scale's exploratory factor analysis, confirmatory factor analysis, and reliability and validity test were conducted on 7053 college students from 18 universities in 6 provinces (municipalities directly under the Central Government). RESULTS: The Chinese college students' perception of teachers' differential behavior scale has two dimensions: teacher prejudice and preference. Each dimension includes three aspects: emotional feedback, behavior orientation, and opportunity privilege, and each aspect have a total of 4 items. The consistency test coefficients of each dimension and each factor of the prepared scale are all above 0.7, and the split-half reliability is above 0.6. Confirmatory factor analysis shows that the six-factor structural model fits well (χ2/df = 4.287, RMSEA = 0.066, CFI = 0.950, TLI = 0.919). Using the generalized anxiety disorder scale and the patient health questionaire-9items as empirical criteria, each factor in the scale demonstrated significant correlations with both the GAD scale and the patient health questionaire-9items. CONCLUSIONS: The Chinese college students' perception of teachers' differential behavior scale has a two-dimensional six-factor structure and has good reliability and validity. It can be used as an effective tool to measure Chinese college students' perceived teacher differential behavior.

[Pollution Assessment and Source Apportionment of Heavy Metals in the Surrounding Soil of Typical Mining Areas in Tongling, Anhui Province].

To study the level of heavy metal pollution and ecological risks in the soil around typical mining areas in Tongling, a total of 150 soil samples were collected from the study area. The content characteristics of 10 elements, namely, As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Fe, and Zn, in the soils were analyzed. Methods including enrichment factor, the geo-accumulation index, single-factor pollution index, Nemero comprehensive pollution index, and potential ecological risk index were used to evaluate the pollution status of heavy metals in the soil of the study area. The pollution sources of heavy metals in the soil were also analyzed using correlation analysis, cluster analysis, and principal component analysis. The results showed that except for Cr and Fe, the average contents of the other eight heavy metal elements were higher than the soil background values in the study area. Pb, Zn, As, Cu, and Cd had a high degree of variation and were significantly affected by external interference. The spatial distribution showed that both Cr and Ni showed a decreasing trend from the edge to the central region, whereas the other eight heavy metals showed a decreasing trend from the central region to the surrounding areas. The pollution level of Cd and Cu in the soil of the research area was relatively severe. The overall ecological risk was at a medium to low level. Cd and Hg were the main contributing factors. As, Cd, Cu, Fe, Mn, Pb, and Zn mainly came from agricultural, industrial, and transportation sources, whereas Cr and Ni were mainly from natural sources. However, the sources of Hg were relatively complex. The research results can provide a scientific basis for the prevention and control of soil heavy metal pollution in metal mining areas, as well as the remediation of mine pollution.

LncRNA FAISL Inhibits Calpain 2-Mediated Proteolysis of FAK to Promote Progression and Metastasis of Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive subtype in breast tumors. When re-analyzing TCGA breast cancer dataset, we found cell adhesion molecules are highly enriched in differentially expressed genes in TNBC samples, among which Focal Adhesion Kinase (FAK) is most significantly associated with poor survival of TNBC patients. FAK is precisely modulated in the focal adhesion dynamics. To investigate whether lncRNAs regulate FAK signaling, we performed RNA immunoprecipitation sequencing and found FAISL (FAK Interacting and Stabilizing LncRNA) abundantly enriched in FAK-interacting lncRNAs and frequently overexpressed in TCGA TNBC tissues. FAISL promotes TNBC cell adhesion, cytoskeleton spreading, proliferation, and anchor-independent survival. FAISL doesn't affect FAK mRNA but positively regulates FAK protein level by blocking Calpain 2-mediated proteolysis. FAISL interacts with the C-terminus domain of FAK, whereby masks the binding site of Calpain 2 and prevents FAK cleavage. High level of FAISL correlates with FAK expression in tumor tissues and poor prognosis of TNBC patients. A siRNA delivery system targeting FAISL using reduction-responsive nanoparticles effectively inhibits tumor growth and metastasis in TNBC mouse models. Together, these findings uncover a lncRNA-mediated mechanism of regulating FAK proteolysis in the TNBC progression, and highlight the potential of targeting lncRNA FAISL for TNBC treatment.

Influence path of work-family conflict on primary care physicians' resignation intention: Data from a Chinese cross-sectional survey.

BACKGROUND: Primary care physicians and their teams are the leading force in constructing primary medical services, undertaking the critical responsibility of residents' essential health, and also related to realizing the national health goal. However, primary care physicians generally have a high turnover rate due to problems such as high work pressure, low salary levels, and limited career development. Therefore, exploring primary care physicians' resignation intentions plays a vital role in promoting the construction of primary care physicians' health service system. OBJECTIVE: This study explores the factors influencing the resignation intentions of primary care physicians, specifically examining the roles of work-family conflict, job satisfaction, professional identity, and emotional exhaustion. By understanding these dynamics, the research aims to inform strategies that can enhance the stability and effectiveness of primary care services, ultimately contributing to the improvement of public health infrastructure and achieving national health goals. This investigation will utilize structural equation modeling to analyze the interrelationships among the identified variables, thereby providing a comprehensive framework for addressing the high turnover rates among primary care physicians. METHODS: This study uses the work-family conflict, job satisfaction, professional identity, and emotional exhaustion scales. The data comes from a cross-sectional survey in Zhejiang Province, China, in 2022. Using SPSS 27 and Mplus8.3 software to analyze 1205 primary care physicians and their team members, the selected cases all answered the relevant questions of resignation intention. The potential relationship among work-family conflict, job satisfaction, professional identity, emotional exhaustion, and family doctor resignation intention was explored by constructing structural equations. RESULTS: Work-family conflict can directly and positively affect primary care physicians' resignation intention (ß = -0.546, p < 0.001). The results of the mediation model found that job satisfaction, professional identity, and emotional exhaustion were significantly related to work-family conflict, and primary care physicians' resignation intention has a significant mediating effect. It mainly includes six intermediary approaches: one is through the independent intermediary effect of job satisfaction; the second is through the independent intermediary effect of professional identity; the third is through the chain intermediary effect between Job satisfaction and professional identity; the fourth is through the intermediary effect of Job satisfaction and emotional exhaustion chain intermediary; fifth is through the chain intermediary of professional identity and emotional exhaustion; sixth is through the complex chain intermediary of job satisfaction, professional identity, and emotional exhaustion. CONCLUSION: Primary care physicians have a high score in resignation intention, which deserves continuous attention. Relevant department can help primary care physicians balance work and family roles, provide them with appropriate resources and rewards, as well as a good working environment and career development opportunities, to improve their job satisfaction and professional identity and reduce emotional exhaustion, thereby reducing the risk of resignation intention.

ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance.

The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.

The safety and efficacy of third- and fourth-generation cryoballoons for atrial fibrillation: a systematic review and meta-analysis.

Objectives: An increasing number of studies have shown that third (CB3)- and fourth-generation cryoballoons (CB4) have been used to treat various types of atrial fibrillation (AF), but previous research regarding the safety and efficacy of CB3 or CB4 ablation remains controversial. Therefore, a meta-analysis was performed to further evaluate the safety and efficacy of pulmonary vein isolation (PVI) using the CB3 and CB4 in the treatment of AF. Methods: We searched PubMed, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, and Clinicaltrials.gov up to December 2023 for qualified trials and data extraction according to inclusion and exclusion criteria. All analyses were carried out using Review Manager 5.3 software. Results: The meta-analysis included 13 observational studies consisting of 3,281 subjects and did not include a randomized controlled trial. Overall analyses indicated that the CB3 significantly reduced total procedure time [weighted mean difference (WMD) = -8.69 min, 95% confidence interval (CI) = -15.45 to -1.94 min, I2 = 93%], increased the PVI recording [relative risk (RR) = 1.24, 95% CI = 1.03-1.49, I2 = 90%], and increased the mean nadir temperature of overall PVs (WMD = 2.80°C, 95% CI = 1.08-4.51°C, I2 = 89%) compared with the CB2. Moreover, the CB4 significantly reduced the total procedure time (WMD = -14.50 min, 95% CI = -20.89 to -8.11 min, I2 = 95%), reduced the fluoroscopy time (WMD = -2.37 min, 95% CI = -4.28 to -0.46 min, I2 = 95%), increased the PVI recording (RR = 1.40, 95% CI = 1.15-1.71, I2 = 90%) compared with the CB2. Time-to-isolation, the success rate of PVI, AF recurrence, and complications in the CB3 and CB4 were not significantly different compared with the CB2. Conclusion: These findings demonstrated that the CB3 and CB4 tended to be more effective than the CB2 in the treatment of AF, with shorter procedure times, more PVI recording, and similar safety endpoints.

Comparing the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone.

INTRODUCTION: Cocaine is commonly consumed with ethanol, which leads to the formation of cocaethylene through transesterification. Cocaethylene is an active metabolite of cocaine with a longer duration of action. Literature on the combined toxicity of cocaine, ethanol, and cocaethylene is conflicting. We aimed to compare the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone in Hong Kong. METHODS: This was a retrospective study on acute cocaine toxicities reported to the Hong Kong Poison Control Center from 1 January 2010 to 22 January 2023. Cocaine exposure was confirmed by urine immunoassays/laboratory tests and ethanol co-ingestion was confirmed by blood ethanol concentrations. A serious outcome was defined as a National Poison Data System outcome moderate or above. Univariate analyses and multivariable logistic regression were performed to compare the associations of clinical outcomes with and without ethanol, followed by subgroup analyses of cases with complete data. RESULTS: We analyzed 109 patients (median age 29 years, 71% men, 68% Chinese), of whom 20 had confirmed ethanol co-ingestion (mean blood ethanol concentration 1350 mg/L). Multivariable analysis showed that co-exposure to cocaine and ethanol was associated with a lower risk of serious outcomes (adjusted odds ratio 0.09, 95% confidence interval 0.01-0.77; p = 0.03) after adjusting for age, sex, ethnicity, route of cocaine administration, and physical health status. Subgroup analyses showed similar findings. CONCLUSIONS: In contrast to previous studies, we did not identify a higher risk of serious outcomes after co-exposure to cocaine and ethanol compared to cocaine alone in a predominantly Chinese cohort.

Screening Targets and Therapeutic Drugs for Alzheimer's Disease Based on Deep Learning Model and Molecular Docking.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD. Objective: We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective. Methods: Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and molecular docking to screen targets and drugs for AD. Results: We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aß formation. Conclusions: This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment.

Association of total bilirubin with depression risk in adults with diabetes: A cross-sectional study.

BACKGROUND: Individuals with diabetes mellitus are more likely to experience depression, although most patients remain undiagnosed. The relation between total bilirubin and depression has been increasingly discussed, but limited studies have examined the association of total bilirubin with depression risk in adults with diabetes, which warrants attention. AIM: To investigate the association between total bilirubin levels and the risk of depression in adults with diabetes. METHODS: The study included adults with diabetes from the National Health and Nutrition Examination Survey 2007-2018. Depression was determined using the Patient Health Questionnaire-9. Multivariable logistic regression, propensity score-matched analysis and restricted cubic spline models were utilized to investigate the association between total bilirubin levels and depression risk in adults with diabetes. RESULTS: The study included 4758 adults with diabetes, of whom 602 (12.7%) were diagnosed with depression. After adjusting for covariates, we found that diabetic adults with lower total bilirubin levels had a higher risk of depression (OR = 1.230, 95%CI: 1.006-1.503, P = 0.043). This association was further confirmed after propensity score matching (OR = 1.303, 95%CI: 1.034-1.641, P = 0.025). Subgroup analyses showed no significant dependence of age, body mass index, sex, race or hypertension on this association. Restricted cubic spline models displayed an inverted U-shaped association of total bilirubin levels with depression risk within the lower range of total bilirubin levels. The depression risk heightened with the increasing levels of total bilirubin, reaching the highest risk at 6.81 µmol/L and decreasing thereafter. CONCLUSION: In adults with diabetes, those with lower levels of total bilirubin were more likely to have depressive symptoms. Serum total bilirubin levels may be used as an additional indicator to assess depression risk in adults with diabetes.

Syphilis susceptibility factors atlas: A wide-angled Mendelian randomization study.

OBJECTIVE: The pathogenic mechanisms of syphilis and the host defense mechanisms against syphilis remain poorly understood. Exploration of the susceptibility factors of syphilis may provide crucial clues for unraveling its underlying mechanisms. METHODS: A two-sample Mendelian Randomization framework was utilized, and the inverse-variance weighted method was used as the main analysis. All data was sourced from Genome-wide association studies datasets from 2015 to 2022 in Europe, and all participants were of European descent. Only summary-level statistics were used. Sensitivity analyses were conducted to evaluate the heterogeneity and pleiotropy of the datasets. RESULTS: Our study established 18 exposure factors (12 risk factors and 6 protective factors) for syphilis susceptibility. Twelve factors encompassing body mass index, waist circumference, darker natural skin, cooked vegetable intake, processed meat intake, diabetes mellitus, glucose regulation disorders, gout, autoimmune diseases, rheumatoid arthritis, diverticulitis, and longer menstrual cycles were found to increase susceptibility to syphilis. In contrast, 6 factors including easier skin tanning, blonde natural hair color, irritability, higher neuroticism scores, extended sleep duration, and delayed age at first sexual intercourse were connected to a reduced risk of syphilis infection (all P < 0.05). CONCLUSIONS: This study identified 18 influencing factors of syphilis susceptibility. These findings offered novel insights for further probing into the underlying pathogenic mechanisms of syphilis and underscored the importance of multifaceted prevention strategies against syphilis.

Transurethral En Bloc Resection Versus Standard Resection of Bladder Tumour: A Randomised, Multicentre, Phase 3 Trial.

BACKGROUND AND OBJECTIVE: Conventionally, standard resection (SR) is performed by resecting the bladder tumour in a piecemeal manner. En bloc resection of the bladder tumour (ERBT) has been proposed as an alternative technique in treating non-muscle-invasive bladder cancer (NMIBC). The objective of this study is to investigate whether ERBT could improve the 1-yr recurrence rate of NMIBC, as compared with SR. METHODS: A multicentre, randomised, phase 3 trial was conducted in Hong Kong. Adults with bladder tumour(s) of ≤ 3cm were enrolled from April 2017 to December 2020, and followed up until 1 yr after surgery. Patients were randomly assigned to receive either ERBT or SR in a 1:1 ratio. The primary outcome was 1-yr recurrence rate. A modified intention-to-treat analysis on patients with histologically confirmed NMIBC was performed. The main secondary outcomes included detrusor muscle sampling rate, operative time, hospital stay, 30-d complications, any residual or upstaging of disease upon second-look transurethral resection, and 1-yr progression rate. KEY FINDINGS AND LIMITATIONS: A total of 350 patients underwent randomisation, and 276 patients were histologically confirmed to have NMIBC. At 1 yr, 31 patients in the ERBT group and 46 in the SR group developed recurrence; the Kaplan-Meier estimate of 1- yr recurrence rates were 29% (95% confidence interval, 18-37) in the ERBT group and 38% (95% confidence interval, 28-46) in the SR group (p = 0.007). Upon a subgroup analysis, patients with 1-3 cm tumour, single tumour, Ta disease, or intermediate-risk NMIBC had a significant benefit from ERBT. None of the patients in the ERBT group and three patients in the SR group developed progression to muscle-invasive bladder cancer; the Kaplan-Meier estimates of 1-yr progression rates were 0% in the ERBT group and 2.6% (95% confidence interval, 0-5.5) in the SR group (p = 0.065). The median operative time was 28 min (interquartile range, 20-45) in the ERBT group and 22 min (interquartile range, 15-30) in the SR group (p < 0.001). All other secondary outcomes were similar in the two groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with NMIBC of ≤ 3cm, ERBT resulted in a significant reduction in the 1-yr recurrence rate when compared with SR. The study results support ERBT as the first-line surgical treatment for patients with bladder tumours of≤ 3cm.

Platelet-derived major histocompatibility complex class I coating on Treponema pallidum attenuates natural killer cell lethality.

The evasive tactics of Treponema pallidum pose a major challenge in combating and eradicating syphilis. Natural killer (NK) cells mediate important effector functions in the control of pathogenic infection, preferentially eliminating targets with low or no expression of major histocompatibility complex (MHC) class I. To clarify T. pallidum's mechanisms in evading NK-mediated immunosurveillance, experiments were performed to explore the cross-talk relations among T. pallidum, NK cells, and platelets. T. pallidum adhered to, activated, and promoted particle secretion of platelets. After preincubation with T. pallidum, platelets expressed and secreted high levels of MHC class I, subsequently transferring them to the surface of T. pallidum, potentially inducing an immune phenotype characterized by the "pseudo-expression" of MHC class I on the surface of T. pallidum (hereafter referred to a "pseudo-expression" of MHC class I). The polA mRNA assay showed that platelet-preincubated T. pallidum group exhibited a significantly higher copy number of polA transcript than the T. pallidum group. The survival rate of T. pallidum mirrored that of polA mRNA, indicating that preincubation of T. pallidum with platelets attenuated NK cell lethality. Platelets pseudo-expressed the MHC class I ligand on the T. pallidum surface, facilitating binding to killer cell immunoglobulin-like receptors with two immunoglobulin domains and long cytoplasmic tail 3 (KIR2DL3) on NK cells and initiating dephosphorylation of Vav1 and phosphorylation of Crk, ultimately attenuating NK cell lethality. Our findings elucidate the mechanism by which platelets transfer MHC class I to the T. pallidum surface to evade NK cell immune clearance.

Erratum: [Corrigendum] Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis.

[This corrects the article DOI: 10.3892/ol.2017.7635.].

AßPP-tau-HAS1 axis trigger HAS1-related nuclear speckles and gene transcription in Alzheimer's disease.

As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AßPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AßPP/PS1 mice. Phosphorylated tau (p-tau) mediates AßPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AßPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems.

Association between the HHEX polymorphism and delayed memory in first-episode schizophrenic patients.

The hematopoietically-expressed homeobox gene (HHEX) played a critical role in regulating the immune system that the abnormality of which was involved in the psychopathology and cognitive deficits of psychiatric disorders. The aim of this study was to investigate the effect of HHEX rs1111875 polymorphism on the susceptibility and cognitive deficits of first-episode schizophrenic patients (FSP). We assessed cognitive function in 239 first-episode patients meeting DSM-IV for schizophrenia, and 368 healthy controls using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The HHEX rs1111875 polymorphism was genotyped. Our results showed that the allelic and genotypic frequencies of HHEX rs1111875 polymorphism didn't differ between FSP and healthy controls (both p > 0.05) after adjusting for sex and age. Cognitive test scores in FSP were significantly lower than those in healthy controls on all scales (all p < 0.001) except for the visuospatial/constructional score (p > 0.05) after adjusting for covariates. There was a significant genotype (p < 0.05) rather than genotype × diagnosis (p > 0.05) effect on the delayed memory score after adjusting for covariates. The HHEX rs1111875 polymorphism was significantly associated with the delayed memory score in FSP (p < 0.05), but not in healthy controls (p > 0.05) after adjusting for covariates. Our findings supported that the HHEX rs1111875 polymorphism did not contribute to the susceptibility to FSP. However, this polymorphism might influence the delayed memory in FSP. Moreover, FSP had poorer cognitive function than healthy controls except for the visuospatial/constructional domain.

The Clinical Toxicology Recommendations Collaborative: purpose, organization, and methodology.

INTRODUCTION: Scientific societies aim to provide a collective voice and unified stance on important issues. The Clinical Toxicology Recommendations Collaborative was formed in 2016 to develop evidence- and consensus-based recommendations for the management of patients exposed to common and/or serious poisonings for which the management is unclear or controversial. ORGANIZATION: The Clinical Toxicology Recommendations Collaborative is led jointly by the American Academy of Clinical Toxicology, the Asia Pacific Association of Medical Toxicology, and the European Association of Poison Centres and Clinical Toxicologists. The Governance Committee is chaired by a Past-President of one of these Societies and comprised of the six Presidents and Immediate Past-Presidents of the three Societies. A Steering Committee oversees the process of each project workgroup. METHODOLOGY: The overall process is guided by standards set forth by the Institute of Medicine for developing trustworthy guidelines and the Appraisal of Guidelines for Research and Evaluation Instrument. Systematic reviews are produced using the framework set in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Workgroup members jointly review the evidence and prepare statements on which they vote anonymously using a 9-point Likert scale. A two-round modified Delphi method is used to reach a consensus on clinical recommendations using the RAND/UCLA Appropriateness Method. Final recommendations are approved by unanimous consent of the workgroup and are expressed as both levels of evidence and strength of recommendations. LIMITATIONS: The major limitations of the Clinical Toxicology Recommendations Collaborative process centre around the amount and quality of evidence, the assessment of that evidence, and the voting of the panel. CONCLUSIONS: By using a transparent evidence- and consensus-based approach to produce systematic reviews and clinical recommendations, the Clinical Toxicology Recommendations Collaborative aims to create an international framework for clinical toxicology education and decision-making and foster positive change for the benefit of poisoned patients.