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Mounting evidence indicates that tumor-derived exosomes (TDEs) play critical roles in tumor development and progression by regulating components in the tumor microenvironment (TME) in an autocrine or paracrine manner. Moreover, due to their delivery of critical molecules that react to chemotherapy and immunotherapy, TDEs also contribute to tumor drug resistance and impede the effective response of antitumor immunotherapy, thereby leading to poor clinical outcomes. There is a pressing need for the inhibition or removal of TDEs to facilitate the treatment and prognosis of cancer patients. Here, in the present review, we systematically overviewed the current strategies for TDE inhibition and clearance, providing novel insights for future tumor interventions in translational medicine. Moreover, existing challenges and potential prospects for TDE-targeted cancer therapy are also discussed to bridge the gaps between progress and promising applications.

DNA interstrand crosslinks are tumor-inducing lesions that block DNA replication and transcription. When crosslinks are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2-FANCI clamp by the Fanconi anemia (FA) core complex. Monoubiquitinated FANCD2-FANCI is locked onto DNA and recruits nucleases that mediate DNA repair. However, it remains unclear how phosphorylation activates this pathway. Here, we report structures of FANCD2-FANCI complexes containing phosphomimetic FANCI. We observe that, unlike wild-type FANCD2-FANCI, the phosphomimetic complex closes around DNA, independent of the FA core complex. Surprisingly, the phosphomimetic mutations do not substantially alter DNA binding but instead destabilize the open state of FANCD2-FANCI and alter its conformational dynamics. Overall, our results reveal that phosphorylation primes the FANCD2-FANCI clamp for ubiquitination, showing how multiple post-translational modifications are coordinated to control DNA-repair.

Research reported prevalence of post-traumatic stress disorder (PTSD) among prisoners varies between countries, with most studies based on Western samples. The trajectory of symptoms has also been controversial. Trauma can affect prisoners' emotions and their emotional regulation tends to be maladaptive.To examine changes in PTSD and psychiatric comorbidity among prisoners in China over time and to determine whether anger and self-concealment predicts later distress.In a longitudinal, prospective study, sentenced men in one prison in China were asked to complete a demographic page and several self-rating scales: the Post-traumatic Stress Diagnostic Scale, the General Health Questionnaire-28, the Clinical Anger Scale and the Self-Concealment Scale at baseline and at 6 and 12 months after the initial assessment.More than half of the 496 participating men were diagnosed with PTSD. For those completing the scales at each evaluation, PTSD-DS scores were significantly lower at baseline than at the 6-month and 1-year assessments. No significant differences were found between the two follow-up scores. There was no significant difference in psychiatric comorbidity between the three phases. At the cross-sectional level, after controlling for age and education level, PTSD, anger and self-concealment were associated with psychiatric comorbidity. At the prospective level, anger predicted PTSD 6 months and 1 year later. Self-concealment predicted psychiatric comorbidity over time.Among these prisoners the prevalence of chronic PTSD was far higher than in general population estimates. Early identification of aspects of coping styles is likely to help predict disorder trajectory and inform interventions. Early signs of anger were indicative of the chronic severity of trauma reactions, while the intention to hide distress was related to other later mental health problems.

Purpose: This study aims to characterize antimicrobial resistance (AMR), with particular reference to carbapenems and aminoglycosides, in MDR A. baumannii isolates recovered from an intensive care unit in a tertiary hospital. Methods: A. baumannii (n = 95 strains) isolated from patients were subjected to antimicrobial susceptibility test (AST) by Vitek 2 Compact system to determine minimum inhibitory concentrations, followed by genotyping by enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR). Resistance genes of interest were PCR-amplified and sequenced. Results: All isolates were qualified as MDR, with a resistance rate of >80% to 8 antimicrobials tested. In terms of beta-lactamase detection, the blaOXA23 and blaTEM-1 genes were detected frequently at 92.63% and 91.58%, respectively. The metallo-β-lactamase genes blaIMP, blaVIM, and blaNDM were undetected. Aph (3’)-I was detected in 82 isolates (86.32%), making it the most prevalent aminoglycoside-modifying enzyme (AMEs) encoding gene. In addition, ant (3”)-I was detected at 30.53%, while 26.32% of the strains harboured an aac (6')-Ib gene. ERIC-PCR typing suggested moderate genetic diversity among the isolates, which might be organized into 10 distinct clusters, with Cluster A (n = 86 isolates or 90.53%) being a dominant cluster of epidemic clones.Conclusions: Substantial fractions of the A. baumannii strains prevailing in the ICU were MDR clones exhibiting extremely high resistance to carbapenems and aminoglycosides as monitored throughout the study period. They principally belonged to a single cluster of isolates carrying blaOXA23 and armA co-producing different AMEs genes.

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth. An analysis of human papillomavirus (HPV)-specific CD8 T cells in patients with head and neck cancer identifies functional PD-1+TCF-1+CD8 T cells in the tumour with implications for therapeutic vaccination and PD-1 directed immunotherapy.

FAT atypical cadherin 1 (FAT1) is among the most frequently mutated genes in many types of cancer. Its highest mutation rate is found in head and neck squamous cell carcinoma (HNSCC), in which FAT1 is the second most frequently mutated gene. Thus, FAT1 has great potential to serve as a target or prognostic biomarker in cancer treatment. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular “brake” on mitochondrial respiration and acts as a receptor for a signaling pathway regulating cell–cell contact interaction and planar cell polarity. In many cancers, loss of FAT1 function promotes epithelial-mesenchymal transition (EMT) and the formation of cancer initiation/stem-like cells. However, in some types of cancer, overexpression of FAT1 leads to EMT. The roles of FAT1 in cancer progression, which seems to be cancer-type specific, have not been clarified. To further study the function of FAT1 in cancers, this review summarizes recent relevant literature regarding this protein. In addition to phenotypic alterations due to FAT1 mutations, several signaling pathways and tumor immune systems known or proposed to be regulated by this protein are presented. The potential impact of detecting or targeting FAT1 mutations on cancer treatment is also prospectively discussed.

Background. As the important components in polycomb repressive complexes 1 (PRC1) and heterochromatin protein 1 (HP1), Chromobox (CBX) family members are involved in epigenetic regulatory function, transcriptional repression, and other cellular metabolisms. Increasing studies have indicated significant associations between CBX and tumorigenesis, which is a progression in different types of cancers. However, the information about the roles of each CBX in gastric cancer is extremely limited. Methods. We explored CBX mRNA expression, corrections with clinicopathological parameters, protein expression, prognostic values, enrichment analysis with several databases including Oncomine, Human Protein Atlas, UALCAN, Kaplan-Meier plotter, cBioPortal, GeneMANIA, and Enrichr. Results. In our study, comparing to the normal tissues, higher mRNA expression of CBX1/2/3/4/5/8 and lower mRNA expression of CBX7 were found in GC tissues while upregulations of CBX1/2/3/4/5/8 and downregulations of CBX7 were indicated to be significantly correlated to the nodal metastasis status and individual cancer stages in GC patients. As for protein level, the expression of CBX2/3/4/5/6 was higher and the expression of CBX7 was lower in the GC tissues than those in the normal. What is more, higher mRNA expression of CBX1/5/6/8 and lower mRNA expression of CBX7 were markedly correlated to poor outcomes of OS and FP in GC patients. Besides, high mutation rate of CBXs (42%) was observed in GC patients. Conclusions. We suggest that CBX5/7 may serve as potential therapeutic targets for GC while CBX1/8 may serve as potential prognostic indicators for GC.

Prolonged survival and expanded treatment options in myeloma patients have led to adverse events associated with treatment getting increased attention. This systematic review and meta-analysis aimed to determine the incidence of ixazomib-associated cardiovascular adverse events (CVAEs) and to compare the rates of ixazomib-associated CVAEs and related therapies. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and high-grade CVAEs and study characteristics were recorded. A total of 266 potentially relevant articles were identified, and 246 were excluded after review. Twenty studies of 1715 patients with multiple myeloma were thus considered in this study. The estimated rates of all-grade and high-grade ixazomib associated CVAEs were 11.2 and 3.7%, respectively. Subgroup analysis showed that median age ≥65 years, none phase 1 trial and combination regimen were associated with higher rates of high-grade ixazomib associated CVAEs. Ixazomib was association with increased high-grade CVAEs risk (RR = 1.679, 95% CI: 1.078-2.615

Child abuse is a common experience among prisoners in China and associated with elevated psychiatric comorbidity. However, the association between child abuse profiles and dissociation is unclear. The extent to which the relationship between these profiles and dissociation might influence psychiatric comorbidity and self-concealment is also unclear. This study examined the impact of this relationship on the preceding outcomes among prisoners in China using Latent Class Analysis. Four hundred and ninety-six male prisoners from China completed questionnaires measuring child abuse, dissociation, self-concealment, and psychiatric comorbidity. A three-class solution was achieved: Class 1 (neglected with moderate dissociation) prisoners had a minimal level of abuse, the highest level of neglect experience, and a medium level of dissociation; Class 2 (low neglect with low dissociation) prisoners also had a minimal level of abuse but lower levels of neglect experience and dissociation; Class 3 (abused and neglected with high dissociation) prisoners had high levels of child abuse, neglect, and dissociation. Controlling for age, Class 3 reported significantly higher psychiatric comorbidity and self-concealment than the other two classes. Class 1 was more depressed than Class 2; Class 2 was more likely to engage in self-concealment than Class 1. To conclude, the kinds of childhood maltreatment experienced by prisoners and their readiness to detach from distressing emotions can influence the severity of current distress symptoms and the tendency to conceal things about themselves.

Myxofibrosarcoma (MFS) is a highly malignant subtype of soft tissue sarcoma, accounting for 5% of cases. Immunotherapy guided by immune cell infiltration (ICI) is reportedly a promising treatment strategy. Here, MFS samples (n = 104) from two independent databases were classified as ICI clusters A/B/C and gene clusters A/B/C. Then, a close relationship between ICI and gene clusters was established. We found that the features of these clusters were consistent with the characteristics of immune-inflamed tumors (cluster C), immune-desert tumors (cluster B), and immune-excluded tumors (cluster A). Moreover, cluster C was sensitive to immunotherapy. Finally, an independent ICI score was established to predict the therapeutic effect, which has prospects for application in guiding immunotherapy during clinical practice.

Spiritually incorporating couple therapy (SICT)-couple therapy that incorporates spiritual interventions-has a growing research base. Information is limited on how spiritual interventions are used in practice; thus we studied treatment-as-usual (TAU). SICT is treatment that, at a couple's request, sometimes draws upon spiritual resources when addressing relational issues. We tracked 65 couples from 29 couple therapists (who advertised as spiritually incorporating therapists) over 402 sessions of SICT. Couple spirituality predicted use of spiritual interventions more than did therapist spirituality. The most used spiritual interventions included silent prayer for the couple, discussions of hope and forgiveness, and encouragement to consult their heart. In SICT, therapists used evidence-based couple therapy approaches. SICT should (a) treat highly religious couples in high distress as being at risk for early drop out; (b) follow couples' leads in using spiritual methods; and (c) draw on evidence-based couple and spiritual practices. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Hope has been conceptualized as agency and pathways to achieve goals. However, this goal-directed conceptualization does not encapsulate all situations in which hope may be beneficial. To address the dispositional motivation to endure when a desired goal seems unattainable, unlikely, or even impossible (i.e., goal-transcendent hope), we provide initial psychometric evidence for the new Persevering Hope Scale (PHS). We developed and refined the PHS with undergraduates at a public college (Study 1) and replicated our findings in a community adult sample (Study 2). We replicated and extended these findings using longitudinal data with undergraduates at a faith-based college (Study 3) and a community sample of chronically ill adults (Study 4), and examined measurement invariance (Study 5). Scores on the PHS demonstrated robust evidence of estimated internal consistency and of criterion-related, convergent/discriminant, and incremental validity. Estimated temporal stability was modest. Partial scalar invariance was evidenced across samples, and full scalar invariance was evidenced across gender, race/ethnicity, and time. These preliminary findings suggest that the PHS is a psychometrically sound measure of persevering hope. Its use can broaden the current body of literature on trait hope to include goal-transcendent hope and advance research on the nature and benefits of this important construct.

Type 2 diabetes (T2DM) is a well known risk factor for Alzheimer’s disease. Mitochondria are the center of intracellular energy metabolism and the main source of reactive oxygen species. Mitochondrial dysfunction has been identified as a key factor in diabetes-associated brain alterations contributing to neurodegenerative events. Defective insulin signaling may act in concert with neurodegenerative mechanisms leading to abnormalities in mitochondrial structure and function. Mitochondrial dysfunction triggers neuronal energy exhaustion and oxidative stress, leading to brain neuronal damage and cognitive impairment. The normality of mitochondrial function is basically maintained by mitochondrial quality control mechanisms. In T2DM, defects in the mitochondrial quality control pathway in the brain have been found to lead to mitochondrial dysfunction and cognitive impairment. Here, we discuss the association of mitochondrial dysfunction with T2DM and cognitive impairment. We also review the molecular mechanisms of mitochondrial quality control and impacts of mitochondrial quality control on the progression of cognitive impairment in T2DM.

Purpose The chemotherapy-induced taste alteration scale (CiTAS) is a reliable and valid instrument to comprehensively assess patients’ taste alterations in an easy way. We aimed to translate it and test its psychometric properties among Chinese cancer patients undergoing chemotherapy. Method A convenience sample of 227 cancer patients were recruited in a tertiary cancer hospital in Beijing. The Chinese version of the CiTAS (C-CiTAS) was developed via rigorous translation methods. An exploratory structural equation model (ESEM) was used to test its construct validity. Correlations between the C-CiTAS scores and the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 scores were calculated for convergent validity. The overall taste alterations scale (OTAS) score was used to test its discriminant validity. Reliabilities were also examined. Results The majority of patients undergoing chemotherapy experienced minor to mild taste alterations. The current factor analysis results using the ESEM supported the original factor solution of the CiTAS, and no item of the CiTAS was dropped. The C-CiTAS demonstrated good construct validity, convergent validity and discriminant validity. The Cronbach's alphas of the C-CiTAS were 0.900 for the overall scale and from 0.570 to 0.857 for the four subscales. Its test-retest reliability was 0.815 (p Conclusions The Chinese version of the CiTAS is a reliable and valid instrument to evaluate cancer patients’ Chemotherapy-induced taste alterations in China.

Introduction: This study aimed to characterize antimicrobial resistance (AMR), molecular determinants of AMR and virulence, as well as clonal relationship of Streptococcus agalactiae isolates from women at 35-37 weeks of gestation in the Chaoshan metropolitan area of southern China. Methodology: Bacterial strains isolated from vaginal swabs were identified and antimicrobial susceptibility tests were performed by using a Vitek 2 Compact system (BioMérieux, France). Resistance and virulence genes were detected by polymerase chain reaction (PCR) and the clonal relationship was analysed by multiple locus variable number tandem repeat analysis (MLVA). Statistical analysis was carried out by using SPSS software, version 19.0. Results: All GBS were susceptible to benzylpenicillin, ampicillin, quinupristin/dalfopristin, tigecycline, linezolid and vancomycin, but a considerable proportion was resistant to clindamycin (29.67%), erythromycin (46.15%)， azithromycin (63.74%), tetracycline (84.62%) and quinolones (25.27%). The carrier rates of ermB (69.04%) and mefA/E (64.28%) were detected in these GBS strains resistant to erythromycin. In terms of MLVA detection, 91 GBS strains were categorized into 43 genotypes and 6 clusters. All GBS harboured hylB and cylE genes, most of which carried a combination of PI-1 and PI-2a genes as a common virulence gene profile. Conclusions: The high level of resistance conferred by some corresponding resistance genes to macrolides, lincosamides and quinolones of GBS isolates from pregnant women in southern China, has reinforced the necessity for monitoring GBS strain resistance to the above agents. Comparative genetic studies of GBS isolates, especially efforts to understand the relationship between pilus islands and genotype, were essential for conducting infection control and epidemiological comparisons between countries.

Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers.

Summary Background Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. Methods In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology–Oncology Programs Evaluation System in China. Young patients (16–60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61–80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1–5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01852435 . Findings From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6–77·6) and in the R-CEOP70 group was 72·4% ([66·5–77·5]; HR 1·00 [0·73–1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1–93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7–82·3]; 0·44 [0·25–0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4–83·7%]; 0·49 [0·27–0·86]; p=0·017). Grade 3–4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. Interpretation R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. Funding National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

Activated neutrophil-derived exosomes reportedly contribute to the proliferation of airway smooth muscle cells (ASMCs), thereby aggravating the airway wall remodeling during asthma; however, the specific mechanism remains unclear. Lipopolysaccharide (LPS)-EXO and si-CRNDE-EXO were extracted from the media of human neutrophils treated with LPS and LPS + si-CRNDE (a siRNA targets long non-coding RNA CRNDE), respectively. Human ASMCs were co-cultured with LPS-EXO or si-CRNDE-EXO, and cell viability, proliferation and migration were measured. The interplay of colorectal neoplasia differentially expressed (CRNDE), inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) and nuclear receptor subfamily 2 group C member 2 (TAK1) was explored using RNA immunoprecipitation (RIP) and Co-IP assays. A mouse model of asthma was induced using ovalbumin. CRNDE was upregulated in LPS-EXO and successfully transferred from LPS-treated neutrophils to ASMCs through exosome. Mechanically, CRNDE loaded in LPS-EXO reinforced TAK1-mediated IKKβ phosphorylation, thereby activating the nuclear factor kappa B (NF-κB) pathway. Functionally, silencing CRNDE in LPS-EXO, an IKKβ inhibitor, and an NF-κB inhibitor all removed the upregulation of cell viability, proliferation and migration induced by LPS-EXO in ASMCs. In the end, the in vivo experiment demonstrated that CRNDE knockdown in neutrophils effectively reduced the thickness of bronchial smooth muscle in a mouse model for asthma. Activated neutrophils-derived CRNDE was transferred to ASMCs through exosomes and activated the NF-κB pathway by enhancing IKKβ phosphorylation. The latter promoted the proliferation and migration of ASMCs and then contributed to airway remodeling in asthma.

Objective To test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts for the majority of HNSCC. Materials and Methods Cell growth, apoptosis and signaling changes in HNSCC cells following tipifarnib exposure in vitro were assessed by SRB, colony formation assay, annexin V staining and Western blot, respectively. A patient-derived xenograft (PDX) animal model was adopted to evaluate the efficacy of tipifarnib in vivo with and without cetuximab. Results Treatment of wild-type H-Ras HNSCC cell lines in vitro with tipifarnib reduced cell growth and increased levels of defarnesylated H-Ras in a dose-dependent manner. In a PDX mouse model, treatment with single-agent tipifarnib led to only near-significant growth inhibition. The addition of cetuximab resulted in increased anti-proliferative effect both in culture and in PDX models, which was also mirrored by Western blot and apoptosis assay results. Conclusion Tipifarnib has only a moderate ability to slow tumor growth as a single agent in HNSCC with wild type H-Ras, despite specifically inhibiting the farnesyltransferase upon which the function of H-Ras depends. The combination of cetuximab and tipifarnib appears to enhance the anti-proliferative effect of single-agent tipifarnib and marginally enhance that of single agent cetuximab. These findings deserve further evaluation.

The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations., The phosphatidylinositol-3-phosphate (PI3P) is generated by the lipid kinase VPS34, in the context of VPS34 complex I on autophagosomes or complex II on endosomes. Biochemical and structural analyses provide insights into the mechanism of both VPS34 complexes recruitment to and activation on membranes by specific Rab GTPases.

The development of antibodies that target specific glycan structures on cancer cells or human pathogens poses a significant challenge due to the immense complexity of naturally occurring glycans. Automated glycan assembly enables the production of structurally homogeneous glycans in amounts that are difficult to derive from natural sources. Nanobodies (Nbs) are the smallest antigen-binding domains of heavy-chain-only antibodies (hcAbs) found in camelids. To date, the development of glycan-specific Nbs using synthetic glycans has not been reported. Here, we use defined synthetic glycans for alpaca immunization to elicit glycan-specific hcAbs, and describe the identification, isolation, and production of a Nb specific for the tumor-associated carbohydrate antigen Globo-H. The Nb binds the terminal fucose of Globo-H and recognizes synthetic Globo-H in solution and native Globo-H on breast cancer cells with high specificity. These results demonstrate the potential of our approach for generating glycan-targeting Nbs to be used in biomedical and biotechnological applications.

The second King’s College London Symposium on Ageing and Long-term Care in China was convened from 4 to 5th July 2019 at King’s College London in London. The aim of the Symposium was to have a better understanding of health and social challenges for aging and long-term care in China. This symposium draws research insights from a wide range of disciplines, including economics, public policy, demography, gerontology, public health and sociology. A total of 20 participants from eight countries, seek to identify the key issues and research priorities in the area of aging and long-term care in China. The results published here are a synthesis of the top four research areas that represent the perspectives from some of the leading researchers in the field. © The Author(s) 2020.

Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. However, information on its correlation with other relevant cancer related proteins stratified by p16 status and its prognostic significance in OPSCC is limited. We examined FGFR3 expression and its correlation with clinical characteristics, p16 status, and mutant p53 (mp53) among 220 retrospectively collected OPSCC cases and 40 prospectively collected SCCHN cases, including a majority of OPSCC. Correlations of FGFR3 Weighted Index (WI) with p16 status and mp53 WI as well as its association with disease-free survival (DFS) and overall survival (OS) were evaluated. FGFR3 expression was detected in 61% and 70% of cases in cohorts 1 and 2, respectively. FGFR3 level was significantly higher in p16-negative tumors in both cohorts (p

Despite widespread interest in chemoprevention and therapy due to the high margin of safety of dietary natural compounds, clinical intervention with single agents has failed to yield the expected outcomes, mostly due to poor bioavailability and low potency. Combinations of natural agents with synergistic effects are gaining increasing attention. In the present study, in vitro and in vivo antitumor effects of a combination of two natural dietary agents, green tea epigallocatechin gallate (EGCG) and resveratrol were investigated. It was revealed that their combination at low doses (at which single agents induce minimal apoptosis) synergistically increased apoptosis (combination index

FAT1 is frequently mutated in head and neck squamous cell carcinoma (HNSCC), but the biological and clinical effects of FAT1 mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with FAT1 mutations and clinical outcomes of HNSCC patients. FAT1 mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. FAT1 mutation was significantly more prevalent among HPV(−), female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. FAT1 mutation was also significantly associated with lower FAT1 gene expression and increased protein expression of HER3_pY1289, IRS1, and CAVEOLIN1. From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer co-occurred with top mutated genes TP53 and CASP8. Poorer overall survival or progression-free survival was observed in patients with FAT1 mutation or altered HER3_pY1289, IRS1, or CAVEOLIN. Pathway analysis revealed dominant ERBB/neuregulin pathways mediated by FAT1 mutations in HNSCC, and protein signature panels uncovered the heterogeneity of patient subgroups. Decreased pEGFR, pHER2, and pERK and upregulated pHER3 and HER3 proteins were observed in two FAT1 knockout HNSCC cell lines, supporting that FAT1 alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of FAT1 and EGFR gene expression was identified. Collectively, these results suggest that alteration of FAT1 appears to involve mostly HPV(−) HNSCC and may contribute to resistance to EGFR-targeted therapy.

This study examined the interrelationship between child abuse, emotional processing difficulties, alexithymia, and psychological symptoms with posttraumatic stress disorder (PTSD) symptoms from past traumas adjusted among Chinese adolescents. Eight hundred adolescents completed questionnaires measuring the preceding psychological constructs. After controlling for PTSD from past trauma, structural equation modeling showed that child abuse correlated with emotional processing difficulty which correlated with alexithymia. In turn, alexithymia correlated with psychological symptom severity. To conclude, child abuse can affect psychological health among Chinese adolescents. This relationship, however, is influenced by the degree to which processing distressing emotions and getting in touch with internal feelings is avoided.

Aims To describe turnover intention of emergency nurses and clarify the effects of organizational commitment, job satisfaction and workplace violence on turnover intention. Background Research has showed the predictors of turnover intention differed among nurses of different specialties. However, research on turnover intention has mostly focused on general nurses rather than emergency nurses. Design A descriptive, cross-sectional study was conducted. Methods A self-administered questionnaire was used to collect data from 415 emergency nurses in Beijing, China, using convenience sampling. Path analysis was used to test the relationships between organizational commitment, job satisfaction, workplace violence and turnover intention. Results Most emergency nurses (90.2%) had a high level or very high level of turnover intention. Contrary to previous studies, organizational commitment had a significant direct positive effect on workplace violence. It also had a direct positive effect on job satisfaction and a negative effect on turnover intention. Workplace violence had a negative effect on job satisfaction and a positive effect on turnover intention. Job satisfaction had a direct negative effect on turnover intention. Conclusion To reduce turnover intention in the emergency department, measures should be taken to reduce workplace violence and increase nurses' job satisfaction, especially those with high organizational commitment.

Aim: The aim of our study was to describe the characteristics of postinfectious inflammatory response syndrome (PIIRS) in HIV-uninfected and nontransplant men after cryptococcal meningitis (CM). Patients & methods: A case-control study was designed to compare HIV-uninfected and nontransplant male CM patients with and without PIIRS. Results: CM-PIIRS patients had increased rates of hearing loss, V-P shunt placement, amphotericin B treatment, higher cerebrospinal fluid pressures and Cryptococcus counts in the first CM episode. CM-PIIRS episode was characterized by higher frequencies of headache and fever, higher C-reactive protein, erythrocyte sedimentation rate, cerebrospinal fluid white blood cell (WBC) counts and modified Rankin Score. Brain MRI scans revealed the high signal lesions on axial flair imaging. Receipt of corticosteroid therapy was associated with lower rates of fever and better modified Rankin Score scores at 1 month after treatment. Conclusion: CM-PIIRS episode differs to the initial presentation, may help to identify which patients are at risk to develop PIIRS. Steroids therapy could be beneficial.

CLCN2-related leukoencephalopathy (CC2L) is a rare disease due to autosomal recessive loss-of-function mutations in CLCN2 gene. We generated an induced pluripotent stem cell (iPSC) line (SKLOi001-A) from urine cells isolated from a CC2L patient carrying a homozygotic mutation: c.2257C>T (p.Arg753*) in CLCN2 gene via an integration-free methods. The established iPSC line kept the CLCN2 mutation and displayed a normal karyotype, expressed pluripotency markers, showed differentiation potential. This newly iPSC line could be served as a possible tool to unravel the mechanisms underlying CLCN2-associated diseases and screen drugs for the treatment.

The biophysical properties of cells such as their compressibility have been found to be closely related to disease progression such as cancer development and metastasis. As cancer cells are heterogeneous, rapid and high-throughput evaluation of cell biophysical properties at single-cell resolution is needed to assess their potential as biomarkers for cancer staging and prognosis. Acoustofluidics has shown promise as a contactless method for accurately measuring cell biophysical properties; however, previously reported methods had relatively low throughput due to their requirement of no-flow conditions. This work presents a high-throughput continuous flow-based acoustofluidic cell mechanotyping method at single-cell resolution that retains the advantage of simplicity and low-cost.

Cryptococcal meningitis (CM) is found to occur in immunosuppressed patients and those who are immunocompetent. This study aimed to compare the presentation and outcome of CM in patients who are human immunodeficiency virus (HIV) negative with and without immunosuppression. We reviewed 255 clinical records from patients with CM who are HIV negative. The demographic and clinical characteristics, cerebrospinal fluid profiles, brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. Among the 255 patients with CM, 91 (35.7%) appeared immunocompetent. CM was present in a younger population in the immunocompetent group (above 50 y, 19.8% vs. 32.3%, P=0.026), with higher initial complaints of visual and auditory symptoms (45.1% vs. 27.4%, P=0.004; 19.8% vs. 9.1%, P=0.016; respectively) and higher cerebrospinal fluid white blood cell counts (30.8% vs. 45.1%, P=0.009) compared with the immunocompromised patients. In addition, the immunocompetent patients had a higher proportion of normal brain images than did the immunocompromised patients (10% vs. 2%, P=0.028). There were no differences in hospital mortality and satisfactory outcomes between the groups (mortality: 10.9% vs. 7.0%, P=0.416; satisfactory outcomes: 76.4% vs. 80.2%, P=0.585). We found significant differences between the immunocompetent and HIV-negative immunocompromised patients; however, there were fewer differences between the groups than expected. Further studies assessing the immune responses in both groups should be performed.

To explore the clinical effects of oral small dose of cyclophosphamide (CTX) in the treatment of T-cell large granular lymphocytic leukemia (T-LGLL) accompanied with pure red cell aplasia (PRCA).The clinical features, characteristics of laboratory examinations and the process of oral small dose of CTX treatment after the ineffective treatment of cyclosporine A combining with prednisone in 1 case of T-LGLL with PRCA were reported and discussed with related references.The elderly female patient had indolent process, mainly presenting with anemia and significant low hyperplasia of bone marrow erythrocyte cells. Peripheral blood smear showed mainly with characteristic large granular lymphocytic morphology. The results of immunophenotypic analyses and genetic reassortment were compatible with T-LGLL. No effects were shown after 5 months of cyclosporine A combining with prednisone treatment and the patient still needed recurrent blood transfusion. CTX was prescribed as a second-line medication and the dose was 100 mg/d. Hemoglobin could returned to normal level and the efficacy remained for 1 year even after the medication was stopped.T-LGLL accompanied with PRCA is a rare disease and oral small dose CTX can be an effective therapeutic regimen.口服环磷酰胺治疗难治性T细胞大颗粒淋巴细胞白血病合并纯红细胞再生障碍性贫血的疗效.探讨小剂量环磷酰胺口服治疗难治性T-大颗粒淋巴细胞白血病（T-LGLL）伴纯红细胞再生障碍性贫血（PRCA）的疗效.报告1例T-LGLL合并PRCA患者的临床表现、实验室检查特征，及应用环孢素A联合强的松无效后给予口服小剂量环磷酰胺的治疗经过，并结合文献进行讨论.患者为老年女性，临床进展缓慢，以贫血为主要表现，骨髓红系细胞增生显著低下，血涂片以大颗粒淋巴细胞为主，免疫分型及基因重排符合T-LGLL，应用环孢素A联合强的松治疗5个月无效，需要依赖反复输血。二线改用环磷酰胺100 mg/d口服，血红蛋白恢复至正常水平，停药1年仍维持疗效.T-LGLL合并PRCA少见，小剂量环磷酰胺可作为有效的治疗方案.

Objective We aimed to develop novel combinations of inhibitors targeting EGFR family members and c-Met for the treatment of recurrent SCCHN. Materials and Methods Three different c-Met inhibitors in combination with a pan-HER inhibitor (crizotinib/afatinib, tivantinib/afatinib and cabozantinib/afatinib) were investigated for their anti-tumor effects on SCCHN cell lines in vitro. In vivo activity of the combinations was tested in SCCHN cell line xenografts and patient-derived xenograft (PDX) animal models generated from patients with recurrent SCCHN. Results Western blot assay indicated that activation of EGFR, HER2, HER3, and c-Met was blocked by all three combinations and the downstream PI3K/AKT and ERK signaling pathways were inhibited. Sulforhodamine B colorimetric assay revealed SCCHN cell growth was more effectively inhibited by the combinations than by single agents, particularly in cell lines with high c-Met expression. Furthermore, the combinations were more potent in inducing apoptosis than each of the single agents. In the PDX models, the combination treatments exhibited significantly better efficacy in tumor growth inhibition compared to the respective single agents. Conclusion In conclusion, we demonstrated that the simultaneous targeting of EGFR, HER2, and c-Met is more effective than the individual inhibition of these targets in vitro and in SCCHN cell line xenograft and PDX models. Our findings pave the way for further clinical investigation of such combinations in SCCHN.

A rapid and efficient analysis and screening method is adopted for cell affinity capture coupled with HPLC-MS (CAC-HPLC-MS) analysis of bioactive components that have possible efficiency against cardiovascular diseases. This method involves affinity capture, concentration, and separation of bioactive components from Danshen library using oxidatively damaged endothelial cells induced by H2 O2 , as well as analysis and identification of targeted compounds with HPLC and MS. It combines the specific interaction between cell membrane receptors and bioactive components with the powerful analysis and identification function of HPLC-MS. The CAC-HPLC-MS method was also used for analysis and screening of bioactive components from crude extracts of Danshen. A total of 19 components were found to be bound to oxidatively damaged endothelial cells with seven of these identified. Existing literature confirms that these seven components have many activities related to cardioprotective diseases. Therefore, the combination of biological affinity capture with HPLC-MS should be regarded as an attractive method with great potential for rapid and efficient screening of bioactive components related to anti-cardiovascular diseases from natural product libraries.

Background There is conflicting evidence regarding the role of peritumoral lymphatic vessel density (LVD) and blood microvessel density (MVD) in the metastasis and prognosis of head and neck squamous cell carcinoma (HNSCC). Existing studies are limited to one or two head and neck subsites and/or small sample sizes. A larger study incorporating multiple sub‐sites is needed to address the role of peritumoral LVD and MVD in HNSCC metastasis and prognosis. Methods Tissue samples from 200 HNSCC cases were stained simultaneously using immunohistochemistry (IHC) for markers of peritumoral LVD (lymphatic vessel marker D240) and MVD (blood vessel marker CD31). Of the stained slides, 166 and 167 were evaluable for LVD and MVD, respectively. The results were then correlated with clinicopathologic features and patient outcomes. Results Patients with metastatic disease were more likely to have high peritumoral MVD. Through multivariable analyses, MVD was not significantly related to DFS and OS, while low LVD was related to higher risk of disease progression and poor survival. Conclusions Peritumoral MVD was found to be positively associated with metastasis, while LVD was found to be inversely related to both metastasis and progression of HNSCC. These findings may suggest a prognostic role of both peritumoral LVD and MVD in patients with HNSCC.

Quantitative cross-linking/mass spectrometry (QCLMS/QXL-MS) probes structural changes of proteins in solution. This method has revealed induced conformational changes, composition shifts in conformational ensembles and changes in protein interactions. It illuminates different structural states of proteins or protein complexes by comparing which residue pairs can be cross-linked in these states. Cross-links provide information about structural changes that may be inaccessible by alternative technologies. Small local conformational changes affect relative abundances of nearby cross-links, whereas larger conformational changes cause new cross-links to be formed. Distinguishing between minor and major changes requires a robust analysis based on carefully selected replicates and, when using isotope-labeled cross-linkers, replicated analysis with a permutated isotope-labeling scheme. A label-free workflow allows for application of a wide range of cross-linking chemistries and enables parallel comparison of multiple conformations. In this protocol, we demonstrate both label-free and isotope-labeled cross-linker-based workflows using the cross-linker bis(sulfosuccinimidyl)suberate (BS3). The software XiSearch, developed by our group, is used to identify cross-linked residue pairs, although the workflow is not limited to this search software. The open-access software Skyline is used for automated quantitation. Note that additional manual correction greatly enhances quantitation accuracy. The protocol has been applied to purified multi-protein complexes but is not necessarily limited to that level of sample complexity. Optimizing the cross-linker/protein ratio and fractionating peptides increase the data density of quantified cross-links, and thus the resolution of QCLMS. The entire procedure takes ~1-3 weeks.

Item does not contain fulltext BACKGROUND: While previous studies have investigated the interplay between affect and health (1) over an extended period of time, (2) in a representative population, and (3) while modelling positive and negative affect simultaneously, no single study has done all three at once. METHODS: The present study accomplishes this by sampling adults from the Midlife Development in the US study who completed affect (Mroczek & Kolarz, 1998) and health measures (chronic conditions, Charlson, Szatrowski, Peterson, & Gold, 1994; functional limitations, McHorney, Ware, Lu, & Sherbourne, 1994; self-reported health) measured three times over 20 years. We ran three (one per health metric) random-intercept cross-lagged panel models, where positive and negative affect were modelled simultaneously. RESULTS: Results indicated that positive and negative affect significantly predicted future heath (functional limitations/self-reported health) and that this relationship was reciprocal (i.e. health measures predicted future affect). However, there were no significant cross-lagged relations between affect and chronic conditions. CONCLUSION: Our results suggest that both positive and negative affect play an equal role in predicting future health for functional limitations and self-reported health as well as highlight the bi-directionality of this relationship. Additionally, the degree to which affect predicts future health may be moderated by the type of health outcome.

This study addresses the hypothesis that IL-6/STAT3 signaling is of clinical relevance in oropharyngeal squamous cell carcinoma (OPSCC). We evaluated relationships between key components of this pathway in tumors from a unique cohort of n = 59 fully annotated, treatment-naïve patients with OPSCC. The multiplex Opal platform was utilized for immunofluorescence (IF) analysis of tissues to detect IL-6 and phosphorylated STAT3 (pSTAT3), taking into consideration its nuclear versus cytoplasmic localization. Abundant staining for both IL-6 and pSTAT3 was evident in tumor-rich regions of each specimen. IL-6 correlated with cytoplasmic pSTAT3 but not nuclear or total pSTAT3 in this cohort of OPSCC tumors, regardless of p16 status (r = 0.682, p

DNA origami is a promising molecular delivery system for a variety of therapeutic applications including cancer therapy, given its capability to fabricate homogeneous nanostructures whose physicochemical properties (size, shape, surface chemistry) can be precisely tailored. However, the correlation between DNA-origami design and internalization efficiency in different cancer cell lines remains elusive. We investigated the cellular uptake of four DNA-origami nanostructures (DONs) with programmed sizes and shapes in multiple human cancer cell lines. The cellular uptake efficiency of DONs was influenced by size, shape, and cell line. Scavenger receptors were responsible for the internalization of DONs into cancer cells. We observed distinct stages of the internalization process of a gold nanoparticle (AuNP)-tagged rod-shape DON, using high-resolution transmission electron microscopy. This study provides detailed understanding of cellular uptake and intracellular trafficking of DONs in cancer cells, and offers new insights for future optimization of DON-based drug delivery systems for cancer treatment.

OBJECTIVE Previous studies of American English isms terms have uncovered as many as five broad factors: tradition-oriented religiousness (TR), subjective spirituality (SS), communal rationalism (CR), unmitigated self-interest (USI), and inequality aversion (IA). The present studies took a similar lexical approach to investigate the Chinese-language isms structures in both mainland China and Taiwan. METHOD AND RESULTS In Study 1, exploratory factor analyses with 915 mainland Chinese subjects uncovered four interpretable factors dimensionalizing 165 mainland Chinese dictionary isms terms. These factors represented contents of a combination of TR and SS, USI, CR, and a culturally unique Communist Party of China (CPC) ideology factor. In Study 2, exploratory factor analyses with 467 Taiwan Chinese subjects revealed four interpretable factors categorizing 291 Taiwan Chinese dictionary isms terms. These factors represented contents of a combination of TR and SS, USI, CR, and a culturally unique dimension expressing aspirations for happiness. CONCLUSIONS The results gave evidence for the existence of the isms factors TR and SS, USI, and CR in Chinese culture. Cultural uniqueness was reflected in the merging of TR and SS into the factor Syncretic Religiousness and the culture-specific factors of CPC ideology in China and Happiness/Peace Promotion in Taiwan.

Objectives Compelling evidence demonstrates that CXC-chemokine receptor 4 (CXCR4) is involved in tumor invasion, angiogenesis, metastasis, and resistance to chemotherapy in addition to being one of the coreceptors for T-tropic human immunodeficiency virus entry into T cells. However, it remains controversial as to how to identify functionally activated CXCR4 in tumor biopsies, which would assist in determining which patients may benefit from potential CXCR4-targeted therapy. Materials and Methods Immunohistochemistry (IHC) staining on archival tissues of patients with non–small-cell lung cancer (NSCLC) was used to detect a panel of biomarkers, including phospho-ERK1/2, phospho-AKT, and E-cadherin, which are relevant to downstream signaling of CXCR4 and epithelial to mesenchymal transition (EMT). We also examined whether subcellular localization of CXCR4 could help define possible activation of CXCR4. Results A total of 94 primary tumor tissue samples from patients with NSCLC were included. Sixty-six patients had both cytomembranous and nuclear staining of CXCR4, 22 had solely nuclear staining, 5 had solely cytomembranous staining, and 1 had negative staining. Cytoplasmic location of CXCR4 with or without nuclear location was associated with loss of the epithelial marker E-cadherin ( P = .0015) and activation of ERK1/2 ( P = .0121) and AKT ( P = .0024), suggesting EMT in these tumors; whereas tumors with only nuclear location of CXCR4 were more indolent and preserved an epithelial phenotype. Conclusions Our study suggests that different subcellular localization of CXCR4 may be associated with different activation states; cytoplasmic CXCR4 seems to correlate with biomarker changes associated with EMT in NSCLC.

The current research investigated whether various aspects of mindfulness were differentially associated with risk preference in decision-making. In Studies 1 and 2, attention and present-focus aspects of trait mindfulness were associated with lower risk preference in making monetary gains. In Study 3, participants completed either a mindfulness training or listened to a comparable control recording. Compared to the control condition, subjects in the mindfulness condition were more risk-averse in making choices for monetary gains. The attention and present-focus aspects of state mindfulness mediated this connection. Study 4 introduced a loss framing, where attention and present-focus no longer associated with lower risk preference, but awareness and acceptance aspects of trait mindfulness associated with higher risk preference in avoiding monetary losses. The results suggest that different aspects of mindfulness have potential for mitigating risk preference, but such potential is limited depending on the framing of a decision context.

Child abuse among adolescents in China has been documented and can lead to a whole range of psychological and behavioural problems. This study examined whether male and female adolescents would differ in level of child abuse, emotional processing difficulties, alexithymia, psychological symptoms and behavioural problems, and whether the pattern of association between these variables would vary depending on gender. Eight hundred adolescents were recruited from China and completed the Childhood Trauma Questionnaire, Emotional Processing Scale, Toronto Alexithymia Scale, General Health Questionnaire, and Prediction Test of Problem Children. Male adolescents reported significantly higher levels of emotional and physical neglect, and external oriented thinking style than female adolescents. Females reported significantly more anxiety symptoms and problems with learning than males. For males, child abuse was associated with emotional processing difficulties which were associated with alexithymia. In turn, alexithymia was associated with both psychological and behavioural problems. For females, the same association was established for predicting behavioural problems but not psychological symptoms. Male and female adolescents differed in level of child abuse, alexithymia, psychological symptoms and behavioural problems. These psychological constructs were connected in a specific pattern to trigger psychological and behavioural problems for male adolescents whereas for females, different patterns were involved.

Watson, Paul/0000-0001-9116-5174; Tekke, Mustafa/0000-0003-0412-4353 WOS: 000522841400019 PubMed: 30120689 Amanah refers to the accountability of Muslims to their community. In Malaysian Muslim university students (N = 209), an Amanah Scale predicted a stronger sense of identity along with more adaptive religious and psychosocial functioning. Multiple regression analyses identified Accountability to Society as especially influential, but Accountability to Allah exhibited at least some problematic implications. Amanah mediated Identity linkages with some measures of religious and psychological adjustment, but also suppressed Identity relationships with greater self-knowledge and lower anxiety. These data confirmed the importance of communal commitments in Muslim mental health, suggested that accountability may have limited liabilities as well as more obvious psychosocial advantages, and identified possible complexities in the assessment of Accountability to Allah.

Summary The γ-tubulin ring complex (γTuRC) is the major microtubule nucleator in cells. The mechanism of its regulation is not understood. We purified human γTuRC and measured its nucleation properties in a total internal reflection fluorescence (TIRF) microscopy-based real-time nucleation assay. We find that γTuRC stably caps the minus ends of microtubules that it nucleates stochastically. Nucleation is inefficient compared with microtubule elongation. The 4 Å resolution cryoelectron microscopy (cryo-EM) structure of γTuRC, combined with crosslinking mass spectrometry analysis, reveals an asymmetric conformation with only part of the complex in a “closed” conformation matching the microtubule geometry. Actin in the core of the complex, and MZT2 at the outer perimeter of the closed part of γTuRC appear to stabilize the closed conformation. The opposite side of γTuRC is in an “open,” nucleation-incompetent conformation, leading to a structural asymmetry explaining the low nucleation efficiency of purified human γTuRC. Our data suggest possible regulatory mechanisms for microtubule nucleation by γTuRC closure., Graphical Abstract, Highlights • The γ-tubulin ring complex (γTuRC) nucleates microtubules and caps their minus ends • Microtubule nucleation from purified γTuRC is highly cooperative, yet inefficient • A partly open, asymmetric structure of γTuRC explains inefficient nucleation • Actin and MZT2 stabilize the closed part of the γTuRC structure, Consolati et al. find that microtubule nucleation by individual γTuRC complexes is inefficient despite its proposed role as a nucleating template. A 4 Å structure of the complex reveals a mismatch with the microtubule structure, explaining the inefficiency of nucleation and providing a possible mechanism for the regulation of nucleation.

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 (“tumor-only” mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC.

H-Ras is a unique isoform of the Ras GTPase family, one of the most prominently mutated oncogene families across the cancer landscape. Relative to other isoforms, though, mutations of H-Ras account for the smallest proportion of mutant Ras cancers. Yet, in recent years, there have been renewed efforts to study this isoform, especially as certain H-Ras–driven cancers, like those of the head and neck, have become more prominent. Important advances have therefore been made not only in the understanding of H-Ras structural biology but also in approaches designed to inhibit and impair its signaling activity. In this review, we outline historic and present initiatives to elucidate the mechanisms of H-Ras–dependent tumorigenesis as well as highlight ongoing developments in the quest to target this critical oncogene.

Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.

// Zhixiang Zhao 1,2,* , Mohammad Aminur Rahman 1,* , Zhuo G. Chen 1 and Dong M. Shin 1 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States of America 2 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China * These authors have contributed equally to this study Correspondence to: Dong M. Shin, email: // Keywords : twist1, EMT, stemness, angiogenesis, chemo-resistance Received : June 29, 2016 Accepted : January 01, 2017 Published : January 12, 2017 Abstract Twist1 is a well-known regulator of transcription during embryonic organogenesis in many species. In humans, Twist1 malfunction was first linked to Saethre-Chotzen syndrome and later identified to play an essential role in tumor initiation, stemness, angiogenesis, invasion, metastasis, and chemo-resistance in a variety of carcinomas, sarcomas, and hematological malignances. In this review, we will first focus on systematically elaborating the diverse pathological functions of Twist1 in various cancers, then delineating the intricate underlying network of molecular mechanisms, based on which we will summarize current therapeutic strategies in cancer treatment that target and modulate Twist1-involved signaling pathways. Most importantly, we will put special emphasis on revealing the independence and interdependency of these multiple biological functions of Twist1, piecing together the whole delicate picture of Twist1’s diversified pathological roles in different cancers and providing new perspectives to guide future research.

This study investigated whether child abuse was associated with psychiatric co-morbidity in a group of Chinese adolescents, and whether this association would be mediated by emotional processing difficulties and moderated by the severity of PTSD from other traumas in the past. Four hundred seventy-four adolescents participated in the study. They completed the Childhood Trauma Questionnaire-Short Form, General Health Questionnaire-28, the Posttraumatic Stress Diagnostic Scale, and Emotional processing scale-25. The results showed that after adjusting for the total number of traumatic events and how long ago the most traumatic event occurred, child abuse was associated with psychiatric co-morbidity. This association was not moderated by the severity of PTSD from past traumas but mediated by emotion processing difficulties. To conclude, adolescents who experience child abuse can develop emotional processing difficulties which in turn impact on psychiatric symptoms. Experience of past trauma does not influence these psychological processes.