Lactate enhances NMNAT1 lactylation to sustain nuclear NAD+ salvage pathway and promote survival of pancreatic adenocarcinoma cells under glucose-deprived conditions.

The aim of this study was to investigate the underlying molecular mechanism behind the promotion of cell survival under conditions of glucose deprivation by l-lactate. To accomplish this, we performed tissue microarray and immunohistochemistry staining to analyze the correlation between the abundance of pan-Lysine lactylation and prognosis. In vivo evaluations of tumor growth were conducted using the KPC and nude mice xenograft tumor model. For mechanistic studies, multi-omics analysis, RNA interference, and site-directed mutagenesis techniques were utilized. Our findings robustly confirmed that l-lactate promotes cell survival under glucose deprivation conditions, primarily by relying on GLS1-mediated glutaminolysis to support mitochondrial respiration. Mechanistically, we discovered that l-lactate enhances the NMNAT1-mediated NAD+ salvage pathway while concurrently inactivating p-38 MAPK signaling and suppressing DDIT3 transcription. Notably, Pan-Kla abundance was significantly upregulated in patients with Pancreatic adenocarcinoma (PAAD) and associated with poor prognosis. We identified the 128th Lysine residue of NMNAT1 as a critical site for lactylation and revealed EP300 as a key lactyltransferase responsible for catalyzing lactylation. Importantly, we elucidated that lactylation of NMNAT1 enhances its nuclear localization and maintains enzymatic activity, thereby supporting the nuclear NAD+ salvage pathway and facilitating cancer growth. Finally, we demonstrated that the NMNAT1-dependent NAD+ salvage pathway promotes cell survival under glucose deprivation conditions and is reliant on the activity of Sirt1. Collectively, our study has unraveled a novel molecular mechanism by which l-lactate promotes cell survival under glucose deprivation conditions, presenting a promising strategy for targeting lactate and NAD+ metabolism in the treatment of PAAD.

DNMT3a-mediated upregulation of the stress inducible protein sestrin-2 contributes to malignant transformation of human bronchial epithelial cells following nickel exposure.

BACKGROUND: Nickel is a confirmed human lung carcinogen. Nonetheless, the molecular mechanisms driving its carcinogenic impact on lung tissue remain poorly defined. In this study, we assessed SESN2 expression and the signaling pathways responsible for cellular transformation in human bronchial epithelial cells (HBECs) as a result of nickel exposure. METHODS: We employed the Western blotting to determine the induction of SESN2 by nickel. To clarify the signaling pathways leading to cellular transformation following nickel exposure, we applied techniques such as gene knockdown, methylation-specific PCR, and chromatin immunoprecipitation. RESULT: Exposure to nickel results in the upregulation of SESN2 and the initiation of autophagy in human bronchial epithelial cells (HBECs). This leads to degradation of HUR protein and consequently downregulation of USP28 mRNA, PP2AC protein, ß-catenin protein, and diminished VHL transcription, culminating in the accumulation of hypoxia-inducible factor-1α (HIF-1α) and the malignant transformation of these cells. Mechanistic studies revealed that the increased expression of SESN2 is attributed to the demethylation of the SESN2 promoter induced by nickel, a process facilitated by decreased DNA methyl-transferase 3 A (DNMT3a) expression, while The downregulation of VHL transcription is linked to the suppression of the PP2A-C/GSK3ß/ß-Catenin/C-Myc pathway. Additionally, we discovered that SESN2-mediated autophagy triggers the degradation of HUR protein, which subsequently reduces the stability of USP28 mRNA and inhibits the PP2A-C/GSK3ß/ß-Catenin pathway and c-Myc transcription in HBECs post nickel exposure. CONCLUSION: Our results reveal that nickel exposure leads to the downregulation of DNMT3a, resulting in the hypomethylation of the SESN2 promoter and its protein induction. This triggers autophagy-dependent suppression of the HUR/USP28/PP2A/ß-Catenin/c-Myc pathway, subsequently leading to reduced VHL transcription, accumulation of HIF-1α protein, and the malignant transformation of human bronchial epithelial cells (HBECs). Our research offers novel insights into the molecular mechanisms that underlie the lung carcinogenic effects of nickel exposure. Specifically, nickel induces aberrant DNA methylation in the SESN2 promoter region through the decrease of DNMT3a levels, which ultimately leads to HIF-1α protein accumulation and the malignant transformation of HBECs. Specifically, nickel initiates DNA-methylation of the SESN2 promoter region by decreasing DNMT3a, ultimately resulting in HIF-1α protein accumulation and malignant transformation of HBECs. This study highlights DNMT3a as a potential prognostic biomarker or therapeutic target to improve clinical outcomes in lung cancer patients.

The causal relationship between COVID-19 and seventeen common digestive diseases: a two-sample, multivariable Mendelian randomization study.

OBJECTIVES: In clinical practice, digestive symptoms such as nausea, vomiting are frequently observed in COVID-19 patients. However, the causal relationship between COVID-19 and digestive diseases remains unclear. METHODS: We extracted single nucleotide polymorphisms associated with the severity of COVID-19 from summary data of genome-wide association studies. Summary statistics of common digestive diseases were primarily obtained from the UK Biobank study and the FinnGen study. Two-sample Mendelian randomization analyses were then conducted using the inverse variance-weighted (IVW), Mendelian randomization-Egger regression (MR Egger), weighted median estimation, weighted mode, and simple mode methods. IVW served as the primary analysis method, and Multivariable Mendelian randomization analysis was employed to explore the mediating effect of body mass index (BMI) and type 2 diabetes. RESULTS: MR analysis showed that a causal association between SARS-CoV-2 infection (OR = 1.09, 95% CI 1.01-1.18, P = 0.03), severe COVID-19 (OR = 1.02, 95% CI 1.00-1.04, P = 0.02), and COVID-19 hospitalization (OR = 1.04, 95% CI 1.01-1.06, P = 0.01) with gastroesophageal reflux disease (GERD). Mediation analysis indicated that body mass index (BMI) served as the primary mediating variable in the causal relationship between SARS-CoV-2 infection and GERD, with BMI mediating 36% (95% CI 20-53%) of the effect. CONCLUSIONS: We found a causal relationship between SARS-CoV-2 infection and gastroesophageal reflux disease. Furthermore, we found that the causal relationship between SARS-CoV-2 infection and GERD is mainly mediated by BMI.

LINC00955 suppresses colorectal cancer growth by acting as a molecular scaffold of TRIM25 and Sp1 to Inhibit DNMT3B-mediated methylation of the PHIP promoter.

BACKGROUND: Long non-coding RNAs play an important role in the development of colorectal cancer (CRC), while many CRC-related lncRNAs have not yet been identified. METHODS: The relationship between the expression of LINC00955 (Long Intergenic Non-protein Coding RNA 955) and the prognosis of colorectal cancer patients was analyzed using the sequencing results of the TCGA database. LINC00955 expression levels were measured using qRT-PCR. The anti-proliferative activity of LINC00955 was evaluated using CRC cell lines in vitro and xenograft models in nude mice in vivo. The interaction of TRIM25-Sp1-DNMT3B-PHIP-CDK2 was analyzed by western blotting, protein degradation experiment, luciferase, RNA-IP, RNA pull-down assays and immunohistochemically analysis. The biological roles of LINC00955, tripartite motif containing 25 (TRIM25), Sp1 transcription factor (Sp1), DNA methyltransferase 3 beta (DNMT3B), pleckstrin homology domain interacting protein (PHIP), cyclin dependent kinase 2 (CDK2) in colorectal cancer cells were analyzed using ATP assays, Soft agar experiments and EdU assays. RESULTS: The present study showed that LINC00955 is downregulated in CRC tissues, and such downregulation is associated with poor prognosis of CRC patients. We found that LINC00955 can inhibit CRC cell growth both in vitro and in vivo. Evaluation of its mechanism of action showed that LINC00955 acts as a scaffold molecule that directly promotes the binding of TRIM25 to Sp1, and promotes ubiquitination and degradation of Sp1, thereby attenuating transcription and expression of DNMT3B. DNMT3B inhibition results in hypomethylation of the PHIP promoter, in turn increasing PHIP transcription and promoting ubiquitination and degradation of CDK2, ultimately leading to G0/G1 growth arrest and inhibition of CRC cell growth. CONCLUSIONS: These findings indicate that downregulation of LINC00955 in CRC cells promotes tumor growth through the TRIM25/Sp1/DNMT3B/PHIP/CDK2 regulatory axis, suggesting that LINC00955 may be a potential target for the therapy of CRC.

CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.

Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in patients with non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca2+ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation and, in turn, enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca2+-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.

Mechanistic exploration on neurodevelopmental toxicity induced by upregulation of alkbh5 targeted by triclosan exposure to larval zebrafish.

Because triclosan (TCS) has been confirmed to cause severe neurotoxicity, it is urgent to disclose the underlying toxicity mechanisms at varying levels. TCS exposure resulted in a series of malformations in larval zebrafish, including reduced neurons, blood-vessel ablation and abnormal neurobehavior. Apoptosis staining and the upregulated expression of proapoptotic genes demonstrated that TCS induced neuronal apoptosis and neurotransmitter disorders. By integrating RT-qPCR analysis with the effects of pathway inhibitors and agonists, we found that TCS triggered abnormal regulation of neuron development-related functional genes, and suppressed the BDNF/TrkB signaling pathway. TCS inhibited total m6A-RNA modification level by activating the demethylase ALKBH5, and induced neurodevelopmental toxicity based on the knockdown experiments of alkbh5 and molecular docking. The main novelties of this study lies in: (1) based on specific staining and transgenic lines, the differential neurotoxicity effects of TCS were unravelled at individual, physiological, biochemical and molecular levels in vivo; (2) from a epigenetics viewpoint, the decreasing m6A methylation level was confirmed to be mediated by alkbh5 upregulation; and (3) both homology modeling and molecular docking evidenced the targeting action of TCS on ALKBH5 enzyme. These findings open a novel avene for TCS's risk assessment and early intervention of the contaminant-sourcing diseases.

Low rectus femoris mass index is closely associated with diabetic peripheral neuropathy.

Aims: To assess the association of rectus femoris mass index (RFMI) with diabetic peripheral neuropathy (DPN) in individuals with type 2 diabetes mellitus (T2DM). Methods: Totally 948 T2DM cases were enrolled. Nerve conduction parameters, quantitative sensory threshold and rectus femoris cross-sectional area (RFCSA) were obtained, and rectus femoris mass index (RFMI=RFCSA/height2) was derived. The patients were assigned to four groups based on interquartile spacing of RFMI. Results: Motor/sensory nerve amplitude and conduction velocity (CV) were significantly lower in the low-level RFMI groups (all P<0.05). RFMI was positively associated with mean motor/sensory nerve amplitude and CV (both P<0.05). T2DM duration above 10 years and RFMI below 2.37cm²/m² had significant associations with DPN (both P<0.001). Receiver operating characteristic (ROC) curve analysis demonstrated cutoffs for T2DM duration and RFMI of 7 years and 2.2 cm²/m², respectively (AUC=0.75, 95% CI: 0.72-0.79; sensitivity, 68.4%; specificity, 66.8%). Conclusion: DPN is significantly associated with reduced RFMI in T2DM patients. Decreased muscle mass seems to be associated with motor/sensory nerve amplitude and CV. RFMI combined with T2DM duration may represent a potent tool for predicting DPN occurrence in T2DM cases. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2100049150.

Development and validation of the scale for symptom clusters in patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis(MG)often experience multiple symptoms concurrently, which can have an adverse effect on their quality of life(QOL). However, a specific, systemic and reliable scale for symptom clusters in MG is lacking. AIMS: To develop reliable assessment scale for symptom clusters in patients with MG. DESIGN: A cross-sectional descriptive study. METHODS: Based on the unpleasant symptom theory(TOUS), the first draft of the scale was developed through review literature, qualitative interview, and Delphi expert correspondence, the items of the scale were presented and adjusted through cognitive interviews with 12 patients. To conveniently assess the validity and reliability of the scale, a cross-sectional survey was conducted in 283 patients with MG who were recruited from Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, from June to September 2021. RESULTS: The final symptom cluster scale for patients with MG consisted of 19 items(MGSC-19), with a content validity index ranging from 0.828 to 1.000 for each item and the content validity index was 0.980. Four common variables (ocular muscle weakness, general muscular weakness, treatment-related side effects, and psychiatric problems) were identified by exploratory factor analysis, which explained 70.187% of the total variance. The correlation coefficients between the scale dimension and the overall score ranged from 0.395 to 0.769 (all P < 0.01), while the correlation coefficients between dimensions varied from 0.324 to 0.510 (all P < 0.01). The Cronbach's alpha, retest reliability, and half reliability were 0.932, 0.845, and 0.837, respectively. CONCLUSION: The validity and reliability of MGSC-19 were generally good. This scale can be employed to identify the symptom clusters to help healthcare givers develop individualized symptom management measures for patients with MG.

Immunotoxicity induced by triclocarban exposure in zebrafish triggering the risk of pancreatic cancer.

Owing to frequent application as a broad-spectrum bactericide, triclocarban (TCC) exposure has raised great concern for aquatic organisms and human health. Herein, based on transcriptome sequencing data analysis of zebrafish, we confirmed that TCC induced oxidative stress and dysimmunity through transcriptional regulation of the related genes. With aid of the Cancer Genome Atlas (TCGA) assembler database, 52 common differentially expressed genes, whose functions were related to immunity, were screened out by virtue of the meta-analysis of pancreatic cancer sample data and differential transcription profiles from TCC-exposed larvae. Acute TCC exposure affected formation of the innate immune cells, delayed mature thymic T-cell development, reduced immunoglobulin M (IgM) levels and promoted excessive release of the pro-inflammatory factors (IL-6, IL-1ß and tnfα). Under TCC exposure, the expressions of the genes associated with immune cell abundance in pancreatic cancer were significantly down-regulated, while the levels of ROS were prominently increased in concomitant with suppressed antioxidant activity. Moreover, a series of marker genes (pi3k, nrf2, keap1, ho-1 and nqo1) in the PI3K/Nrf2 antioxidant-stress pathway were abnormally expressed under TCC exposure. Interestingly, vitamin C decreased the malformation and increased the survival rate of 120-hpf larvae and effectively alleviated TCC-induced oxidative stress and immune responses. Overall, TCC exposure induced immunotoxicity and increased the risk of pancreatic cancer by inhibiting the antioxidant capacity of the PI3K/Nrf2 signal pathway. These observations enrich our in-depth understanding of the effects of TCC on early embryonic-larval development and immune damage in zebrafish.

Visceral fat correlates with insulin secretion and sensitivity independent of BMI and subcutaneous fat in Chinese with type 2 diabetes.

Aim: Clinical heterogeneity exists in overall obesity and abdominal obesity in terms of insulin secretion and sensitivity. Further, the impact of visceral fat (VF) on the first- and second-phase insulin secretion (FPIS and SPIS) is controversial. We aim to investigate insulin secretion and sensitivity in Chinese patients with T2DM according to different BMI and VF levels. Methods: This study enrolled 300 participants. A dual bioelectrical impedance analyzer was used to assess the visceral and subcutaneous fat area (VFA and SFA). VF levels were categorized as normal or high, with the cutoff value of 100 cm2. FPIS and SPIS were evaluated by arginine stimulation test and standardized steamed bread meal tolerance test, respectively. ß-cell function (HOMA2-ß), insulin resistance (HOMA2-IR), and Gutt's insulin sensitivity index (Gutt-ISI) were also calculated. Spearman's correlation analysis and multivariate linear regression analysis were adopted for statistical analysis. Results: Participants were categorized into four groups: normal weight-normal VF, normal weight-high VF, overweight/obese-normal VF and overweight/obese-high VF. Multivariate linear regression showed that both VFA and SFA were correlated with FPIS, HOMA2-IR and Gutt-ISI after controlling for gender and diabetes duration. After further adjustment for BMI and VFA, some associations of SFA with insulin secretion and sensitivity disappeared. After adjustment for gender, diabetes duration, BMI and SFA, VFA was positively correlated with FPIS, SPIS and HOMA2-IR. Subjects with overweight/obese-high VF were more likely to have higher FPIS, HOMA2-IR and lower Gutt-ISI (all p < 0.05). Conclusion: VF affects both FPIS and SPIS, and worsens insulin sensitivity independent of BMI and subcutaneous fat in Chinese patients with T2DM. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2200062884.

C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis.

Colorectal cancer (CRC) is one of the most common malignant tumors in the gastrointestinal tract, and has been attracted a great deal attention and extensive investigation due to its high morbidity and mortality rates. The C4orf19 gene encodes a protein with uncharacterized function. Our preliminary exploration of the TCGA database indicated that C4orf19 is markedly downregulated in CRC tissues in comparison to that observed in normal colonic tissues, suggesting its potential association with CRC behaviors. Further studies showed a significant positive correlation between C4orf19 expression levels and CRC patient prognosis. Ectopic expression of C4orf19 inhibited the growth of CRC cells in vitro and tumorigenic ability in vivo. Mechanistic studies showed that C4orf19 binds to Keap1 at near the Lys615, which prevents the ubiquitination of Keap1 by TRIM25, thus protecting the Keap1 protein from degradation. The accumulated Keap1 results in USP17 degradation and in turn leading to the degradation of Elk-1, further attenuates its regulated CDK6 mRNA transcription and protein expression, as well as its mediated proliferation of CRC cells. Collectively, the present studies characterize function of C4orf19 as a tumor suppressor for CRC cell proliferation by targeting Keap1/USP17/Elk-1/CDK6 axis.

Challenges faced when living with schizophrenia in the community: A narrative inquiry.

BACKGROUND: Schizophrenia is a chronic and severe mental disorder. People with schizophrenia have transferred from hospital-based care to community-based care with the support of mental health legal policies. Challenges faced in the community should be emphasized. Limited qualitative studies have explored the challenges of living with schizophrenia. AIMS: To explore the challenges of people living with schizophrenia in the community. METHODS: A narrative method was used, including semi-structured, face-to-face interviews. Thematic analysis approach was used to analyze data. RESULTS: Ten clients and their family members participated in the study. Analysis revealed three main themes related to their challenges in the community: deficits in self-management of illness; insufficient community mental health care; and the influence of policy. These challenges prevent those with schizophrenia from effectively managing their illness, returning to a productive role in society, and improving their quality of life. CONCLUSIONS: There are challenges in mental health rehabilitation and social reintegration of individuals with schizophrenia. There is a need for continuous community mental rehabilitation services, appropriate policy support, and the need to educate the public to reduce social bias and discrimination which allows individuals with schizophrenia to assume a productive role in the community.

Effects of symptom clusters on quality of life mediated by self-efficacy among individuals with myasthenia gravis: A structural equation modelling analysis.

AIMS AND OBJECTIVES: To determine whether self-efficacy mediates the relationship between Symptom Clusters (SC) and quality of life (QOL) in patients with myasthenia gravis (MG). BACKGROUND: The QOL in patients with MG can be affected not only by the SC but the self-efficacy in previous studies, while the latter may also be contributed by the former. However, it is still unclear whether self-efficacy mediates the relationship between SC and QOL in patients with MG. DESIGN: A cross-sectional survey was conducted in patients with MG who were recruited from our institution from October 2021 to March 2022, which was reported in line with the STROBE guidelines. METHODS: The hypothetical model was tested and all the effects of SC and self-efficacy on QOL were estimated based on structural equation modelling (SEM) analysis after conducting a confirmatory factor analysis of the scales in a separate cohort. RESULTS: Three scales for symptoms (four summated items), self-efficacy (four plus one parcelled item) and MG-QOL (three summated items) were validated according to the confirmatory factor analysis in 72 patients. An SEM analysis of another 310 participants revealed that SC exerted significant direct effects on QOL and self-efficacy, with values of .585 and -.293, respectively, and self-efficacy also had a significant effect on QOL (-.141). The indirect effect of SC on QOL via self-efficacy was .041, accounting for 6.6% of the overall effect. Male and female patients did not differ in the direct and indirect effects of symptoms on QOL. CONCLUSIONS: This study suggests that, although self-efficacy partially mediates the relationship between SC and QOL in patients with MG, worsening of symptoms remains the leading contributor to the decreased QOL. RELEVANCE TO CLINICAL PRACTICE: These results may provide a potential clue for doctors, nurses, and other caregivers to optimise treatment strategies for targeted patients with MG. PATIENT OR PUBLIC CONTRIBUTION: Involved in developing and answering research questions, management and conduct.

Development and validation of a nomogram to predict postoperative delirium in type B aortic dissection patients underwent thoracic endovascular aortic repair.

Objective: Postoperative delirium (POD) is a common postoperative complication after cardiovascular surgery with adverse outcomes. No prediction tools are currently available for assessing POD in the type B aortic dissection (TBAD) population. The purposes of this study were to develop and validate a nomogram for predicting POD among TBAD patients who underwent thoracic endovascular aortic repair (TEVAR). Methods: The retrospective cohort included 631 eligible TBAD patients who underwent TEVAR from January 2019 to July 2021. 434 patients included before 2021 were in the develop set; 197 others were in the independent validation set. Least absolute shrinkage and selection operator (LASSO) and logistic regression were applied to identify the most useful predictive variables for constructing the nomogram. Discrimination and the agreement of the model was assessed with the area under the receiver operating characteristic curve (AUC), Brier score and the Hosmer-Lemeshow goodness-of-fit test. The results were validated using a bootstrap resampling and the validation set. Results: The incidence rate of POD observed in the development and validation cohort were 15.0% and 14.2%, respectively. Seven independent risk factors, including age ≥60 years, syncope or coma, postoperative blood transfusion, atelectasis, estimated glomerular filtration rate (eGFR) <80 ml/min/1.73 m2, albumin <30 g/L, and neutrophil to lymphocyte ratio, were included in the nomogram. The model showed a good discrimination with an AUC of 0.819 (95% CI, 0.762-0.876) in the developed set, and adjusted to 0.797 (95% CI, 0.735-0.849) and 0.791 (95% CI, 0.700-0.881) in the internal validation set and the external validation, respectively. Favorable calibration of the nomogram was confirmed in both the development and validation cohorts. Conclusion: The nomogram based on seven readily available predictors has sufficient validity to identify POD risk in this population. This tool may facilitate targeted initiation of POD preventive intervention for healthcare providers.

Diabetic kidney disease progression is associated with decreased lower-limb muscle mass and increased visceral fat area in T2DM patients.

Aim: This study aimed to explore the relationship between lower-limb muscle mass/visceral fat area and diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 879 participants with T2DM were divided into 4 groups according to the prognosis of CKD classification from Kidney Disease: Improving Global Outcomes (KDIGO). Rectus femoris cross-sectional area (RFCSA) was measured through ultrasound, and visceral fat area (VFA) was evaluated with bioelectric impedance analysis (BIA). Results: T2DM patients with high to very high prognostic risk of DKD showed a reduced RFCSA (male P < 0.001; female P < 0.05), and an enlarged VFA (male P < 0.05; female P < 0.05). The prognostic risk of DKD was negatively correlated with RFCSA (P < 0.05), but positively correlated with VFA (P < 0.05). Receiver-operating characteristic analysis revealed that the cutoff points of T2DM duration combined with RFCSA and VFA were as follows: (male: 7 years, 6.60 cm2, and 111 cm2; AUC = 0.82; 95% CI: 0.78-0.88; sensitivity, 78.0%; specificity, 68.6%, P < 0.001) (female: 9 years, 5.05 cm2, and 91 cm2; AUC = 0.73; 95% CI: 0.66-0.81; sensitivity, 73.9%; specificity, 63.3%, P < 0.001). Conclusion: A significant association was demonstrated between reduced RFCSA/increased VFA and high- to very high-prognostic risk of DKD. T2DM duration, RFCSA, and VFA may be valuable markers of DKD progression in patients with T2DM. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2100042214.

SOX2 Promotes Invasion in Human Bladder Cancers through MMP2 Upregulation and FOXO1 Downregulation.

SOX2, a member of the SRY-related HMG-box (SOX) family, is abnormally expressed in many tumors and associated with cancer stem cell-like properties. Previous reports have shown that SOX2 is a biomarker for cancer stem cells in human bladder cancer (BC), and our most recent study has indicated that the inhibition of SOX2 by anticancer compound ChlA-F attenuates human BC cell invasion. We now investigated the mechanisms through which SOX2 promotes the invasive ability of BC cells. Our studies revealed that SOX2 promoted SKP2 transcription and increased SKP2-accelerated Sp1 protein degradation. As Sp1 is a transcriptionally regulated gene, HUR transcription was thereby attenuated, and, in the absence of HUR, FOXO1 mRNA was degraded fast, which promoted BC cell invasion. In addition, SOX2 promoted BC invasion through the upregulation of nucleolin transcription, which resulted in increased MMP2 mRNA stability and expression. Collectively, our findings show that SOX2 promotes BC invasion through both SKP2-Sp1-HUR-FOXO1 and nucleolin-MMP2 dual axes.

Experiences and challenges faced by community mental health workers when providing care to people with mental illness: a qualitative study.

BACKGROUND: Mental illness is a major burden of disease worldwide. Community Mental Health Services (CMHS) are key to achieving community-based recovery for people with mental illness. In China, even though the community management of patients with mental illness is improving, the barriers faced by Community Mental Health Workers (CMHWs) are unclear. This study explores the difficulties and challenges in CMHS from the perspective of CMHWs. The results of this study may provide a practical basis for the training of CMHWs. METHODS: We carried out a qualitative study using an empirical phenomenological approach. Nine CMHWs were recruited from nine communities in Wuhan, Hubei Province, using purposive and snowball sampling. Face to face semi-structured in-depth interviews were conducted with them from December 27 to 28, 2019. Interview recordings were converted to text content by Nvivo 11.0 software and analyzed using Colaizzi's phenomenological method. RESULTS: Three main themes were identified in this study: 1) Lack of role orientation leads to role ambiguity, 2) Failure to establish a therapeutic trust relationship with patients, and 3) Lack of communication and collaboration with various departments and peers. Seven sub themes were also identified. In these themes, CMHWs emphasized the importance of role clarity, therapeutic trusting relationships, and effective communication and coordination mechanisms. CONCLUSION: Although China has made great efforts on the road to improving the quality of CMHS, several salient issues regarding CMHWs must be addressed to optimize the quality of services provided by CMHWs. Community mental health institutions should help CMHWs overcome these difficulties, by maximizing its value and promoting the development of CMHS.

Visceral fat might impact left ventricular remodeling through changes in arterial stiffness in type 2 diabetes: A cross-sectional study.

AIMS: Visceral fat (VF) influences left ventricular (LV) structure and diastolic function in type 2 diabetes (T2DM). However, there are limited data on the association among them based on different BMI levels as well as accounting for arterial stiffness. This study investigated the association of fat distribution, arterial stiffness, left ventricular (LV) structure and diastolic function in T2DM patients. MATERIALS AND METHODS: This cross-sectional study comprised 905 patients. VF area (VFA) and subcutaneous fat area (SFA) were assessed by a dual bioelectrical impedance analyzer. Brachial-ankle pulse wave velocity (baPWV) was measured by a volume-plethysmographic apparatus and LV structure and diastolic function were echocardiography. Patients were divided into three groups based on BMI levels. Linear and logistic regression analysis were used to investigate the association. RESULTS: In multivariate linear regression, relative wall thickness (RWT) was negatively correlated with E/A in obese patients (ß = -0.203, p = 0.004). LV mass/height2.7 was positively correlated with E/E' in normal weight (ß = 0.232, p = 0.002) and obese patients (ß = 0.232, p = 0.008). In multivariate logistic regression, baPWV was an independent determinant of LV remodeling (LVRM) in normal weight (OR = 1.001; 95% CI, 1.000, 1.002; P = 0.006), overweight (OR = 1.001; 95% CI, 1.000, 1.002; P = 0.008) and obese groups (OR = 1.003; 95% CI, 1.001, 1.004; P = 0.001), while VFA was correlated with arterial stiffness in normal weight (OR = 1.032; 95% CI, 1.017, 1.047; P < 0.001) and overweight groups (OR = 1.011; 95% CI, 1.002, 1.021; P = 0.015). CONCLUSIONS: VF might impact LVRM through changes in baPWV in T2DM patients, thus influencing diastolic function.

Preliminary evaluation of the Chinese version of the patient-reported outcomes measurement information system 29-item profile in patients with aortic dissection.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System 29-item Profile (PROMIS-29) has been widely used to measure health outcomes from the patient's perspective. It has not been validated in adults with aortic disease. The aim of this study was to explore the reliability and validity of the Chinese PROMIS-29 among patients undergoing surgery for aortic dissection (AD). METHODS: A cross-sectional design was applied. Eligible patients completed a questionnaire that contained the PROMIS-29 and legacy measures, including the Short Form-12 Health Survey (SF-12), 8-item Somatic Symptom Scale (SSS-8), Generalized Anxiety Disorder-2 (GAD-2), and Patient Health Questionnaire-2 (PHQ-2). The structural validity of the PROMIS-29 was evaluated using confirmatory factor analysis (CFA). Reliability was evaluated with Cronbach's α. Construct validity was assessed by calculating Spearman's rank correlations and comparing known-group differences. RESULTS: In total, a sample of 327 AD patients was included in the final analysis. Most of them were male (89%) with a mean age of 52.7 (± 10.3). CFA revealed good model fit of the seven-factor structure within PROMIS-29, as well as most domains in single-factor analysis. Reliability was confirmed with Cronbach's α > 0.90. Correlations between comparable domains of the PROMIS-29 and those of legacy questionnaires and most know-group comparisons were observed as hypothesized. CONCLUSIONS: This study found evidence for acceptable structural validity, construct validity and internal consistency of the PROMIS-29 in a sample of AD patients. It can be applied to AD survivors by researchers or clinicians, measuring outcomes after surgery and identifying those with worse health status.

Reflexive Hospice Care: A Concept Analysis.

Background: Currently, the definition and naming of reflexive hospice care (RHC) vary, hindering its correct application in hospice care. Aims and Objectives: The study aims to understand the meaning of RHC by clarifying its uses, attributes, antecedents, and consequences. Design: The study focused on concept analysis. Methods: Walker and Avant's model was adopted for concept analysis, with a review based on PRISMA principles. Results: RHC included three attributes: supporting a person verbally, actionally, spiritually, materially, and/or through actions; providing reverse care (from patient to his/her relatives, friends, and/or care team); and a two-way flow of love. Its antecedents were terminal patients' knowledge, affection, and intention for RHC, strong emotional connection between patients and their family members, and medical staff's knowledge and skills of RHC. Its consequences benefit the patients and their family members, medical staff, and society. Conclusions: RHC could improve patients' quality of life, alleviate the anxiety and depression of their family members, and deepen society's cognition of life and death. There is an urgent need to develop strategies, assessment tools, and courses for RHC to promote its application. Relevance to Clinical Practice: Terminally ill patients who provide RHC will have better quality-of-life outcomes and face death more peacefully. Identifying the concept of RHC can help nurses and other health care professionals who wish to serve patients and their families better in hospice care.