Depressive Symptoms, Antidepressants, and Clinical Outcomes in Chronic Kidney Disease: Findings from the CRIC Study.

Rationale & Objective: The extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with nondialysis CKD. Study Design: Observational cohort study. Setting and Participants: Adults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC). Exposure: The Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use was identified from medication bottles and prescription lists. Individual effects of DS and antidepressants were examined along with categorization as follows: (1) BDI <11 and no antidepressant use, (2) BDI <11 with antidepressant use, (3) BDI ≥11 and no antidepressant use, and (4) BDI ≥11 with antidepressant use. Outcomes: CKD progression, incident cardiovascular disease composite, all-cause hospitalizations, and mortality. Analytic Approach: Cox regression models were fitted for outcomes of CKD progression, incident cardiovascular disease, and all-cause mortality, whereas hospitalizations used Poisson regression. Results: At baseline, 27.3% of participants had elevated DS, and 19.7% used antidepressants. Elevated DS at baseline were associated with significantly greater risk for an incident cardiovascular disease event, hospitalization, and all-cause mortality, but not CKD progression, adjusted for antidepressants. Antidepressant use was associated with higher risk for all-cause mortality and hospitalizations, after adjusting for DS. Compared to participants without elevated DS and not using antidepressants, the remaining groups (BDI <11 with antidepressants; BDI ≥11 and no antidepressants; BDI ≥11 with antidepressants) showed higher risks of hospitalization and all-cause mortality. Limitations: Inability to infer causality among depressive symptoms, antidepressants, and outcomes. Additionally, the absence of nonpharmacological data, and required exploration of generalizability and alternative analytical approaches. Conclusions: Elevated DS increased adverse outcome risk in nondialysis CKD, unattenuated by antidepressants. Additionally, investigation into the utilization and counterproductivity of antidepressants in this population is warranted.

We analyzed data from 4,839 nondialysis chronic kidney disease (CKD) patients in the Chronic Renal Insufficiency Cohort Study to explore how depression and antidepressants affect CKD-related outcomes. Using the Beck Depression Inventory (BDI), we assessed depressive symptoms (DS) and identified antidepressant use through medication records. Outcomes included CKD progression, cardiovascular events, hospitalizations, and mortality. Elevated DS at baseline raised the risk of cardiovascular events, hospitalizations, and mortality, regardless of antidepressant use. Antidepressant use alone was associated with higher mortality and hospitalization risks. In comparison to those without elevated DS and no antidepressant use, all other groups faced increased hospitalization and mortality risks. Elevated DS posed a significant risk to nondialysis CKD patients, and antidepressants did not mitigate this risk.

Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.

The value of preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and red blood cell distribution width in predicting positive surgical margin after laparoscopic radical prostatectomy.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignant tumors in men, and laparoscopic radical prostatectomy (LRP) is commonly used to treat localized and advanced PCa. Positive surgical margin (PSM) is one of the most frequent problems faced by surgeons. AIMS: This study aimed to explore the value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red blood cell distribution width (RDW) in predicting PSM after LRP. METHODS AND RESULTS: Three hundred and twenty patients with PCa were admitted and underwent LRP in Beijing Chaoyang Hospital from January 2017 to June 2023. Patients were randomly divided into a training set (225 cases) and a validation set (95 cases) in a 7:3 ratio. NLR, PLR, and RDW were significantly higher in the PSM group than in the negative surgical margins (NSM) group. In addition, the NLR, PLR, and RDW values correlated with clinical T stage, Gleason score, and seminal vesicle invasion in the PSM group. In training set, ROC curve analysis revealed that the optimal cutoff values of NLR, PLR, and RDW for predicting postoperative PSM in PCa were 2.31, 115.40, and 12.85%, respectively. Multivariate Logistic regression analysis showed NLR and RDW were the clinical independent predictors. The area under the curve (AUC, 0.770, 95% CI 0.709-0.831) for postoperative PSM was the highest when a combination of the three parameters was used, with sensitivity and specificity of 62.5% and 85.2%, respectively. In validation set, the AUC values for NLR, PLR, RDW and the three markers combined were 0.708, 0.675, 0.723, and 0.780, respectively. Correlation analysis showed that in the PSM group, NLR was positively correlated with PLR and RDW, and PLR was positively correlated with RDW. By contrast, in the NSM group, a positive association was only found between NLR and PLR. CONCLUSIONS: Higher preoperative NLR, PLR, and RDW values were associated with postoperative PSM. Additionally, the three markers combined may be useful to predict PSM.

Incidence of Pneumonia, Related Hospitalization, and Mortality Among Younger Unvaccinated IBD Patients in a Nationwide Cohort.

BACKGROUND AND GOALS: Community Acquired Pneumonia (CAP) is among the most common infections among Inflammatory Bowel Disease (IBD) patients. Our aim was to determine the absolute and relative risk of CAP, related hospitalization, and death among younger (age < 65) unvaccinated IBD patients exposed and unexposed to immunosuppressive medications. MATERIALS AND METHODS: We conducted a retrospective cohort study among a nationwide cohort of younger IBD unvaccinated patients in the VAHS. Exposure was administration of any immunosuppressive medication. The primary outcome was the first occurrence of pneumonia; secondary outcomes being pneumonia related hospitalization and mortality. We reported event rate per 1000 person-years, hazard ratio, and 95% confidence intervals (CIs) for each outcome. RESULTS: Among a total of 26,707 patients, 513 patients developed pneumonia. Mean age in years (SD) was 51.67 (11.34) for the exposed and 45.91 (12.34) for the unexposed group. The overall crude incidence rate was 3.2 per 1000 patient-years (PYs) [4.04/1000 PYs in the exposed versus 1.45/1000 PYs in the unexposed]. The overall crude incidence rates for pneumonia-related-hospitalization and mortality 1.12 and 0.09 per 1000 PYs, respectively. In Cox regression, the exposed group was associated with an increased risk of pneumonia (AHR 2.85; 95% CI: 2.21 to 3.66, P < 0.001) and pneumonia-related-hospitalization (AHR 3.46; 95% CI: 2.20 to 5.43, P < 0.001). CONCLUSIONS: Overall incidence of CAP among younger unvaccinated IBD patients was 3.2 per 1000 PYs. The overall associated hospitalization rates were low, however, higher amongst those exposed to immunosuppressive medications. This data will help patients and physicians make informed decisions regarding pneumococcal vaccine recommendations.

Nuclear respiratory factor 1 drives hepatocellular carcinoma progression by activating LPCAT1-ERK1/2-CREB axis.

BACKGROUND: Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. RESULTS: NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. CONCLUSIONS: NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients.

High frequency of alternative splicing variants of the oncogene Focal Adhesion Kinase in neuroendocrine tumors of the pancreas and breast.

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK6/7 in cells. These results suggested that FAK6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.

Case Report: Analysis of four cases of metastatic bladder masses after radical prostatectomy.

Objective: The aim of this study is to investigate the clinical characteristics and diagnostic and therapeutic methods of bladder metastasis after radical prostatectomy and to improve its diagnosis and treatment. Methods: The clinical data of four patients with bladder metastasis after radical prostatectomy were retrospectively analyzed from January 2011 to December 2021. Three cases suffered from intermittent gross hematuria, and only one case was found to have an elevated prostate-specific antigen (PSA) value. Transurethral resection of bladder tumor was performed in four cases, in which one case also underwent resection of urethral mass. Three cases received endocrine therapy, one of which added intravesical instillation and radiation therapy. Another case received chemotherapy based on comprehensive treatment. Results: According to the pathological and immunohistochemical results, three cases were acinar adenocarcinoma of the prostate with Gleason score of 9, and all cases were PSA positive and negative for cytokeratin 7 (CK7) and GATA binding protein 3 (GATA-3). One case was small cell neuroendocrine carcinoma of the prostate and was positive for chromogranin A (CGA), synaptophysin (SYN), and cluster of differentiation 56 (CD56). During the follow-up period of 4 to 13 months, one case was lost to follow-up and three cases were alive. Conclusion: Bladder metastasis after radical prostatectomy is rare, and pathology combined with immunohistochemistry is the gold standard for its diagnosis. Pathological type determines its treatment. Systemic treatment is essential, and local treatment is the most palliative means. Early diagnosis and treatment is significant for better prognosis.

Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. METHODS: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. RESULTS: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. CONCLUSION: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

The effect of 5-α reductase inhibitor on Th1, Th2, and Th17 cell-related inflammatory response in BPH.

OBJECTIVE: To investigate the effect of 5-α reductase inhibitor on the expression of inflammation-related cytokines in Benign prostatic hyperplasia (BPH) specimens after transurethral prostatic resection (TUR-P). METHODS: We prospectively examined the expression of inflammation-related cytokines with immunohistochemistry in the paraffin blocks of 60 patients who underwent TUR-P. 30 cases in the 5-α-reductase inhibitor group were treated with finasteride, 5 mg qd, for more than 6 months; 30 cases in the control group were not treated with medicine before operation. HE staining was used to analyze the difference of inflammation reaction between the two groups, and immunohistochemical staining was used to analyze the effect of 5-α reductase inhibitor on the expression of B-cell lymphoma-2 (Bcl-2), Interleukin-2 (IL-2), Interferon-γ (IFN-γ), Interleukin-4 (IL-4), Interleukin-6 (IL-6), Interleukin-17 (IL-17), Interleukin-21 (IL-21) and Interleukin-23 (IL-23) in prostatic tissue. RESULTS: There was no statistical difference in the location, range and degree of inflammation between the two groups (P > 0.05). When IL-17 expression was low, there was statistical difference between the two groups (P < 0.05). Bcl-2 expression was positively correlated with IL-2, IL-4, IL-6 and IFN-γ (P < 0.05). There was no statistical difference in the expression of IL-21, IL-23 and high expression of IL-17 between the two groups (P > 0.05). CONCLUSIONS: 5-α Reductase inhibitor can inhibit the expression of Bcl-2 in prostatic tissue and the inflammatory response related to T-helper cell 1 (Th1) and T-helper cell 2 (Th2) cells. However, it did not affect Th17 cell-related inflammatory response.

Socioeconomic characteristics of those with peripheral artery disease in the chronic renal insufficiency cohort.

BACKGROUND: The association between socioeconomic factors and peripheral arterial disease (PAD) has not been as well characterized as other cardiovascular conditions. We sought to define how annual income and education level are associated with PAD in a well-characterized diverse set of adults with chronic kidney disease (CKD). METHODS: The Chronic Renal Insufficiency Cohort Study (CRIC) is a multi-center, prospective cohort study designed to examine risk factors for progression of CKD and cardiovascular disease. Demographic, income, and education-level data, as well as clinical data including ankle-brachial index (ABI) were collected at baseline. Annual income was categorized as < $25,000, $25,000-50,000, $50,000-100,000, or above $100,000; educational level was categorized as some high school, high school graduate, some college, or college graduate. Participants with missing income data or incompressible ABI (>1.4) were excluded from initial analysis. Logistic regression was used to estimate the association of income and/or education level with PAD, defined as an enrollment ABI of <0.90, history of PAD, or history of PAD intervention. RESULTS: A total of 4122 were included, mean age of participants was 59.5 years, 56% were male, and 44% were Black. There were 763 CRIC participants with PAD at study enrollment (18.5%). In the final multivariable logistic regression model, Black race (OR = 1.3, 95% CI 1.1-1.6, p = 0.004) and level of annual household income remained independently associated with PAD at the time of enrollment (income <$25,000 OR = 1.9, 95% CI 1.3-2.8, p < 0.001; income $25,000-50,000 OR = 1.6, 95% CI 1.1-2.3, p = 0.011; income $50,000-100,000 OR = 1.2, 95% CI 0.9-1.8, p = 0.246), relative to a baseline annual income of >$100,000 (overall p-value <0.001). Decreasing level of educational attainment was not independently associated with increased PAD at enrollment, but lower level of educational attainment was associated with increased PAD when income data was not adjusted for (p = 0.001). Interestingly, Black race (OR = 0.7, 95% CI 0.6-0.8, p < 0.001), female gender (OR = 0.8, 95% CI 0.7-0.9, p = 0.007), and income <$25,000 (OR = 0.7, 95% CI 0.5-0.9, p = 0.008) were significantly associated with decreased statin use even after controlling for cardiovascular conditions. CONCLUSIONS: In this prospectively followed CKD cohort, lower annual household income and Black race were significantly associated with increased PAD at study enrollment. In contrast, educational level was not associated with PAD when adjusted for patient income data. Black race, female gender, and low income were independently associated with decreased statin use, populations which could be targets of future public health programs.

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study.

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODSWe examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTSIn CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSIONOur findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDINGThis study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Bves maintains vascular smooth muscle cell contractile phenotype and protects against transplant vasculopathy via Dusp1-dependent p38MAPK and ERK1/2 signaling.

BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) plasticity is tightly associated with the pathological process of vasculopathy. Blood vessel epicardial substance (Bves) has emerged as an important regulator of intracardiac vasculogenesis and organ homeostasis. However, the involvement and role of Bves in VSMC plasticity and neointimal lesion development remain unclear. METHODS: We used an in vivo rat model of graft arteriosclerosis and in vitro PDGF-treated VSMCs and identified the novel VSMC contractile phenotype-related gene Bves using a transcriptomic analysis and literature search. In vitro knockdown and overexpression approaches were used to investigate the mechanisms underlying VSMC phenotypic plasticity. In vivo, VSMC-specific Bves overexpression in rat aortic grafts was generated to assess the physiological function of Bves in neointimal lesion development. RESULTS: Here, we found that Bves expression was negatively regulated in aortic allografts in vivo and PDGF-treated VSMCs in vitro. The genetic knockdown of Bves dramatically inhibited, whereas Bves overexpression markedly promoted, the VSMC contractile phenotype. Furthermore, RNA sequencing unraveled a positive correlation between Bves and dual-specificity protein phosphatase 1 (Dusp1) expression in VSMCs. We found that Bves knockdown restrained Dusp1 expression, but enhanced p38MAPK and ERK1/2 activation, resulting in the loss of the VSMC contractile phenotype. In vivo, an analysis of a rat graft model confirmed that VSMC-specific Bves and Dusp1 overexpression in aortic allografts significantly attenuated neointimal lesion formation. CONCLUSIONS: Bves maintains the VSMC contractile phenotype through Dusp1-dependent p38MAPK and ERK1/2 signaling, and protects against neointimal formation, underscoring the important role of Bves in preventing transplant vasculopathy.

Benzodiazepine and antipsychotic use among hospitalized older adults before versus after restricting visitation: March to May 2020.

BACKGROUND: Hospital visitation restrictions during the COVID-19 pandemic prompted concerns about unintended consequences for older patients, including an increased incidence of delirium and agitation. While first-line interventions for these conditions are non-pharmacologic, a lack of family support could result in increased use of benzodiazepines and antipsychotics, which are associated with poor outcomes in older adults. Little is known about the association of visitation policies with use of these medications among older adults. METHODS: We conducted a retrospective cross-sectional study among adults aged ≥65 hospitalized from March 1 through May 31, 2020 at four hospitals in the Mid-Atlantic. The dates of onset of visitation restrictions (i.e., hospital-wide guidelines barring visitors) were collected from hospital administrators. Outcomes were use of benzodiazepines and antipsychotics, assessed using patient-level electronic health record data. Using multivariable logistic regression with hospital and study-day fixed effects, the quasi-experimental study design leveraged the staggered onset of visitation restrictions across the hospitals to measure the odds of receiving each medication when visitors were versus were not allowed. RESULTS: Among 2931 patients, mean age was 76.6 years (SD, 8.3), 51.6% were female, 58.6% white, 32.5% black, and 2.6% Hispanic. Overall, 924 (31.5%) patients received a benzodiazepine and 298 (10.2%) an antipsychotic. The adjusted odds of benzodiazepine use was lower on days when visitors were versus were not allowed (adjusted odds ratio [AOR], 0.62; 95% CI, 0.39, 0.99). Antipsychotic use did not significantly differ between days when visitors were versus were not allowed (AOR, 0.98; 95% CI, 0.43, 2.21). CONCLUSIONS: Among older patients hospitalized during the first wave of the pandemic, benzodiazepine use was lower on days when visitors were allowed. These findings suggest that the presence of caregivers impacts use of potentially inappropriate medications among hospitalized older adults, supporting efforts to recognize caregivers as essential members of the care team.

Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells.

Angiotensin-converting enzyme 2 (ACE2) is the receptor of COVID-19 pathogen SARS-CoV-2, but the transcription factors (TFs) that regulate the expression of the gene encoding ACE2 (ACE2) have not been systematically dissected. In this study we evaluated TFs that control ACE2 expression, and screened for small molecule compounds that could modulate ACE2 expression to block SARS-CoV-2 from entry into lung epithelial cells. By searching the online datasets we found that 24 TFs might be ACE2 regulators with signal transducer and activator of transcription 3 (Stat3) as the most significant one. In human normal lung tissues, the expression of ACE2 was positively correlated with phosphorylated Stat3 (p-Stat3). We demonstrated that Stat3 bound ACE2 promoter, and controlled its expression in 16HBE cells stimulated with interleukin 6 (IL-6). To screen for medicinal compounds that could modulate ACE2 expression, we conducted luciferase assay using HLF cells transfected with ACE2 promoter-luciferase constructs. Among the 64 compounds tested, 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone in Chinese medicinal herb Centipeda minima (CM), represented the most potent ACE2 repressor. 6-OAP (2.5 µM) inhibited the interaction between Stat3 protein and ACE2 promoter, thus suppressed ACE2 transcription. 6-OAP (1.25-5 µM) and its parental medicinal herb CM (0.125%-0.5%) dose-dependently downregulated ACE2 in 16HBE and Beas-2B cells; similar results were observed in the lung tissues of mice following administration of 6-OAP or CM for one month. In addition, 6-OAP/CM dose-dependently reduced IL-6 production and downregulated chemokines including CXCL13 and CX3CL1 in 16HBE cells. Moreover, we found that 6-OAP/CM inhibited the entry of SARS-CoV-2 S protein pseudovirus into target cells. These results suggest that 6-OAP/CM are ACE2 inhibitors that may potentially protect lung epithelial cells from SARS-CoV-2 infection.

High-Throughput Metabolomics and Diabetic Kidney Disease Progression: Evidence from the Chronic Renal Insufficiency (CRIC) Study.

INTRODUCTION: Metabolomics could offer novel prognostic biomarkers and elucidate mechanisms of diabetic kidney disease (DKD) progression. Via metabolomic analysis of urine samples from 995 CRIC participants with diabetes and state-of-the-art statistical modeling, we aimed to identify metabolites prognostic to DKD progression. METHODS: Urine samples (N = 995) were assayed for relative metabolite abundance by untargeted flow-injection mass spectrometry, and stringent statistical criteria were used to eliminate noisy compounds, resulting in 698 annotated metabolite ions. Utilizing the 698 metabolites' ion abundance along with clinical data (demographics, blood pressure, HbA1c, eGFR, and albuminuria), we developed univariate and multivariate models for the eGFR slope using penalized (lasso) and random forest models. Final models were tested on time-to-ESKD (end-stage kidney disease) via cross-validated C-statistics. We also conducted pathway enrichment analysis and a targeted analysis of a subset of metabolites. RESULTS: Six eGFR slope models selected 9-30 variables. In the adjusted ESKD model with highest C-statistic, valine (or betaine) and 3-(4-methyl-3-pentenyl)thiophene were associated (p < 0.05) with 44% and 65% higher hazard of ESKD per doubling of metabolite abundance, respectively. Also, 13 (of 15) prognostic amino acids, including valine and betaine, were confirmed in the targeted analysis. Enrichment analysis revealed pathways implicated in kidney and cardiometabolic disease. CONCLUSIONS: Using the diverse CRIC sample, a high-throughput untargeted assay, followed by targeted analysis, and rigorous statistical analysis to reduce false discovery, we identified several novel metabolites implicated in DKD progression. If replicated in independent cohorts, our findings could inform risk stratification and treatment strategies for patients with DKD.

Mutations and clinical significance of calcium voltage-gated channel subunit alpha 1E (CACNA1E) in non-small cell lung cancer.

CACNA1E is a gene encoding the ion-conducting α1 subunit of R-type voltage-dependent calcium channels, whose roles in tumorigenesis remain to be determined. We previously showed that CACNA1E was significantly mutated in patients with non-small cell lung cancer (NSCLC) who were long-term exposed to household air pollution, with a mutation rate of 19% (15 of 79 cases). Here we showed that CACNA1E was also mutated in 207 (12.8%) of the 1616 patients with NSCLC in The Cancer Genome Atlas (TCGA) datasets. At mRNA and protein levels, CACNA1E was elevated in tumor tissues compared to counterpart non-tumoral lung tissues in NSCLCs of the public datasets and our settings, and its expression level was inversely associated with clinical outcome of the patients. Overexpression of wild type (WT) or A275S or R249G mutant CACNA1E transcripts promoted NSCLC cell proliferation with activation of epidermal growth factor receptor (EGFR) signaling pathway, whereas knockdown of this gene exerted inhibitory effects on NSCLC cells in vitro and in vivo. CACNA1E increased current density and Ca2+ entrance, whereas calcium channel blockers inhibited NSCLC cell proliferation. These data indicate that CACNA1E is required for NSCLC cell proliferation, and blockade of this oncoprotein may have therapeutic potentials for this deadly disease.

TAK1 accelerates transplant arteriosclerosis in rat aortic allografts by inducing autophagy in vascular smooth muscle cells.

BACKGROUND AND AIMS: The proliferation and migration of vascular smooth muscle cells (VSMCs) are fundamental hallmarks of vasculopathy. Transforming growth factor ß-activated kinase-1 (TAK1) plays a crucial role in mediating cellular functions, including autophagy, which has been recently linked to the regulation of VSMC functions and the development of vasculopathy. This study aims to better dissect how TAK1 controls VSMC proliferation and migration. METHODS: A rat model of graft arteriosclerosis was employed to explore the influence of TAK1 signaling activation on VSMC proliferation, migration, autophagy, and neointima formation in vivo. Knockdown and pharmacological inhibition of TAK1 were utilized in cultured VSMCs to investigate the mechanisms underlying the progression of VSMC proliferation and migration. RESULTS: Increased phosphorylation of TAK1 (Thr-184/Thr-187) was examined in SMα-actin positive cells in the medial and neointimal lesions of aortic allografts. Lentivirus-mediated Tak1 shRNA transfection of aortic allografts robustly suppressed neointimal formation and lumen stenosis, as well as autophagy and cell proliferative responses. In cultured PDGF-BB-incubated VSMCs, genetic and pharmacological inhibition of TAK1 markedly attenuated autophagy activation, and blocked the progression of cell cycle, proliferation, and migration responses. CONCLUSIONS: Activation of TAK1 in VSMCs in the setting of aortic transplantation is an early and critical event in VSMC proliferation and migration, as well as neointima formation, because it controls autophagy activation, constituting a potential molecular mechanism and target for preventing transplant vasculopathy.

The impact of IBD medications on risk of pneumonia and pneumonia-related hospitalisation: a nationwide cohort study of 56 410 IBD patients.

BACKGROUND: There are limited data on the incidence of pneumonia and pneumonia-related hospitalisation in the IBD population, and on any association of IBD medications with such outcomes. AIMS: To evaluate the impact of IBD medications on the risk of pneumonia, pneumonia-related hospitalisations and death. METHODS: We conducted a retrospective cohort study of IBD patients from the nationwide Veteran Affairs (VA) dataset. The exposure of interest was different IBD medication groups. We estimated the incidence rate of pneumonia, pneumonia-related hospitalisation and mortality based on IBD medication subgroups. We used a multivariable Cox regression to estimate the adjusted hazard ratios (AHR) and 95% confidence intervals (CIs) for these outcomes. RESULTS: Out of 56 410 patients with IBD, 3759 developed pneumonia, 1489 were hospitalised, and 248 died within 30 days of their pneumonia diagnosis. The crude incidence rates of pneumonia, pneumonia-related hospitalisation and pneumonia-related mortality were 6.47, 2.52 and 0.43, respectively, per 1000 person-years. In multivariable Cox regression analysis, compared to 5-ASA alone, anti-TNF medication was associated with an increased risk of pneumonia (AHR 1.39; 95% CI 1.22-1.59) and hospitalisation (AHR 1.61; 95% CI 1.31-1.98). Use of prednisone in the prior 30 days was associated with increased risk of pneumonia (AHR 2.14; 95% CI 1.92-2.38) and hospitalisation (AHR 2.44; 95% CI 2.08-2.88). CONCLUSION: Anti-TNF medications and prednisone use may be associated with increased risk of developing pneumonia and pneumonia-related hospitalisation. Physicians should evaluate the risk-benefit ratio of IBD medications, especially in the elderly population.

Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells.

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.