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Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by β-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/β-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR). In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3β was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCH 8-5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCH 8-5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCH 8-5 cells. In this study, we observed that the components of Wnt/β-catenin pathway such as Wnt and GSK 3β were activated in multidrug resistant KBCH 8-5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3β in KBCH 8-5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCH 8-5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin-mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCH 8-5 cells. The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/β-catenin signaling in drug-resistant KBCH 8-5 cells.

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Background Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by β-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/β-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR). Methods In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3β was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCH R 8–5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCH R 8–5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCH R 8–5 cells. Results In this study, we observed that the components of Wnt/β-catenin pathway such as Wnt and GSK 3β were activated in multidrug resistant KBCH R 8–5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3β in KBCH R 8–5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCH R 8–5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin-mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCH R 8–5 cells. Conclusion The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/β-catenin signaling in drug-resistant KBCH R 8–5 cells.

This study explores the use of mesenchymal stem cells (MSCs) for intervertebral disc regeneration. We used an in vivo model to investigate the feasibility of exogenous cell delivery, retention, and survival in the pressurized disc space. MSC injection into rat coccygeal discs was performed using 15% hyaluronan gel as a carrier. Injections of gel with or without MSCs were performed. Immediately after injection, fluorescently labeled stem cells were visible on sections of cell-injected discs. Seven and 14 days after injection, stem cells were still present within the disc, but their numbers were significantly decreased. At 28 days, a return to the initial number of injected cells was observed, and viability was 100%. A trend of increased disc height compared to blank gel suggests an increase in matrix synthesis. The results indicate that MSCs can maintain viability and proliferate within the rat intervertebral disc.

Stroke and systemic embolism occur frequently in patients with rheumatic mitral stenosis (MS) in sinus rhythm (SR), but the risk and predictors of embolic events in this population are not well studied. The aim of this study was to determine if transient, subclinical atrial fibrillation (AF) increases the risk of systemic embolism in patients with MS in SR. A single-center, prospective observational study of patients with rheumatic MS in SR was performed. The rate of the composite primary outcome of stroke, transient ischemic attack, or non–central nervous system embolism was determined, as well as the predictive value of Holter-detected episodes of transient (<30 seconds), subclinical AF for this outcome. Hazard ratios were derived for subclinical AF, after adjustment for clinical and echocardiographic predictors of systemic embolism, using Cox regression. The sensitivity, specificity, and area under the receiver-operating characteristic curve of subclinical AF were determined for the primary outcome. Among 179 patients (mean follow-up 10.2 months), the rate of the primary outcome was 5.3/100 patient-years (95% confidence interval [CI] 2.6 to 10.5). In univariate analysis, subclinical AF (hazard ratio 4.54, 95% CI 1.08 to 19.0, p = 0.038) and dense spontaneous echocardiographic contrast (hazard ratio 4.32, 95% CI 1.03 to 18.09, p = 0.045) were predictors of the primary outcome. In multivariate analysis, subclinical AF remained the only significant predictor (hazard ratio 5.02, 95% CI 1.15 to 22.0, p = 0.032). Subclinical AF had an area under the receiver-operating characteristic curve of 0.68 and high negative predictive value (97.7%) for the primary outcome. In conclusion, Holter-detected, transient (<30 seconds), subclinical AF is a predictor of stroke and systemic embolism in patients with rheumatic MS in SR. Considering the high risk for embolism, randomized trials of oral anticoagulation are needed in this population. •Rheumatic MS is a common cause of stroke and systemic embolism in developing countries.•Although most patients who experience strokes are in AF, about 1/5 are in sinus rhythm. There is little information on the risk for and predictors of stroke and systemic embolism in these patients.•This prospective study suggests that in symptomatic patients with rheumatic MS who are in sinus rhythm, the risk for stroke or systemic embolism is high.•The presence of transient (<30 seconds), subclinical runs of AF detected on 24-hour Holter monitoring is a strong predictor of the occurrence of stroke or systemic embolism.•The presence of subclinical AF on Holter monitoring in patients with MS in sinus rhythm may help in the risk stratification of these patients for stroke and systemic embolism.

To study racial disparities in therapeutic interventions and hospitalization outcomes for hepatocellular cancer (HCC) in the United States. Using the 2011 Nationwide Inpatient Sample (comprising hospitalizations between January 1 and December 31, 2011), we identified patients with HCC-related admissions using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among these, we also identified those that were procedure-related (associated with liver transplantation, hepatic resection, radiofrequency ablation, or transarterial chemoembolization). Multivariate regression was performed to identify the contribution of race to therapeutic interventions and outcomes. A total of 22,933 HCC-related hospitalizations were included, of which 10,285 were procedure related (45%). Blacks had a smaller proportion (35%) of procedure-related HCC hospitalizations than did whites (46%) (odds ratio [OR], 0.65; 95% CI, 0.49-0.86). Specifically, blacks had lower odds of liver transplantation (OR, 0.43; 95% CI, 0.26-0.71), hepatic resection (OR, 0.57; 95% CI, 0.33-0.98), and ablation (OR, 0.46; 95% CI, 0.29-0.74) (P=.002) than did whites. Overall, 10.9% of HCC-related admissions resulted in death in blacks as compared with 6.4% in whites (OR, 1.58; 95% CI, 1.12-2.24). Among patients admitted for HCC-related hospitalizations, blacks were less likely to receive liver transplantation, hepatic resection, and ablation than whites and had higher inhospital mortality. Identifying racial disparities in health care is a necessary first step to appropriately address and eliminate them.

Chronic lymphocytic leukemia (CLL) is a chronic, progressive lymphoproliferative disorder characterized by a monoclonal population of functionally incompetent lymphocytes. Renal involvement is rare and poorly described. A 57-year-old male with no prior medical history was diagnosed with CLL and followed with a watch and wait approach. He was referred to our institution several months later due to concern for Richter’s transformation to diffuse large B-cell lymphoma. A positron emission tomography/computed tomography scan showed no evidence of diffuse large B-cell lymphoma; however, the patient was noted to have hypoalbuminemia, nephrotic range proteinuria, an acute left renal vein thrombus, and a right pulmonary embolus. A nephrotic syndrome workup including autoimmunity and infection was unremarkable, and a kidney biopsy was deferred due to concern for renal compromise in the setting of a renal vein thrombus. The patient was treated with 6 cycles of reduced-dose fludarabine, cyclophosphamide, and rituximab for a presumed CLL-associated nephrotic syndrome and anticoagulation for his venous thromboemboli. At 6-month follow-up, the patient achieved complete remission of his CLL with normalization of all cell lines and resolution of his nephrotic range proteinuria. Repeat computed tomography scans showed no evidence of recurrent venous thromboemboli. This case demonstrates a potential role of empiric chemotherapy in cases of CLL-associated nephrotic syndrome given its potentially life-threatening sequelae and response to treatment.

Ulcerative colitis (UC) is an idiopathic inflammatory disorder. These guidelines indicate the preferred approach to the management of adults with UC and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. In instances where the evidence was not appropriate for GRADE, but there was consensus of significant clinical merit, “key concept” statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.

Diabetic retinopathy can be prevented with screening and early detection. We hypothesized that autonomous artificial intelligence (AI) diabetic eye exams at the point-of-care would increase diabetic eye exam completion rates in a racially and ethnically diverse youth population. AI for Children’s diabetiC Eye ExamS (NCT05131451) is a parallel randomized controlled trial that randomized youth (ages 8-21 years) with type 1 and type 2 diabetes to intervention (autonomous artificial intelligence diabetic eye exam at the point of care), or control (scripted eye care provider referral and education) in an academic pediatric diabetes center. The primary outcome was diabetic eye exam completion rate within 6 months. The secondary outcome was the proportion of participants who completed follow-through with an eye care provider if deemed appropriate. Diabetic eye exam completion rate was significantly higher (100%, 95%CI: 95.5%, 100%) in the intervention group ( n  = 81) than the control group ( n  = 83) (22%, 95%CI: 14.2%, 32.4%)(p < 0.001). In the intervention arm, 25/81 participants had an abnormal result, of whom 64% (16/25) completed follow-through with an eye care provider, compared to 22% in the control arm (p < 0.001). Autonomous AI increases diabetic eye exam completion rates in youth with diabetes. Diabetic retinopathy is a complication of diabetes that can be prevented through screening, yet adherence is low. Here, the authors show that autonomous AI increases diabetic eye exam completion in a diverse cohort of youth with diabetes.