Miracle-dz/UniFAR-FTUs huggingface dataset:
ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754–66. ©2018 AACR.
Intrinsic Mesenchymal Stem Cell Dysfunction in Diabetes Mellitus : Implications for Autologous Cell Therapy

Mesenchymal stem cells derived from bone marrow (BM-MSCs) have multifunctional properties that have made them a promising therapeutic agent for many regenerative, anti-inflammatory, and autoimmune applications. Under chronic pathological conditions, however, BM-MSCs can become functionally compromised due to long-term exposure to changes in the systemic and localized stem cell niche microenvironments. In addition to the fact that functionally compromised BM-MSCs may be therapeutically ineffective, impairment of BM-MSCs is potentially a contributing factor to disease progression and development of comorbidities. For the purpose of this review, MSC-based therapies for treatment of nonhealing wounds in diabetic patients will be used as an example to demonstrate the effect that the diabetic host environment has on the regenerative capacity of endogenous BM-MSCs. This review will also discuss the mechanism by which the pathogenesis of diabetes mellitus leads to intrinsic dysfunction of the bone marrow stem cell niche that ultimately results in MSC failure and will highlight potential strategies for counteracting the functional decline of BM-MSCs.
Nutrient Requirements and Interactions Consumption of Buckwheat Protein Lowers Plasma Cholesterol and Raises Fecal Neutral Sterols in Cholesterol-Fed Rats Because of Its Low Digestibility

Buckwheat protein product (BWP) has a strong hypocholesterolemic activity in rats fed a cholesterolenriched diet. In this study, we examined the influence of BWP on fecal excretion of sterols and nitrogen in rats fed a diet containing 5 g/kg cholesterol and 1.25 g/kg sodium cholate, and we examined whether the cholesterollowering activity of BWP is due to its low digestibility. In Experiment 1, rats fed BWP for 3 wk had significantly lower concentrations of plasma cholesterol and enhanced excretion of fecal total neutral sterols and nitrogen compared with rats fed casein. There was a significant correlation between fecal total neutral sterols and nitrogen (r Å 0.89, P õ 0.01). Fecal excretion of acidic sterols was unaffected by BWP. In Experiment 2, plasma cholesterol in rats fed trypsin-digested BWP for 2 wk was significantly higher than that in rats fed intact BWP. In Experiment 3, rats were fed BWP, low-molecular-weight fraction of the digest of BWP (LMF) or high-molecular-weight fraction of the digest of BWP (HMF) for 3 wk. Plasma cholesterol was lower in the BWP group than in the LMF group (P õ 0.05), whereas that in the HMF group was intermediate. The in vitro digestibility of BWP with pepsin and pancreatin was significantly lower than that of casein. The results suggest that the cholesterol-lowering effect of BWP is mediated by higher fecal excretion of neutral sterols and that lower digestibility of BWP is at least partially responsible for the effect. J. Nutr. 127: 1395–1400, 1997.
Individual and System Contributions to Race and Sex Disparities in Thrombolysis Use for Stroke Patients in the United States

Background and Purpose— Intravenous thrombolysis (IVT) is underutilized in ethnic minorities and women. To disentangle individual and system-based factors determining disparities in IVT use, we investigated race/sex differences in IVT utilization among hospitals serving varying proportions of minority patients. Methods— Ischemic stroke admissions were identified from the Nationwide Inpatient Sample between 2007 and 2011. Hospitals were categorized based on the percentage of minority patients admitted with stroke (<25% minority patients [white hospitals], 25% to 50% minority patients [mixed hospitals], or >50% minority patients [minority hospitals]). Logistic regression was used to evaluate the association between race/sex and IVT use within and between the different hospital strata. Results— Among 337 201 stroke admissions, white men had the highest odds of IVT among all race/sex groups in any hospital strata, and the odds of IVT for white men did not differ by hospital strata. For white women and minority men, the odds of IVT were significantly lower in minority hospitals compared with white hospitals (odds ratio, 0.83; 95% confidence interval, 0.71–0.97, for white women; and odds ratio, 0.82; 95% confidence interval, 0.69–0.99, for minority men). Race disparities in IVT use among women were observed in white hospitals (odds ratio, 0.88; 95% confidence interval, 0.78–0.99, in minority compared with white women), but not in minority hospitals (odds ratio, 0.94, 95% confidence interval, 0.82–1.09). Sex disparities in IVT use were observed among whites but not among minorities. Conclusions— Minority men and white women have significantly lower odds of IVT in minority hospitals compared with white hospitals. IVT use in white men does not differ by hospital strata.
The double life of the ribosome: When its protein folding activity supports prion propagation

ABSTRACT It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation. In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.
Patient-specific CT-based 3D passive FSI model for left ventricle in hypertrophic obstructive cardiomyopathy

Abstract Left ventricular outflow tract obstruction is observed in 70% of patients with hypertrophic cardiomyopathy, which occurs in about 1 of every 500 adults in the general population. It has been widely believed that the motion of the mitral valve, in particular, its systolic anterior motion (SAM), attributes significantly to such obstruction. For a better understanding of the mitral valve motion, a 3D patient-specific fluid-structure interaction model of the left ventricle from a patient with hypertrophic obstructive cardiomyopathy based on computed tomography (CT) scan images was proposed in this study. Displacement, structural stress, pressure, flow velocity and shear stress within the left ventricle and mitral valve were extracted to characterize their behavior. The maximum shear stress on mitral valve was 9.68 . The pressure on its posterior leaflet was higher than that on the anterior leaflet and the peak pressure on the mitral valve was 93.5 mm Hg which occurred at pre-SAM time. High angles of attack (54.3 ± 22.4°) were found in this patient. The methodology established in this study may have the potential to clarify the mechanisms of SAM and ultimately optimize surgical planning by comparing the mechanical results obtained from preoperative and postoperative models.
Eudragit S100 coated microsponges for Colon targeting of prednisolone

Abstract Context: Microsponge is a novel approach for targeting the drug to the colon for the management of colon ailments such as inflammatory bowel disease. Objective: Prednisolone loaded microsponges (PLMs) were prepared and coated with Eudragit S 100 (ES) and evaluated for colon-specific drug delivery. Materials and methods: PLMs were prepared using quasi emulsion solvent diffusion technique using ethyl cellulose, triethylcitrate (1% v/v, plasticizer) and polyvinyl alcohol (Mol. Wt. 72 kDa, emulsifying agent). The developed microsponges were compressed into tablets via direct compression technique using sodium carboxymethyl cellulose (Na CMC) and magnesium stearate as super-disintegrant and lubricant, respectively. The tablets were then coated with ES to provide protection against harsh gastric environment and manifest colon-specific drug release. Results: PLMs were found to be nano-porous spherical microstructures with size around 35 µm and 86% drug encapsulation efficiency. Finally, they were compressed into tablets which were coated with Eudragit S 100 In vitro drug release from ES coated tablets was carried out at various simulated gastrointestinal fluids i.e. 1 hr in SGF (pH 1.2), 2 to 3 h in SIF (pH 4.6), 4–5 h in SIF (pH 6.8), and 6–24 h in SCF (pH 7.4) and the results showed the biphasic release pattern indicating prolonged release for about 24 h. Discussion and conclusion: In vitro drug release studies revealed that drug starts releasing after 5 h by the time PLMs may enter into the proximal colon. Hence maximum amount of drug could be released in the colon that may result in reduction in dose and dose frequency as well as side effects of drug as observed with the conventional dosage form of prednisolone.
Triple Therapy Versus Biologic Therapy for Active Rheumatoid Arthritis: A Cost-Effectiveness Analysis.

Background The RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial found triple therapy to be noninferior to etanercept-methotrexate in patients with active rheumatoid arthritis (RA). Objective To determine the cost-effectiveness of etanercept-methotrexate versus triple therapy as a first-line strategy. Design A within-trial analysis based on the 353 participants in the RACAT trial and a lifetime analysis that extrapolated costs and outcomes by using a decision analytic cohort model. Data Sources The RACAT trial and sources from the literature. Target Population Patients with active RA despite at least 12 weeks of methotrexate therapy. Time Horizon 24 weeks and lifetime. Perspective Societal and Medicare. Intervention Etanercept-methotrexate first versus triple therapy first. Outcome Measures Incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results of Base-Case Analysis The within-trial analysis found that etanercept-methotrexate as first-line therapy provided marginally more QALYs but accumulated substantially higher drug costs. Differences in other costs between strategies were negligible. The ICERs for first-line etanercept-methotrexate and triple therapy were $2.7 million per QALY and $0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept-methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental $77 290, leading to an ICER of $521 520 per QALY per patient. Results of Sensitivity Analysis Considering a long-term perspective, an initial strategy of etanercept-methotrexate and biologics with similar cost and efficacy is unlikely to be cost-effective compared with using triple therapy first, even under optimistic assumptions. Limitation Data on the long-term benefit of triple therapy are uncertain. Conclusion Initiating biologic therapy without trying triple therapy first increases costs while providing minimal incremental benefit. Primary Funding Source The Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, Canadian Institutes for Health Research, and an interagency agreement with the National Institutes of Health-American Recovery and Reinvestment Act.
Acute kidney injury is associated with early cytokine changes after trauma

BACKGROUND Acute kidney injury (AKI) occurs in 26% of trauma patients and is associated with increased mortality and risk for nosocomial infections (NCIs). We compared serial plasma cytokine levels in patients with posttraumatic AKI to determine whether the early cytokine changes are associated with the occurrence of AKI and NCI. METHODS We performed a secondary analysis of the Inflammation and the Host Response to Injury database to include adult blunt trauma patients who had available plasma proteomic analyses. AKI was defined by the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) classification, which requires a 50% increase in serum creatinine. The association among AKI, NCI, and plasma cytokines was analyzed using a mixed model analyses and logistic regression. RESULTS Among 147 patients in the cohort, prevalence of NCI was 73% and 52% for patients with and without AKI, respectively. In mixed model analyses adjusted for clinical factors, AKI patients developed significant early increase in IL-1ra, IL-8, MCP1, and IL-6; early decrease in sTNFR2; and late decrease in IL-1ra, IL-4, and IL-6 concentrations, compared with patients without AKI and regardless of NCI. The change in cytokine pattern differed for sIL1R2, CXCL1, and MIP1&bgr;, depending on the occurrence of NCI. Patients with AKI and NCI had lower early and late sIL1R2 and higher early and late CXCL1 and MIP1&bgr; levels. Within the first 24 hours of injury, adding plasma levels of IL-1ra, IL-8, MCP1, IL-6, and sTNFR2 to clinical parameters of injury severity provided a predictive model for AKI superior to clinical model only (p < 0.001). CONCLUSION AKI trauma patients exhibit simultaneous changes in proinflammatory and anti-inflammatory serial plasma cytokine levels. The predictive model for AKI that combines plasma cytokine levels with clinical data within 24 hours of injury requires further prospective validation in larger studies. LEVEL OF EVIDENCE Prognostic study, level III.
Accessing new prognostic significance of preoperative carcinoembryonic antigen in colorectal cancer receiving tumor resection: More than positive and negative.

OBJECTIVE Evaluating the prognostic significance of carcinoembryonic antigen (CEA) for colorectal cancer (CRC) patients in new cutoffs. PATIENTS Three hundred and seventy cases and 1164 cases of CRC patients receiving tumor resection from hospitals of Sun Yat-sen University were retrospectively investigated as training cohort and validation cohort respectively. CEA was categorized into quintiles for Kaplan-Meier analysis and Cox proportional hazards regression analysis. RESULTS CEA was categorized into quintiles with the cutoff points of (0-1.5) ng/ml, (1.5-2.3) ng/ml, (2.3-3.98) ng/ml, (3.98-8.02) ng/ml, (8.02-Maximum) ng/ml. In CRC patients from training cohort, progressively worse outcomes were observed in each increasing quintile of CEA in term of overall survival (Log-rank Test: P< 0.0001, Log-rank Test for Trend: P< 0.0001) and progression free survival (Log-rank Test: P= 0.0002, Log-rank Test for Trend: P< 0.0001). CEA quintile was associated with overall survival (HR: 1.209, 95%CI: 1.033-1.416, P= 0.018) and progression free survival (HR: 1.195, 95%CI: 1.024-1.394, P= 0.024). Validation analysis also showed that patients with increasing CEA quintile suffered unfavorable overall survival (Log-rank Test: P= 0.0001, Log-rank Test for Trend: P= 0.0001) and progression free survival (Log-rank Test: P= 0.0001, Log-rank Test for Trend: P= 0.0001). CEA quintile was associated with overall survival (HR: 1.330, 95%CI: 1.123-1.576, P< 0.001) and progression free survival (HR: 1.218, 95%CI: 1.089-1.362, P= 0.001). CONCLUSIONS Preoperative CEA quintile was an independent predictor of unfavorable prognosis in CRC patients. Even within normal range, CEA quintile might still impact prognosis outcomes of CRC.
Fetal femur length is influenced by maternal dairy intake in pregnant African American adolescents.

BACKGROUND Pregnant adolescents may compete with their developing fetuses for the nutrients required for optimal bone mineralization. OBJECTIVE The objective of this study was to determine the effect in pregnant African American adolescents of maternal dairy intake at entry into prenatal care on fetal femur development between 20 and 34 wk of gestation. DESIGN A 10-y retrospective chart review was carried out in 1120 pregnant African American adolescents (<or= 17 y of age) who had received care at an inner-city maternity clinic between 1990 and 2000. Generalized multiple linear regression models were used to address significant determinants of fetal femur length after control for gestational age, biparietal diameter, maternal age and height, and prepregnancy body mass index. Dairy intake was estimated at entry into prenatal care on the basis of 24-h dietary recall and a food-frequency questionnaire. Data from 350 subjects, for whom data on all variables were available, were included in the model. RESULTS In these pregnant adolescents with a mean (+/- SD) age of 15.9 +/- 1.1 y (range: 12.7-17.9 y), dairy intake had a significant positive effect on fetal femur growth after adjustment for gestational age, biparietal diameter, maternal age and height, and prepregnancy body mass index (P = 0.001, R(2) = 0.97). Fetal femur length was significantly lower in the lowest dairy-intake group (< 2 servings/d) than in the highest dairy-intake group (> 3 servings/d), and a dose-response relation was suggested in the intermediate dairy-intake group (2-3 servings/d; P = 0.089). CONCLUSION These data suggest that consumption of < 2 servings of dairy products/d by pregnant adolescents may negatively affect fetal bone development by limiting the amount of calcium provided to the fetus.
Vertical Lip Position and Thickness in Facial Reconstruction: A Validation of Commonly Used Methods for Predicting the Position and Size of Lips

This study examined several methods used to estimate oral fissure position, lip margin position, and lip thickness recommended by Angel, George, Lebedinskaya, Taylor, Wilkinson et al., Balueva and Veselovskaya. A sample of 86 lateral head cephalograms of adult subjects from central Europe were measured and the actual and predicted dimensions were compared. The best estimation for oral fissure position was “opposite the lower ¾ mark of maxillary incisors” (error of 1.3 mm). Upper lip margin was predicted best by “upper ¼ mark of maxillary incisors” (error of 1.7 mm), and lower lip margin by “cementum‐enamel junction of mandibular incisors” (error of 2.3 mm). The regression equations of Wilkinson et al. displayed least error (1.3 mm and 1.8 mm, respectively) for upper and lower lip thickness, and method of George (error of 3.4 mm) for total lip thickness.
Smoking-associated Squamous Metaplasia in Olfactory Mucosa of Patients with Chronic Rhinosinusitis

Few studies have examined the induction of squamous metaplasia in human olfactory nasal tissue caused by tobacco use and the implications it may have for olfaction, particularly when there are pre-existing insults, such as chronic rhinosinusitis (CRS). Quantitative histopathological analyses were performed on Alcian blue- and H&E-stained sections of nasal biopsies taken from the upper aspect of the middle turbinate of CRS patients. Chronic rhinosinusitis patients who were current smokers had a predominance of squamous metaplasia in the olfactory sensory epithelium, whereas CRS patients who were nonsmokers and were not exposed to secondhand cigarette smoke had a prevalence of goblet cell hyperplasia. In spite of this difference, the groups did not differ significantly in olfactory threshold sensitivity. The impact of primary cigarette smoke on olfaction and a possible role of squamous metaplasia in preserving olfactory neurogenesis are discussed.
Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials.

BACKGROUND Clinical trials have reported the cholesterol-lowering effects of soy protein intake, but the components responsible are not known. OBJECTIVE This meta-analysis was primarily conducted to evaluate the precise effects of soy isoflavones on lipid profiles. The effects of soy protein that contains enriched and depleted isoflavones were also examined. DESIGN PUBMED was searched for English-language reports of randomized controlled trials published from 1990 to 2006 that described the effects of soy protein intake in humans. Eleven studies were selected for the meta-analysis. RESULTS Soy isoflavones significantly decreased serum total cholesterol by 0.10 mmol/L (3.9 mg/dL or 1.77%; P = 0.02) and LDL cholesterol by 0.13 mmol/L (5.0 mg/dL or 3.58%; P < 0.0001); no significant changes in HDL cholesterol and triacylglycerol were found. Isoflavone-depleted soy protein significantly decreased LDL cholesterol by 0.10 mmol/L (3.9 mg/dL or 2.77%; P = 0.03). Soy protein that contained enriched isoflavones significantly decreased LDL cholesterol by 0.18 mmol/L (7.0 mg/dL or 4.98%; P < 0.0001) and significantly increased HDL cholesterol by 0.04 mmol/L (1.6 mg/dL or 3.00%; P = 0.05). The reductions in LDL cholesterol were larger in the hypercholesterolemic subcategory than in the normocholesterolemic subcategory, but no significant linear correlations were observed between reductions and the starting values. No significant linear correlations were found between reductions in LDL cholesterol and soy protein ingestion or isoflavone intakes. CONCLUSIONS Soy isoflavones significantly reduced serum total and LDL cholesterol but did not change HDL cholesterol and triacylglycerol. Soy protein that contained enriched or depleted isoflavones also significantly improved lipid profiles. Reductions in LDL cholesterol were larger in hypercholesterolemic than in normocholesterolemic subjects.