Miracle-dz/UniFAR-FTUs huggingface dataset:
Proteomic Maps of Human Gastrointestinal Stromal Tumor Subgroups*

Quantitative proteome profiling of GIST from 13 patients classified into very low/low, intermediate and high-risk subgroups were performed. An extended cohort of GIST (n = 131) was used for immunohistochemical validation of proteins of interest. Functional insights into proteins associated with GIST risk grade were assessed. Immunohistochemical analysis revealed that GIST patients with high PTPN1 had low chances of developing metastasis. This work provides valuable information for understanding the inherent biology and evolution of GIST. Graphical Abstract Highlights Quantitative proteomes of GIST very low/low, intermediate and high risk subgroups. 9177 quantified proteins covering 57% of the GIT transcriptome. Functional insights into proteins associated with different GIST risk stage. GIST patients with high PTPN1 expression have low chances of developing metastasis. Gastrointestinal stromal tumor (GIST) is a common sarcoma of gastrointestinal tract (GIT) with high metastatic and recurrence rates, but the proteomic features are still less understood. Here we performed systematic quantitative proteome profiling of GIST from 13 patients classified into very low/low, intermediate and high risk subgroups. An extended cohort of GIST (n = 131) was used for immunohistochemical validation of proteins of interest. In total, 9177 proteins were quantified, covering 55.9% of the GIT transcriptome from The Human Protein Altas. Out of the 9177 quantified proteins, 4930 proteins were observed in all 13 cases with 517 upregulated and 187 downregulated proteins in tumorous tissues independent of risk stage. Pathway analysis showed that the downregulated proteins were mostly enriched in metabolic pathway, whereas the upregulated proteins mainly belonged to spliceosome pathway. In addition, 131 proteins showed differentially expressed patterns among GIST subgroups with statistical significance. The 13 GIST cases were classified into 3 subgroups perfectly based on the expression of these proteins. The intensive comparison of molecular phenotypes and possible functions of quantified oncoproteins, tumor suppressors, phosphatases and kinases between GIST subgroups was carried out. Immunohistochemical analysis of the phosphatase PTPN1 (n = 117) revealed that the GIST patients with high PTPN1 expression had low chances of developing metastasis. Collectively, this work provides valuable information for understanding the inherent biology and evolution of GIST.
Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

The role of asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD) is unclear. Through inhibition of type I protein arginine methyltransferases (PRMTs), a novel strategy, we aimed to determine the effect of ADMA on renal fibrosis and explore its underlying working mechanisms. After sham or unilateral ureter ligation (UUO) operation, 20–25 g male c57 mice were treated with vehicle or PT1001B, an inhibitor of type I PRMTs, for 13 d. Moreover, human kidney 2 (HK2) and normal rat kidney 49F (NRK‐49F) cells were treated with various concentrations of PT1001B or ADMA in the presence of 2.5 ng/ml TGF‐β. We found that treatment with PT1001B increased the deposition of extracellular matrix proteins, the expression of αsmooth muscle actin, and connective tissue growth factor in UUO‐induced fibrotic kidneys, which is correlated with reduced expression of PRMT1, reduced the production of ADMA, and increased expression of uromodulin. In TGF‐β‐stimulated HK2 and NRK‐49F cells, PT1001B dose‐dependently inhibited ADMA production, increased NO concentrations, and enhanced the expression of profibrotic proteins. Exogenous addition of ADMA inhibited the expression of profibrotic proteins dose‐dependently and attenuated the profibrotic effect of PT1001B. Moreover, ADMA reduced the NO concentration in PT1001B‐treated HK2 cells. Finally, we conclude that ADMA has an antifibrotic effect in obstructed kidneys, and future application of type I PRMT inhibitor should be done cautiously for patients with CKD. —Wu, M. , Lin, P., Li, L. , Chen, D. , Yang, X. , Xu, L. , Zhou, B. , Wang, C. , Zhang, Y. , Luo, C. , Ye, C. Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys. FASEB J. 33, 6948–6956 (2019). www.fasebj. org
ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non–Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms

Breast cancer is a major cause of cancer-related death. TNF-related apoptosis-inducing ligand (TRAIL) has been of interest as a cancer therapeutic, but only a subset of triple-negative breast cancers (TNBC) is sensitive to TRAIL. The small-molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here, we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n = 13). A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The proapoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an antiproliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the antiproliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n = 5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n = 2) shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. Our data demonstrate that ONC201 has potent antiproliferative and proapoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a preclinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. Mol Cancer Ther; 16(7); 1290–8. ©2017 AACR.
Effects of serum granulin levels on anthropometric measures and glucose metabolism in infertile women with different ovarian reserve status.

INTRODUCTION Granulin (GRN) is an adipokine with proinflammatory features and plays important role in glucose metabolism and insulin resistance pathogenesis. It has been reported that granulin precursors were localized in developing follicles in animal studies. The purpose of this study was to evaluate the association of granulin levels with anthropometric features, glucose metabolism and ovarian reserve. METHODS A total of 109 infertile women were included in this cross-sectional, prospective study, who attended to a tertiary clinic. All participants were categorised into diminished ovarian reserve (DOR) and normal ovarian reserve groups (NOR) in accordance with Bologna criteria. The demographic characteristics, including age, BMI, waist-hip circumferences and biochemical parameters were recorded. Serum granulin level was determined by enzyme-linked immunosorbent assay. RESULTS No significant difference was observed between the GRN levels (p=0.229) between the groups. There was a positive correlation between GRN levels and BMI, WC, HC and 75 g oral glucose tolerance values in NOR group (p<0.01, p<0.05, p<0.01 and p<0.05, respectively). CONCLUSIONS Our results suggest that granulin is associated with anthropometric features in infertile patients and might be an important indicator of obesity and impaired glucose metabolism. Elevated levels of granulin may have a diabetogenic effect and predispose women to high glucose levels.
The iPROMOS protocol: a stepped-wedge study to implement routine patient-reported outcomes in a medical oncology outpatient setting

Introduction Patient-reported outcome measures (PROMs) are data capture tools that collect information directly from patients. Several large research studies provide evidence that the use of PROMs in routine care provides benefits to mortality and morbidity outcomes in medical oncology patients. Despite this, implementation of PROMs in daily clinical routine is slow and challenging. Methods and analysis This study will use a stepped-wedge design to assess the implementation of a PROM intervention in highly frequented medical oncology outpatient clinics. During a lead-in period of 4 weeks, control data will be collected. The intervention will then be implemented for 4 weeks in Clinic 1 initially, then in Clinic 2 for another 4 weeks. 500 patient encounters will be measured over the 12 weeks in total. The process of implementation will be informed and evaluated using the Medical Research Council Guidelines for Implementing Complex Interventions. The study will be guided by the Promoting Action Research in Health Services framework approach for implementation. The intervention and implementation outcomes will be measured using qualitative and quantitative data. Ethics and dissemination Ethical approval has been obtained, approval number HREC/16/QRBW/100 by the Royal Brisbane and Women’s Hospital Human Research Ethics Committee. Results will be disseminated in peer-reviewed journals and at scientific meetings. Trial registration ACTRN12618000398202. Trial Status: Opened on 25 March 2018 and will continue until 12 months after the last PROMs reporting encounter.
Corruption and Tax Evasion in Croatia: Institutional Settings and Practical Experiences

South-East European countries continue to suffer from wide-spread and deeply rooted corruption. This article is concerned with the social and economic sources of corruption and disrespect for the rule of law in the Republic of Croatia (rc), with particular attention being paid to tax evasion. Although the government of the rc has expressed a determination to undertake measures against corruption and tax evasion, it faces criticism that the fight against these social evils is not being given sufficient political support and respect. While it is clear that in the run up to joining the eu the rc has enacted different laws and institutions targeted towards the reduction of corruption; a serious problem remains in the low level of law enforcement. Croatia’s ineffective legal system and a lack of transparency have consequently presented significant challenges to investors. Moreover, the fight against corruption is often hampered by an inefficient public administration and a lack of intra-governmental coordination.
Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging

In this study, we investigated the pathophysiological impact of Rho‐associated coiled‐coil–containing protein kinase (ROCK)1 and ROCK2 double deletion vs. single deletion on cardiac remodeling. Utilizing a cardiomyocyte‐specific and tamoxifen‐inducible MerCreMer recombinase (MCM), 3 mouse lines (MCM/ROCK1f1/f1/ ROCK2f1/f1, MCM/ROCK1f1/f1, and MCM/ROCK2f1/f1) were generated. As early as 5 d after inducible deletion, the double ROCK knockout hearts exhibited reduced phosphorylation of myosin light chain (MLC) and focal adhesion kinase (FAK), supporting a role for ROCK activity in regulating the nonsarcomeric cytoskeleton. Moreover, the autophagy marker microtubule‐associated proteins 1A‐1B light chain 3B was increased in the double ROCK knockout, and these early molecular features persisted throughout aging. Mechanistically, the double ROCK knockout promoted age‐associated or starvation‐induced autophagy concomitant with reduced protein kinase B (AKT), mammalian target of rapamycin (mTOR), Unc‐51‐like kinase signaling, and cardiac fibrosis. In contrast, ROCK2 knockout hearts showed increased phosphorylated (p)‐MLC and p‐FAK levels, which were mostly attributable to a compensatory ROCK1 overactivation. Autophagy was inhibited at the baseline accompanying increased mTOR activity, leading to increased cardiac fibrosis in the ROCK2 knockout hearts. Finally, the loss of ROCK1 had no significant effect on p‐MLC and p‐FAK levels, mTOR signaling, or autophagy at baseline. In summary, deletions of ROCK isoforms in cardiomyocytes have different, even opposite, effects on endogenous ROCK activity and the MLC/FAK/AKT/mTOR signaling pathway, which is involved in autophagy and fibrosis of the heart. —Shi, J., Surma, M. , Yang, Y. , Wei, L. Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging. FASEB J. 33, 7348–7362 (2019). www.fasebj. org
Cirrhosis risk score of the donor organ predicts early fibrosis progression after liver transplantation.

BACKGROUND AND AIMS Fibrosis progression (FP) after liver transplantation (LT) increases morbidity and mortality. Biomarkers are needed for early prediction of FP. A recipient's seven-gene cirrhosis risk score (CRS) has been associated with FP, especially in non-transplant cohorts. A broader validation of CRS, including the genotype of the donor-organ and HCV-negative patients is lacking. We therefore analyzed the impact of donor- and recipient-specific genotypes on FP after LT in a large cohort of HCV-positive and -negative patients. METHOD Genotyping from liver biopsies (n=201 donors) and peripheral blood (n=442 recipients) was performed. Cirrhosis risk score was correlated with FP at 1 and 5 years after LT. RESULTS Fibrosis >/=F2 was documented in 26.5% of the recipients' CRS group (R-CRS) (defined by recipient's genotype) and in 23.4% of the donors' CRS- group (D-CRS) (defined by donor's genotype). Cumulative incidence for fibrosis >/=F2 was higher in patients with D-CRS >0.7 (p=0.03). While the R-CRS showed no prognostic relevance, D-CRS >0.7 was associated with higher hazard ratios (HRs) for fibrosis >/=F2 (HR=2.04; p=0.01), especially in HCV-negative patients (HR=2.59, p=0.03). Donors' CRS >0.7 was associated with higher risk for >/=F2 in 1-year protocol biopsies (p<0.001). Among the patients in whom both the recipient's and donor's CRS were available, fibrosis >/=F2 was encountered more frequently in patients with a D-CRS >0.7, in combination with any R-CRS, compared to patients with D-CRS scores </=0.7 (p=0.034). Donors' AZIN1, STXBP5L, TRPM5 genotypes carried a higher risk for fibrosis >/=F2 in subgroups. CONCLUSION High D-CRS >0.7 predicted early FP after LT, especially in HCV negative patients.
Association Between Fetal Congenital Heart Defects and Maternal Risk of Hypertensive Disorders of Pregnancy in the Same Pregnancy and Across Pregnancies

Background: Both pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy often exhibit angiogenic imbalances, suggesting that the same mechanisms are involved in the pathogenesis of the former and the pathophysiology of the latter. We conducted a register-based cohort study to determine whether offspring congenital heart defects are associated with an increased risk of hypertensive disorders of pregnancy and whether the mechanisms driving any association are primarily maternal or fetal. Methods: Among singleton pregnancies without chromosomal abnormalities lasting ≥20 weeks in Denmark from 1978 to 2011 (n= 1 972 857), we identified pregnancies complicated by offspring congenital heart defects or early preterm preeclampsia, late preterm preeclampsia, term preeclampsia, and gestational hypertension. We used polytomous logistic regression to estimate odds ratios (ORs) for associations between offspring congenital heart defects and maternal hypertensive disorders of pregnancy overall and for specific heart defects. Results: Offspring congenital heart defects were strongly associated with early preterm preeclampsia (OR, 7.00; 95% confidence interval [CI], 6.11–8.03) and late preterm preeclampsia (OR, 2.82; 95% CI, 2.38–3.34) in the same pregnancy and weakly associated with term preeclampsia (OR, 1.16; 95% CI, 1.06–1.27), but they were not associated with gestational hypertension (OR, 1.07; 95% CI, 0.92–1.25). Association strengths were consistent across heart defect types. Offspring congenital heart defects in a previous pregnancy were also strongly associated with preterm preeclampsia in subsequent pregnancies (early preterm preeclampsia: OR, 2.37; 95% CI, 1.68–3.34; late preterm preeclampsia: OR, 2.04; 95% CI, 1.52–2.75) but were only modestly associated with term preeclampsia and not associated with gestational hypertension. Similarly, preterm preeclampsia in a previous pregnancy, but not term preeclampsia or gestational hypertension, was associated with offspring congenital heart defects in later pregnancies (early preterm preeclampsia: OR, 7.91; 95% CI, 6.06–10.3; late preterm preeclampsia: OR, 2.83; 95% CI, 2.11–3.79; term preeclampsia: OR, 0.98; 95% CI, 0.88–1.10; gestational hypertension: OR, 1.13; 95% CI, 0.92–1.38). Conclusions: Linked pathophysiological mechanisms may be involved in some congenital heart defects and preterm preeclampsia. The strong associations across pregnancies support a predominantly maternal origin of effect.
Absence of Drug‐Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial

Intravaginal rings (IVRs) are an established option for continuous administration of drugs in women. The combination of anastrozole (ATZ) and levonorgestrel (LNG) in an IVR with an intended 4‐week wearing period has been considered for long‐term treatment of endometriosis‐associated pelvic pain. A randomized, parallel‐group, multicenter phase 2b study to assess the efficacy and safety of different dose combinations in women with symptomatic endometriosis has recently been performed. This paper will focus on the investigation of pharmacokinetic (PK) effects of ATZ on LNG using data collected from this study. Two hundred sixteen patients were randomized to the treatment group with IVRs releasing LNG 40 μg/day alone or in combination with ATZ 300 μg/day, 600 μg/day, or 1050 μg/day for 12 weeks. PK blood samples were taken before dosing and before IVR replacement or removal (days 28, 56, and 84). The primary PK parameter was the plasma concentration in apparent steady state of ATZ and LNG at the end of each IVR wearing period. Results of PK analysis demonstrate that ATZ concentrations increased proportionally with increasing dose (geometric mean values of 7.85, 15.48, and 22.61 μg/L at 300, 600, and 1050 μg/day nominal release, respectively). All point estimates for LNG concentration in apparent steady state ratios between the mono and combination IVR groups were close to 1, and the 90% confidence interval limits were in the 0.80 to 1.25 range (1.01 [0.85‐1.19], 1.03 [0.88‐1.20], 0.94 [0.80‐1.10]). In conclusion, our data indicate there is no evidence of drug‐drug interaction of ATZ on LNG.
Coffee consumption and plasma biomarkers of metabolic and inflammatory pathways in US health professionals.

BACKGROUND Coffee consumption has been linked to lower risk of various health outcomes. However, the biological pathways mediating the associations remain poorly understood. OBJECTIVES The aim of this study was to assess the association between coffee consumption and concentrations of plasma biomarkers in key metabolic and inflammatory pathways underlying common chronic diseases. METHODS We investigated the associations of total, caffeinated, and decaffeinated coffee consumption with 14 plasma biomarkers, including C-peptide, insulin-like growth factor 1 (IGF-1), IGF binding protein (IGFBP) 1, IGFBP-3, estrone, total and free estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), total adiponectin, high-molecular-weight (HMW) adiponectin, leptin, C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFR-2). Data were derived from 2 cohorts of 15,551 women (Nurses' Health Study) and 7397 men (Health Professionals Follow-Up Study), who provided detailed dietary data before blood draw and were free of diabetes, cardiovascular disease, or cancer at the time of blood draw. Multivariable linear regression was used to calculate the percentage difference of biomarker concentrations comparing coffee drinkers with nondrinkers, after adjusting for a variety of demographic, clinical, and lifestyle factors. RESULTS Compared with nondrinkers, participants who drank ≥4 cups of total coffee/d had lower concentrations of C-peptide (-8.7%), IGFBP-3 (-2.2%), estrone (-6.4%), total estradiol (-5.7%), free estradiol (-8.1%), leptin (-6.4%), CRP (-16.6%), IL-6 (-8.1%), and sTNFR-2 (-5.8%) and higher concentrations of SHBG (5.0%), total testosterone (7.3% in women and 5.3% in men), total adiponectin (9.3%), and HMW adiponectin (17.2%). The results were largely similar for caffeinated and decaffeinated coffee. CONCLUSION Our data indicate that coffee consumption is associated with favorable profiles of numerous biomarkers in key metabolic and inflammatory pathways. This trial was registered at clinicaltrials.gov as NCT03419455.
Molecular profile of ultrastructure changes of the ligamentum flavum related to lumbar spinal canal stenosis

Lumbar spinal canal stenosis (LSCS) is a degenerative disease observed by hypertrophy of the ligamentum flavum (LF) that cause compression of the lumbar neural content. Diabetes mellitus (DM) is a risk factor for the disease and we have shown previously that DM increases the fibrosis and elastic fiber loss in patients with LSCS. The purpose of this study was to find the proteins that play a role in the development of this clinical pathogenesis and the effect of DM on protein expression. LF tissue retrieved from patients diagnosed with LSCS, some were also diagnosed with DM, were compared with LF from patients diagnosed with herniated nucleus pulposus (HNP). The tissues were analyzed by mass spectrometry for proteins profile alteration. We found that LF of LSCS/DM patients exhibited significantly higher levels of proteoglycan proteins and latent transforming growth factor β‐binding protein (LTBP2 and LTBP4). Additionally, an increase of HTRA serine protease 1 and insulin‐like growth factor binding protein‐5 were noted. The higher fibrosis was also associated with proteins related to inflammation and slower tissue repair. Collagen 6 and transforming growth factor inhibitor are related to activation of the anti‐inflammatory M2 pathway that is associated with tissue repair. The decrease of these proteins expression in LSCS/DM is associated with increased levels and activation of M1 pro‐inflammatory pathways. Interestingly, C3 and C4b members of the complement complex and mannose receptor‐like protein (CLEC18) paralogous proteins were detectable solely at the LSCS/DM patients’ samples. Histology analysis shows that inflammatory was induced by the hyperglycemic conditions in diabetic patients involve in altering the matrix compositions. Thus, the protein profiles associated with inflammatory pathways affecting the LF suggested increasing susceptibility of developing the degeneration under hyperglycemic conditions.
Family size and educational attainment in England and Wales

In this paper, we use linked census data from England and Wales to investigate whether having a large number of siblings leads to lower educational attainment. There is a large literature suggesting that with large sibship size, parental resources will be diluted and this, in turn, will lead to lower educational attainment. Using twin births and the sex composition of the sibling group as instrumental variables, we find that the evidence of a family size effect on educational attainment is rather uncertain. Similar results are obtained when we use occupational attainment as the dependent variable. We also demonstrate the confounding of birth order and family size effects, and show that an adjusted birth order index proposed by Booth and Kee provides an effective solution to this estimation problem.