Miracle-dz/UniFAR-FTUs huggingface dataset:
Association analysis of SNPs present in plasma with adverse events and population pharmacokinetics in Chinese sunitinib treated patients with renal cell carcinoma

Background Sunitinib is a tyrosine kinase inhibitor with effective therapeutic outcomes in patients with renal-cell carcinoma. The study were to analyze the association of single-nucleotide polymorphisms present in cell-free DNA and pharmacokinetics with sunitinib treatment-emergent adverse events in Chinese patients with renal-cell carcinoma. Materials and Methods We genotyped 8 keys SNPs in 6 candidate genes. The plasma concentrations of sunitinib and N-desethyl sunitinib were measured using a high performance liquid chromatography-tandam mass spectrometry method. Correlations between the single-nucleotide polymorphisms and adverse events were investigated by univariate and multivariate logistic regression and we quantitatively evaluated the effect of single-nucleotide polymorphisms on the pharmacokinetics of sunitinib by using a population PK model. Results Necessary dose reductions of sunitinib were significantly correlated with SNP rs1933437 in FLT3. A higher severity of AEs were collected with SNP rs2032582 in ABCB1 and rs1800812 in PDGFRα. Thrombocytopenia was collected with rs1800812 in PDGFRα. Our study provides a population PK model of sunitinib with the ABCB1 genotype as a predictive covariate for apparent oral clearance. Conclusions Our study preliminarily confirmed the hypothesis that the pharmacokinetics of sunitinib is affected by the SNPs of enzyme in Chinese renal-cell carcinoma patients, and this affects the different distribution and severity of adverse events of sunitinib.
The attitudes of medical students in Europe toward the clinical importance of histology

Many studies have been undertaken to assess the attitudes of medical students to the clinical importance of gross anatomy. However, much less is known about their attitudes toward the clinical importance of histology. Using Thurstone and Chave methods to assess attitudes, over 2,000 early stage medical students across Europe provided responses to a survey that tested the hypothesis that the students have a high regard for histology's clinical relevance. Regardless of the university and country surveyed, and of the teaching methods employed for histology, our findings were not consistent with our hypotheses, students providing a more moderate assessment of histology's importance compared to gross anatomy but more positive than their attitudes toward embryology. Histology should play a significant role in medical education in terms of appreciating not just normal structure and function but also pathology. We conclude that teachers of histology should pay special attention to informing newly‐recruited medical students of the significant role played by histology in attaining clinical competence and in underpinning their status as being learned members of a healthcare profession. This work was conducted under the auspices of the Trans‐European Pedagogic Research Group (TEPARG). Clin. Anat. 30:635–643, 2017. © 2017 Wiley Periodicals, Inc.
Ensembling brain regions for brain decoding

In this study, we propose a new method which ensembles the brain regions for brain decoding. The ensemble is generated by clustering the fMRI images recorded during an experimental set-up which measures the cognitive states associated to semantic categories. Initially, voxel clusters are formed by using hierarchical agglomerative clustering with correlation as the similarity metric. Then, for each voxel cluster, a support vector machine (SVM) classifier is trained to estimate the class-posteriori probabilities. Lastly, the class-posteriori probabilities are ensembled by concatenating them under the same feature space, which are then used to train a meta-layer SVM for the final classification of the cognitive states. By using the voxel clusters, we aim to utilize the distributed, but complementing nature of the semantic representations in the brain and improve the classification accuracy. Thus, we make an existential claim that the brain regions provide a natural basis for ensemble learning which should be superior to the random clusters formed over a selected set of voxels. Our approach yields to better classification accuracies in Mitchell dataset on most of the subjects, when compared to state-of-the-art which emphasizes voxel selection and ensemble learning with random subspaces.
Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia.

BACKGROUND Evidence supports an independent association between plasma total homocysteine concentrations and the risk of vascular disease. Recent epidemiologic studies reappraised the possibility that vascular risk factors might play a role in the pathogenesis not only of vascular dementia (VaD) but also of Alzheimer disease (AD). OBJECTIVE The objective was to investigate the relations of mild cognitive impairment, AD, and VaD with blood homocysteine, folate, and vitamin B-12. DESIGN The study population consisted of 314 consecutive subjects, 228 of whom were eligible for analyses. Plasma total homocysteine, serum folate, and serum vitamin B-12 concentrations were measured in 55 nondemented elderly control subjects, 81 mildly cognitively impaired subjects (Clinical Dementia Rating: 0.5), and 92 demented patients prevalently in a mild disease stage and with a clinical diagnosis of AD (n = 74) or VaD (n = 18). RESULTS Subjects in the lowest folate tertile had significantly higher adjusted odds ratios (ORs) for mild cognitive impairment (OR: 3.1; 95% CI: 1.2, 8.1) and dementia (3.8; 1.3, 11.2). Hyperhomocysteinemia was significantly associated with dementia (adjusted OR: 4.3; 1.3, 14.7) and AD (adjusted OR: 3.7; 1.1, 13.1). In subjects with a Clinical Dementia Rating of 0.5, the mean (+/- SE) Mini-Mental State Examination score was significantly lower (P < 0.05) in the highest homocysteine tertile (24.5 +/- 0.5) than in the lowest tertile (26.6 +/- 0.5). No significant associations were found between minimum medial temporal lobe thickness or leukoaraiosis and any biochemical measure in the dementia and AD groups. CONCLUSIONS These findings suggest that relative folate deficiency may precede AD and VaD onset. Hyperhomocysteinemia might also be an early risk factor for cognitive decline in the elderly, but its role in dementia development must be addressed in future longitudinal studies.
Dopamine Modulates the Functional Organization of the Orbitofrontal Cortex

Neuromodulators such as dopamine can alter the intrinsic firing properties of neurons and may thereby change the configuration of larger functional circuits. The primate orbitofrontal cortex (OFC) receives dopaminergic input from midbrain nuclei, but the role of dopamine in the OFC is still unclear. Here we tested the idea that dopaminergic activity changes the pattern of connectivity between the OFC and the rest of the brain and thereby reconfigures functional networks in the OFC. To this end, we combined double-blind, placebo-controlled pharmacology [D2 receptor (D2R) antagonist amisulpride] in humans with resting-state functional magnetic resonance imaging and clustering methods. In the placebo group, we replicated previously observed parcellations of the OFC into two and six subregions based on connectivity patterns with the rest of the brain. Most importantly, while the twofold clustering did not differ significantly between groups, blocking D2Rs significantly changed the composition of the sixfold parcellation, suggesting a dopamine-dependent reconfiguration of functional OFC subregions. Moreover, multivariate decoding analyses revealed that amisulpride changed the whole-brain connectivity patterns of individual OFC subregions. In particular, D2R blockade shifted the balance of OFC connectivity from associative areas in the temporal and parietal lobe toward functional connectivity with the frontal cortex. In summary, our results suggest that dopamine alters the composition of functional OFC circuits, possibly indicating a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks. SIGNIFICANCE STATEMENT A key role of any neuromodulator may be the reconfiguration of functional brain circuits. Here we test this idea with regard to dopamine and the organization of functional networks in the orbitofrontal cortex (OFC). We show that blockade of dopamine D2 receptors has profound effects on the functional connectivity patterns of the OFC, yielding altered connectivity-based subdivisions of this region. Our results suggest that dopamine changes the connectional configuration of the OFC, possibly leading to transitions between different operating modes that favor either sensory input or recurrent processing in the prefrontal cortex. More generally, our findings support a broader role for neuromodulators in the dynamic reconfiguration of functional brain networks and may have clinical implications for understanding the actions of antipsychotic agents.
Reply: Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion.

Sir, Carelli and colleagues (2016) draw attention to an interesting feature of a figure that we published in a Brain article on the role of environmental factors in precipitating visual loss in Leber's hereditary optic neuropathy (LHON), which is an important cause of inherited mitochondrial blindness (Kirkman et al. , 2009 a ). Our original study involved 125 LHON families. One hundred and ninety-six affected and 206 unaffected LHON carriers harbouring one of three common mitochondrial DNA (mtDNA) mutations (m.11778A>G, m.3460A>G, and m.14484T>C) were recruited. All the participants took part in a standardized phone-based interview to collect information on lifestyle habits, in particular smoking and alcohol consumption. Overall, our study showed a strong consistent relationship between smoking and the risk of visual failure in LHON that was independent of gender and alcohol intake. Rather strikingly, the clinical penetrance of the LHON mtDNA mutations was 93% in the males who smoked compared within the 50% overall lifetime risk generally quoted in the literature (Newman et al. , 1991). Figure 3 in our original study (Kirkman et al. , 2009 b ) showed the proportion of LHON mutation carriers that remained symptom-free as a function of age, stratified by their tobacco consumption, both cumulative (Fig. 3A) and the maximum intensity (Fig. 3B). Figure 3A showed an unexpected and unexplained feature that was noticed by reviewers of the manuscript, and subsequently highlighted in the accompanying Scientific Commentary (Newman, 2009). Curiously, for individuals under 50 years of age, the clinical penetrance of the pathogenic LHON mtDNA mutations appeared to be lower in those individuals who have had the highest cumulative smoking exposure up to that age. However, all other statistical analyses gave a consistent message that smoking was a major risk factor for precipitating visual failure in LHON. Of note, when considering maximum intensity of …
The Wisdom of Crowds of Doctors

Background. Evidence suggests that the average prediction across groups is more accurate than for individuals. Our goals were therefore to investigate accuracy of the average predictions for groups of clinicians and to compare this accuracy with a published statistical prediction model. Methods. Twenty-four expert clinicians attending an advisory board meeting were asked to make predictions for 25 patients from a research registry regarding the probability of having a positive bone scan 1 year from today if left untreated. Comparisons were made between the accuracy of average responses and that of an appropriate previously published statistical prediction model. Results. This study suggests that the mean of the clinicians’ predictions can quickly approach the accuracy of the best clinician using as few as 5 clinicians. When all 24 clinicians’ predictions were averaged, the concordance index reached 0.750, still far below that of the published statistical model with 0.812. Conclusions. Averaging clinician predictions may have merit over individual clinician predictions but still not reasonably replace a carefully built statistical model. However, averaging clinician predictions could prove helpful in situations where statistical models do not yet exist or where existing models are inadequate.
Methodological challenges in studying the causal determinants of child growth.

Background Previous studies of early life influences on later growth in childhood have varied in their analytical approaches, particularly with respect to 'adjustment' for differences in size at the beginning of the growth period examined. Methods We compared three commonly used statistical models to assess the effect of maternal body mass index (BMI) on growth between 6.5 and 11.5 years in a large cohort of Belarusian children, as follows: (Model 1) analysis of the difference in anthropometric measurements between the two ages; (Model 2) analysis of the measurement at 11.5 years after adjustment for the same measurement at 6.5 years; and (Model 3) analysis of the difference in measurements after adjustment for the measurement at 6.5 years (mathematically identical to Model 2). Results Among PROBIT children of obese mothers (BMI ≥ 30 kg/m 2 ) vs those of mothers with normal BMI (18.5 to < 25 kg/m 2 ), Model 1 yielded larger increases in most weight and adiposity outcomes than did Model 2. We show that these larger effects arise because Model 2 parameterizes the effect of maternal BMI twice in same model: once for its effect on size at 6.5 years, and a second time for its effect on growth over the 5-year period between 6.5 and 11.5 years. Similar results were obtained in analogous analyses from cohorts in Boston, MA, and Singapore. Conclusion Analysing the effect of exposure on change in outcome between two ages (Model 1) is clearly preferable to 'adjustment' for the outcome at the earlier age whenever the exposure under study affects the outcome at the earlier age.
A Selective Biomarker Panel Increases the Reproducibility and the Accuracy in Endometrial Biopsy Diagnosis

Grading and histologic typing of endometrial cancer in biopsy material has a direct impact on the decision to perform lymphadenectomy and/or omentectomy in many cancer centers. Endometrial biopsies are among the most common general surgical pathology specimens. Multiple studies have shown that biopsy diagnosis suffers from a lack of reproducibility. Although many biomarkers have been proposed, none have been demonstrated to improve the diagnosis in the biopsy setting. In this study, 70 biopsies with endometrial carcinoma were supplemented with a biomarker panel consisting of ER, PR, P53, and DNA ploidy. A representative H&E slide was scanned digitally and made available to 12 gynecologic pathologists in 4 Nordic countries: Finland, Denmark, Sweden, and Norway. Reviewers diagnosed the cases both before and after being provided with the biomarker results. The interobserver percent agreement and Cohen &kgr; improved from 75.8% (&kgr;=0.52, moderate) to 84% (&kgr;=0.68, substantial) with inclusion of the biomarker panel. Agreement with the subsequent hysterectomy diagnosis also improved from 83.6% (&kgr;=0.67) to 88.7% (&kgr;=0.77). There was no statistical improvement between a reflex (84% agreement) and a reflective testing algorithm (82.9% agreement), suggesting that the selective use of biomarkers is appropriate. Difficult cases were almost exclusively high-grade tumors. Finally, a statistical model indicated that only P53 and DNA ploidy, in conjunction with an H&E review, had an impact on the decision to upgrade or downgrade cases.
Insecticidal and antifeedant activities of clerodane diterpenoids isolated from the Indian bhant tree, Clerodendron infortunatum , against the cotton bollworm, Helicoverpa armigera

Abstract The Indian bhant tree, Clerodendron infortunatum L. (Lamialus: Lamiaceae), is a well-known medicinal plant, but little information about its bioefficacy against agricultural pests exists. This scarcity was addressed in the present study, in which dried leaves of C. infortunatum were subjected to extraction with hexane and methanol and then partitioned using different solvents of varying polarity. In a preliminary bioassay, the antifeedant effects of the crude extracts and fractions were tested on a highly polyphagous pest, the cotton bollworm, Helicoverpa armigera Hübner (Lepidoptera: Noctuidae), using the no-choice test method with cabbage leaf discs. The methanol fraction resulted in maximum antifeedant activity. This fraction was further subjected to crystallization and column chromatography in order to isolate the compounds responsible for the activity. Three pure compounds were isolated and identified as clerodin (CL), 15-methoxy-14, 15-dihydroclerodin (MD), and 15-hydroxy-14, 15-dihyroclerodin (HD). The antifeedant activity of these compounds was studied using a choice as well as a no-choice test method with 24 and 48 hr observation periods. Insecticidal activity was measured using the topical application method at 0.5, 1, 1.5, 2, 2.5, and 3% concentrations, and data were recorded 24, 48, and 72 hr after treatment. In the no-choice test conditions, compounds CL and MD showed significantly higher antifeedant activity compared to the key ingredient in many commercial pesticides, azadirachtin, at its highest concentration. Compound HD also showed very good antifeedant activity, which did not differ significantly from that of azadirachtin. In the choice test conditions, all three compounds and azadirachtin showed 100% antifeedant activity at the highest concentration. Antifeedant Index (AI50) values of CL, MD, and HD were 6, 6, and 8 ppm in choice tests, and increased to 8, 9, and 11 ppm in the no-choice tests, respectively. Insecticidal activity of the isolated compounds was not significant compared to the control condition, even at the highest conconcentrations of the compounds. These results suggest that extracts of C. infortunatum have very good antifeedant effects against H. armigera due to the presence of specific compounds. These compounds could be utilized in the development of new biopesticides.
Crystal structure of peptidoglycan recognition protein SA in Apis mellifera (Hymenoptera: Apidae)

Peptidoglycan recognition protein SA (PGRP‐SA) is a key pattern recognition receptor in the insect innate immune system. PGRP‐SA can bind to bacterial PGN and activate the Toll pathway, which triggers the expression and release of antimicrobial peptides to prevent bacterial infection. Here, we report the first structure of Apis mellifera PGRP‐SA from Hymenoptera at 1.86 Å resolution. The overall architecture of Am‐PGRP‐SA was similar to the Drosophila PGRP‐SA; however, the residues involved in PGN binding groove were not conserved, and the binding pocket was narrower. This structure gives insight into PGN binding characteristics in honeybees.
In vivo evidence supporting a metastasis suppressor role for Stard13 (Dlc2) in ErbB2 (Neu) oncogene induced mouse mammary tumors

Overexpression of dominant oncogenes and the loss of tumor suppressor genes are basic genetic events in the acquisition of the malignant phenotype. The erb‐b2 receptor tyrosine kinase 2 (ERBB‐2) proto‐oncogene is overexpressed in 20‐30% of human breast cancers. The StAR related lipid transfer domain containing 13 gene (STARD13), also known as Deleted in Liver Cancer‐2 (DLC‐2), maps to chromosome band 13q12.3 and is frequently downregulated in human cancers, including 72% of breast cancers. It encodes a RhoGAP protein with sterile α motif (SAM) and StAR‐related lipid transfer (START) domains. The objective of this study was to determine if loss of Stard13 plays a role in mammary tumor progression using transgenic mice expressing the activated ErbB‐2 (Neu) oncogene and Cre recombinase (NIC) in mammary epithelium under transcriptional control of the murine mammary tumor virus (MMTV) promoter (MMTV‐NIC). These mice were crossed with a conditional Stard13 knockout mouse (floxed exon 3), resulting in simultaneous Neu expression and Stard13 deletion, specifically in the mammary epithelium. We found that loss of Stard13 did not alter tumor growth nor significantly modify overall survival and tumor free survival. However, there was an increase in the total number of lung metastases in the Stard13 heterozygous or homozygous mice compared with the parental MMTV‐NIC strain. Altogether our results indicate that Stard13 acts as a metastasis suppressor rather than a tumor suppressor gene, in Neu oncogene induced mammary tumorigenesis.
The prediction models for postoperative overall survival and disease‐free survival in patients with breast cancer

The goal of this study is to establish a method for predicting overall survival (OS) and disease‐free survival (DFS) in breast cancer patients after surgical operation. The gene expression profiles of cancer tissues from the patients, who underwent complete surgical resection of breast cancer and were subsequently monitored for postoperative survival, were analyzed using cDNA microarrays. We detected seven and three probes/genes associated with the postoperative OS and DFS, respectively, from our discovery cohort data. By incorporating these genes associated with the postoperative survival into MammaPrint genes, often used to predict prognosis of patients with early‐stage breast cancer, we constructed postoperative OS and DFS prediction models from the discovery cohort data using a Cox proportional hazard model. The predictive ability of the models was evaluated in another independent cohort using Kaplan–Meier (KM) curves and the area under the receiver operating characteristic curve (AUC). The KM curves showed a statistically significant difference between the predicted high‐ and low‐risk groups in both OS (log‐rank trend test P = 0.0033) and DFS (log‐rank trend test P = 0.00030). The models also achieved high AUC scores of 0.71 in OS and of 0.60 in DFS. Furthermore, our models had improved KM curves when compared to the models using MammaPrint genes (OS: P = 0.0058, DFS: P = 0.00054). Similar results were observed when our model was tested in publicly available datasets. These observations indicate that there is still room for improvement in the current methods of predicting postoperative OS and DFS in breast cancer.