Miracle-dz/UniFAR-FTUs huggingface dataset:
MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer

Purpose: Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance. Experimental Design: Effects of MEKi (selumetinib), antiestrogen (fulvestrant), or both were assayed in ER-positive HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOC datasets with high versus low pMAPK by RPPA were used to generate a “MAPK-activated gene signature. ” Gene signature components that were reversed by MEKi were then identified. Results: High intratumor pMAPK independently predicts decreased survival (HR, 1.7; CI > 95%,1.3–2.2; P = 0.0009) in 408 HGSOC from The Cancer Genome Atlas. A differentially expressed “MAPK-activated” gene subset was also prognostic. “MAPK-activated genes” in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater antitumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed that dual therapy downregulated DNA replication and cell-cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of “MAPK-activated genes” in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (P = 0.000265) and warrant testing as a signature predictive of MEKi response. Conclusions: High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER-positive HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors. Clin Cancer Res; 22(4); 935–47. ©2015 AACR.
Medical Perceptions of Menopausal Symptoms

Thirty-five physicians in family practice or gynecology, 43 practicing nurses, and 35 menopausal or postmenopausal women rated the frequency, severity, and causality of 15 menopausal symptoms commonly reported in the literature. Subjects also rated their degree of preference for four possible menopause treatments (counseling, estrogen therapy, mood-altering medication, and no treatment) and answered an open-ended question asking them what they saw as the major factor in determining whether a woman would experience difficulty at menopause. The results overall suggest that medical persons see menopausal symptoms as more pathological than women who have experienced or are experiencing menopause and that physicians, relative to menopausal women, adhere to a more psychogenic model in which psychological causality and symptoms are given greater emphasis than menopausal women give them.
Methods used to quit smoking in the United States. Do cessation programs help

Using data from the 1986 Adult Use of Tobacco Survey, we analyzed smoking-cessation methods used by adult smokers in the United States who tried to quit. About 90% of successful quitters and 80% of unsuccessful quitters used individual methods of smoking cessation rather than organized programs. Most of these smokers who quit on their own used a "cold turkey" approach. Multivariate analysis showed that women, middle-aged persons, more educated persons, persons who had made more quit-smoking attempts, and, particularly, heavier smokers were most likely to use a cessation program. Daily cigarette consumption, however, did not predict whether persons would succeed or fail during their attempts to quit smoking. Rather, the cessation method used was the strongest predictor of success. Among smokers who had attempted cessation within the previous 10 years, 47.5% of persons who tried to quit on their own were successful whereas only 23.6% of persons who used cessation programs succeeded. We conclude that cessation programs serve a small, but important, population of smokers that includes heavier smokers, those most at risk for tobacco-related morbidity and mortality. (JAMA. 1990;263:2760-2765)
Impaired Liver Size and Compromised Neurobehavioral Activity are Elicited by Chitosan Nanoparticles in the Zebrafish Embryo Model

The use of chitosan nanoparticles (ChNPs) in various biological and environmental applications is attracting great interest. However, potential side effects related to ChNP toxicity remain the major limitation hampering their wide application. For the first time, we investigate the potential organ-specific (cardiac, hepatic, and neuromuscular) toxicity of ChNPs (size 100–150 nm) using the zebrafish embryo model. Our data highlight the absence of both acute and teratogenic toxic effects of ChNPs (~100% survival rate) even at the higher concentration employed (200 mg/L). Although no single sign of cardiotoxicity was observed upon exposure to 200 mg/L of ChNPs, as judged by heartbeat rate, the corrected QT interval (QTc, which measures the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle), maximum cardiac arrest, and ejection fraction assays, the same dosage elicited the impairment of both liver size (decreased liver size, but without steatosis and lipid yolk retention) and neurobehavioral activity (increased movement under different light conditions). Although the observed toxic effect failed to affect embryo survival, whether a prolonged ChNP treatment may induce other potentially harmful effects remains to be elucidated. By reporting new insights on their organ-specific toxicity, our results add novel and useful information into the available data concerning the in vivo effect of ChNPs.
Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents.

RATIONALE Structural risk factors for obstructive sleep apnea syndrome (OSAS) in adolescents have not been well characterized. Because many adolescents with OSAS are obese, we hypothesized that the anatomic OSAS risk factors would be more similar to those in adults than those in children. OBJECTIVES To investigate the anatomic risk factors in adolescents with OSAS compared with obese and lean control subjects using magnetic resonance imaging (MRI). METHODS Three groups of adolescents (age range: 12-16 yr) underwent MRI: obese individuals with OSAS (n = 49), obese control subjects (n = 38), and lean control subjects (n = 50). MEASUREMENTS AND MAIN RESULTS We studied 137 subjects and found that (1) obese adolescents with OSAS had increased adenotonsillar tissue compared with obese and lean control subjects; (2) obese OSAS adolescents had a smaller nasopharyngeal airway than control subjects; (3) the size of other upper airway soft tissue structures (volume of the tongue, parapharyngeal fat pads, lateral walls, and soft palate) was similar between subjects with OSAS and obese control subjects; (4) although there were no major craniofacial abnormalities in most of the adolescents with OSAS, the ratio of soft tissue to craniofacial space surrounding the airway was increased; and (5) there were sex differences in the pattern of lymphoid proliferation. CONCLUSIONS Increased size of the pharyngeal lymphoid tissue, rather than enlargement of the upper airway soft tissue structures, is the primary anatomic risk factor for OSAS in obese adolescents. These results are important for clinical decision making and suggest that adenotonsillectomy should be considered as the initial treatment for OSAS in obese adolescents, a group that has poor continuous positive airway pressure adherence and difficulty in achieving weight loss.
Decreased Expression of Cyr61 Is Associated with Prostate Cancer Recurrence after Surgical Treatment

Purpose: Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling. Previous studies have suggested that Cyr61 may be a marker for a more aggressive phenotype. In this study, we evaluated the association between Cyr61 staining intensity and subsequent recurrence after surgical treatment of clinically localized prostate cancer. Experimental Design: A study of 229 men with recurrence and 229 controls matched on age, race, pathologic stage, and Gleason sum nested in a cohort of men who underwent radical prostatectomy for clinically localized prostate cancer, utilizing immunohistochemistry analysis of tissue microarray (TMA) sections, was conducted. Odds ratios (OR) of recurrence and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Results: Recurrence was identified in 12.2% of cases, and in 24.0% of controls that had at least 1 TMA spot containing cancer with a staining intensity of 3 (P = 0.001). Taking into account age, pathologic stage and grade, presurgery prostate-specific antigen concentration, and calendar of surgery as a measure of tissue block storage time, men with a Cyr61 staining intensity of 3 were 56% less likely to recur than men with a lower staining intensity (OR = 0.44, 95% CI = 0.22–0.90). Conclusions: High Cyr61 staining intensity in adenocarcinoma was associated with a lower risk of recurrence after surgical treatment of prostate cancer independent of pathologic tumor characteristics. If validated in other sample sets, Cyr61 may serve as a tissue biomarker for stratifying men for risk of recurrence and thus could inform treatment decision making. Clin Cancer Res; 16(23); 5908–13. ©2010 AACR.
Cytomolecular Identification of Individual Wheat-Wheat Chromosome Arm Associations in Wheat-Rye Hybrids

Chromosome pairing in the meiotic metaphase I of wheat-rye hybrids has been characterized by sequential genomic and fluorescent in situ hybridization allowing not only the discrimination of wheat and rye chromosomes, but also the identification of the individual wheat and rye chromosome arms involved in the chromosome associations. The majority of associations (93.8%) were observed between the wheat chromosomes. The largest number of wheat-wheat chromosome associations (53%) was detected between the A and D genomes, while the frequency of B-D and A-B associations was significantly lower (32 and 8%, respectively). Among the A-D chromosome associations, pairing between the 3AL and 3DL arms was observed with the highest frequency, while the most frequent of all the chromosome associations (0.113/cell) was found to be the 3DS-3BS. Differences in the pairing frequency of the individual chromosome arms of wheat-rye hybrids have been discussed in relation to the homoeologous relationships between the constituent genomes of hexaploid wheat.
Inhibitory control in young adolescents: the role of sex, intelligence, and temperament.

OBJECTIVE Inhibitory control is associated with temperament and intelligence, which together form an essential component of the ability to adaptively regulate behavior. Impairments in inhibitory control have been linked with a host of common and debilitating conditions, often in a sex-dependent manner. However, sex differences in inhibitory control are often not expressed experimentally during task performance. Here, we sought to examine how sex, temperament, and intelligence are related to different aspects of inhibitory control. METHOD We recruited a large sample of early adolescents (n = 153; mean age 12.6 years) to comprehensively investigate the relationship between sex, self-reported and parent-reported temperamental effortful control, and intelligence with different aspects of inhibitory control--namely, strategic (or proactive) control and evaluative (or reactive) control, assessed using a modified Stroop task. RESULTS Compared with males, females were more efficient in their use of strategic control to reduce the magnitude of response conflict. There was no sex difference in evaluative control. Further, whereas high intelligence was associated with fewer errors for both males and females, effortful control was associated with performance accuracy only in females. CONCLUSIONS These findings highlight sex differences in the relationship of inhibitory control to individual differences in temperamental effortful control in early adolescents and reinforce the generalized positive effects of intelligence.
Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas

Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (TFH) and T regulatory (TREG) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ. Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors. Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541–52. ©2017 AACR.
Psychological Essentialism and Attention Allocation: Preferences for Stereotype-Consistent Versus Stereotype-Inconsistent Information

People who believe that human attributes are immutable (entity theorists) display preferences for stereotype-consistent over stereotype-inconsistent information (J. E. Plaks, S. J. Stroessner, C. S. Dweck, & J. W. Sherman, 2001). In this article, the authors argue that entity theories are components of broader sets of beliefs that represent differences between people in terms of underlying essences. Consistent with expectations, the authors found that measures of essentialist beliefs (i.e., in the biological basis, discreteness, informativeness, and inherence of human attributes) covaried with the presence of entity theories. Essentialist beliefs as a set were related to stronger preferences for stereotype-consistent information, and this effect was not reducible to the effect of entity theories. The authors propose that research on implicit person theories can be placed within an encompassing framework of psychological essentialism.
Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7.

Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anti-cancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Its function is required for both cell cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target since its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers (SE). Here we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of ovarian and breast cancer patients (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL-XL expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial anti-tumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Anti-tumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematological and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers.
Pulmonary , gastrointestinal and urogenital pharmacology Costunolide and Dehydrocostuslactone , two natural sesquiterpene lactones , ameliorate the in fl ammatory process associated to experimental pleurisy in mice

The aim of this study was to investigate the effect of costunolide (CS) and dehydrocostuslactone (DCE) a well-known sesquiterpene lactones contained in many plants, in a model of lung injury induced by carrageenan administration in the mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and increased production of tumour necrosis factor α (TNF-α). All parameters of inflammation were attenuated by CS and DCE (15 mg/kg 10% DMSO i.p.) administered 1 h before carrageenan. Carrageenan induced an up regulation of the intracellular adhesion molecules-1 (ICAM-1) and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) (PAR) as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PAR was reduced by CS and DCE. Additionally we show that this inflammatory events were associated with NF-κB and STAT3 activation and these sesquiterpenes down-regulated it. Taken together, ours results clearly shown that CS and DCE may offer a novel therapeutic approach for the management of inflammatory diseases. & 2014 Elsevier B.V. All rights reserved.
No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420–4. ©2016 AACR.
Group-Based Trajectory Modeling: An Overview

This article provides an overview of a group-based statistical methodology for analyzing developmental trajectories - the evolution of an outcome over age or time. Across all application domains, this group-based statistical method lends itself to the presentation of findings in the form of easily understood graphical and tabular data summaries. In so doing, the method provides statistical researchers with a tool for figuratively painting a statistical portrait of the predictors and consequences of distinct trajectories of development. Data summaries of this form have the great advantage of being accessible to nontechnical audiences and quickly comprehensible to audiences that are technically sophisticated. Examples of the application of the method are provided. A detailed account of the statistical underpinnings of the method and a full range of applications are provided by the author in a previous study.
Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions

Background— Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. Methods and Results— Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with &agr;2-antiplasmin peptide (&agr;2AP)–targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter <0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, &agr;2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of &agr;2AP-PFCs >60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, &agr;2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. Conclusions— Our results demonstrate that 1H/19F magnetic resonance imaging, together with &agr;2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.