tbuckley/cabot-search huggingface dataset:
Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor Microenvironment Associated with Clinicopathologic Phenotypes
Authors: Shingo Ashida, Mohammed S. Orloff, Gurkan Bebek, Li Zhang, Pan Zheng, Donna M. Peehl, Charis Eng
Journal: Clinical Cancer Research (2012)

Recent studies suggest that tumor microenvironment (stroma) is important in carcinogenesis and progression. We sought to integrate global genomic structural and expressional alterations in prostate cancer epithelium and stroma and their association with clinicopathologic features.We conducted a genome-wide LOH/allelic imbalance (AI) scan of DNA from epithelium and stroma of 116 prostate cancers. LOH/AI hot or cold spots were defined as the markers with significantly higher or lower LOH/AI frequencies compared with the average frequency for markers along the same chromosome. These data were then integrated with publicly available transcriptome data sets and our experimentally derived data. Immunohistochemistry on an independent series was used for validation.Overall, we identified 43 LOH/AI hot/cold spots, 17 in epithelium and stroma (P < 0.001), 18 only in epithelium (P < 0.001), and eight only in stroma (P < 0.001). Hierarchical clustering of expression data supervised by genes within LOH/AI hot/cold spots in both epithelium and stroma accurately separated samples into normal epithelium, primary cancer, and metastatic cancer groups, which could not be achieved with data from only epithelium. Importantly, our experimental expression data of the genes within the LOH/AI hot/cold spots in stroma accurately clustered normal stroma from cancer stroma. We also identified 15 LOH/AI markers that were associated with Gleason score, which were validated functionally in each compartment by transcriptome data. Independent immunohistochemical validation of STIM2 within a stromal significant LOH marker (identified as associated with Gleason grade) confirmed its downregulation in the transition from moderate to high Gleason grade.Compartment-specific genomic and transcriptomic alterations accurately distinguish clinical and pathologic outcomes, suggesting new biomarkers for prognosis and targeted therapeutics.
Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide
Authors: Zhao-Li Zhou, Zhi-Guo Luo, Bing Yu, Yi Jiang, Yi Chen, Jian-Ming Feng, Mei Dai, Lin-Jiang Tong, Zheng Li, Yuan-Chao Li, Jian Ding, Ze-Hong Miao
Journal: Molecular Cancer (2010)

Hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α.Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide.The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1α functions in an unresolved nature or condition.
Indian Education: A Human Systems Analysis
Authors: CARL A. HAMMERSCHLAG, CLAYTON P. ALDERFER, DAVID BERG
Journal: American Journal of Psychiatry (1973)

The problems of Indian boarding schools are examined in the light of both systems theory and data from interviews and questionnaires conducted at one school. The authors conclude that the schools have failed to define their primary task—to educate or to handle children with behavior problems. More importantly, the impact of the whole educational system perpetuates the Indians' powerlessness and dependency on the government. The authors express the hope that, if there is more community involvement in the schools, this will lead to greater assumption of responsibility by Indians in other spheres.
A patient who changed my practice: Never say, "never" again
Authors: B S. Naik
Journal: BMJ (2002)

In the early part my medical career I was full of the enthusiasm and overwhelming confidence about my clinical skill that one generally finds in a novice. A 19 year old college student was admitted with complaints of not talking and giddiness. The history included an emotional upset, as she had quarrelled with her mother before the onset of the symptoms.

When I examined her, she was conscious but kept her eyes tightly …
Processing of Plasmodium falciparum Merozoite Surface Protein MSP1 Activates a Spectrin-Binding Function Enabling Parasite Egress from RBCs
Authors: Sujaan Das, Nadine Hertrich, Abigail J. Perrin, Chrislaine Withers-Martinez, Christine R. Collins, Matthew L. Jones, Jean M. Watermeyer, Elmar T. Fobes, Stephen R. Martin, Helen R. Saibil, Gavin J. Wright, Moritz Treeck, Christian Epp, Michael J. Blackman
Journal: Cell Host & Microbe (2015)

Highlights•Merozoite surface protein MSP1 processing is important for P. falciparum viability•Proteolytic processing activates MSP1's heparin and spectrin-binding functions•The rate of MSP1 processing governs the kinetics of parasite egress•Loss of parasite surface MSP1 results in a severe egress defectSummaryThe malaria parasite Plasmodium falciparum replicates within erythrocytes, producing progeny merozoites that are released from infected cells via a poorly understood process called egress. The most abundant merozoite surface protein, MSP1, is synthesized as a large precursor that undergoes proteolytic maturation by the parasite protease SUB1 just prior to egress. The function of MSP1 and its processing are unknown. Here we show that SUB1-mediated processing of MSP1 is important for parasite viability. Processing modifies the secondary structure of MSP1 and activates its capacity to bind spectrin, a molecular scaffold protein that is the major component of the host erythrocyte cytoskeleton. Parasites expressing an inefficiently processed MSP1 mutant show delayed egress, and merozoites lacking surface-bound MSP1 display a severe egress defect. Our results indicate that interactions between SUB1-processed merozoite surface MSP1 and the spectrin network of the erythrocyte cytoskeleton facilitate host erythrocyte rupture to enable parasite egress.Graphical abstract
Global analysis of the human gastric epithelial transcriptome altered by Helicobacter pylori eradication in vivo
Authors: M B Resnick, E Sabo, P A Meitner, S S Kim, Y Cho, H K Kim, R Tavares, S F Moss
Journal: Gut (2006)

Objective: The transcriptional profile of gastric epithelial cell lines cocultured with Helicobacter pylori and the global gene expression of whole gastric mucosa has been described previously. We aimed to overcome limitations of previous studies by determining the effects of H pylori eradication on the transcriptome of purified human gastric epithelium using each patient as their own control. Design: Laser capture microdissection (LCM) was used to extract mRNA from paraffin-embedded antral epithelium from 10 patients with peptic ulcer disease, before and after H pylori eradication. mRNA was reverse transcribed and applied on to Affymetrix cDNA microarray chips customised for formalin-fixed tissue. Differentially expressed genes were identified and a subset validated by real-time polymerase chain reaction (PCR). Results: A total of 13 817 transcripts decreased and 9680 increased after H pylori eradication. Applying cut-off criteria (p<0.02, fold-change threshold 2.5) reduced the sample to 98 differentially expressed genes. Genes detected included those previously implicated in H pylori pathophysiology such as interleukin 8, chemokine ligand 3, β defensin and somatostatin, as well as novel genes such as GDDR (TFIZ1), chemokine receptors 7 and 8, and gastrokine. Conclusions: LCM of archival specimens has enabled the identification of gastric epithelial genes whose expression is considerably altered after H pylori eradication. This study has confirmed the presence of genes previously implicated in the pathogenesis of H pylori , as well as highlighted novel candidates for further investigation.
The Establishment of the C3H Inbred Strain of Mice for the Study of Spontaneous Carcinoma of the Mammary Gland
Authors: L. C. Strong
Journal: CA A Cancer Journal for Clinicians (1979)

CA: A Cancer Journal for Clinicians publishes information about the prevention, early detection, and treatment of cancer, as well as nutrition, palliative care, survivorship, and additional topics of interest related to cancer care.
Vitamin D dosing for infectious and immune disorders
Authors: Scott T Weiss, Augusto A Litonjua
Journal: Thorax (2015)

The most natural way that humans get vitamin D into their body is through exposure to sunlight. If one is at the equator in the summer without sunscreen, human skin will produce approximately 10 000 IU of vitamin D over one hour, a testament to the incredible reserve that human skin has to translate ultraviolet light B (UVB) exposure into vitamin D3 levels in serum.

However, modern culture has made sun exposure an inefficient transducer of vitamin D. First, humans spend upwards of 90% of their time indoors and, when outside, have clothes and sunscreen on, both of which reduce the exposure to UVB radiation and, consequently, the production of vitamin D in the skin. Finally, in countries such as the UK, that are far north of the equator, for at least 6 months of the year, there is significantly less UVB radiation that reaches the earth's surface given the larger solar zenith angle of the sun's rays with respect to the earth's surface.1 We are a long way from where modern humans originated, 10 000 years ago, naked, at the equator and outdoors 100% of the time.

Thus, to get enough vitamin D, humans must rely on supplementation of their diet to attain appropriate intake. The fact that we have this dual mechanism is testament to the critical biological role that vitamin D plays in human immunity and physiology. This dietary supplementation has been used since the middle of the 18th century when cod-liver oil was regularly …
Autonomic Nervous System Activity Measured Directly and QT Interval Variability in Normal and Pacing-Induced Tachycardia Heart Failure Dogs
Authors: Gianfranco Piccirillo, Damiano Magrì, Masahiro Ogawa, Juan Song, Voon J. Chong, Seongwook Han, Boyoung Joung, Eue-Keun Choi, Samuel Hwang, Lan S. Chen, Shien-Fong Lin, Peng-Sheng Chen
Journal: Journal of the American College of Cardiology (2009)
Understanding the Biology of Bone Metastases: Key to the Effective Treatment of Prostate Cancer
Authors: Christopher J. Logothetis, Nora M. Navone, Sue-Hwa Lin
Journal: Clinical Cancer Research (2008)

Abstract Advanced prostate cancer is dominated by bone-forming osseous metastases. Understanding the biology behind this striking clinical manifestation is the key to its effective treatment. A clinical trial using a bone-targeting radiopharmaceutical agent, strontium 89, combined with chemotherapy showed increased survival time among patients with progression of prostate cancer in bone, suggesting that therapeutic strategies focused on treating the tumor in bone are effective. We and others thus hypothesize that interactions between prostate cancer cells and the bone microenvironment play a role in the progression of prostate cancer in bone. Clinical trials and basic science investigations aiming to understand such interactions have been carried out in parallel. In the laboratory studies, human bone marrow specimens have been collected for identification of proteins involved in the bidirectional interactions between prostate cancer cells and bone. In addition, specimens from bone biopsies of the cancer lesions have been used to generate xenografts in animals to establish animal models for testing therapeutic strategies. Clinical trials using agents to inhibit the stromal-prostate cancer interactions (e.g., docetaxel/imatinib or thalidomide) have been done. Analyses of the specimens from these trials provided support of our hypothesis and future development of diagnosis and therapy strategies.
Exercise induced release of von Willebrand factor: evidence for hypoxic reperfusion microvascular injury in rheumatoid arthritis.
Authors: A J Farrell, R B Williams, C R Stevens, A S Lawrie, N L Cox, D R Blake
Journal: Annals of the Rheumatic Diseases (1992)

Experimental evidence suggests that rheumatoid synovitis may be perpetuated by the generation of reactive oxygen species during hypoxic reperfusion injury. The latter occurs because increased intra-articular pressure during exercise exceeds synovial capillary perfusion pressure, impairing blood flow. The object of this study was to establish a marker for and the mechanism of synovial hypoxic reperfusion injury. Von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury. In vivo exercise induced changes in plasma vWF were therefore investigated in patients with rheumatoid arthritis (RA) compared with controls and in vitro vWF release by human umbilical vein endothelial cells subjected to hypoxia reperfusion. Pre-exercise plasma vWF levels were 1001 and 817 IU/l, increasing after exercise to 1658 and 845 IU/l in patients with RA and controls respectively. Von Willebrand factor release from human umbilical vein endothelial cells followed a biphasic pattern, occurring during both hypoxia and reperfusion. Hypoxia reperfusion induced vWF release by human umbilical vein endothelial cells in vitro suggests that exercise induced vWF release in patients with RA is best explained by synovial hypoxic reperfusion injury. This study supports evidence that generation of reactive oxygen species plays a principal part in synovial hypoxic reperfusion injury and suggests vWF as a useful marker of this phenomenon.
Novel NAD(P)H Oxidase Inhibitor Suppresses Angioplasty-Induced Superoxide and Neointimal Hyperplasia of Rat Carotid Artery
Authors: Gary M. Jacobson, Hector M. Dourron, Jianhua Liu, Oscar A. Carretero, Daniel J. Reddy, Tanja Andrzejewski, Patrick J. Pagano
Journal: Circulation Research (2003)

Neointimal proliferation occurring after vascular or endovascular procedures is a major complication leading to end-organ or limb ischemia. In experimental models, balloon injury has been shown to induce NAD(P)H oxidase to produce vascular superoxide anion (O 2 ·− ) production, which has been implicated in cell proliferation, but a direct link is still unclear. We postulated that inhibition of arterial NAD(P)H oxidase, resulting in decreased O 2 ·− , would lessen the neointimal hyperplasia caused by balloon injury to the common carotid artery (CCA). Sprague-Dawley rats were implanted with osmotic minipumps containing either vehicle, a cell-permeant peptide that inhibits NAD(P)H oxidase (gp91ds-tat, 10 mg/kg per day), or a scrambled peptide control (scrmb-tat). Two days after pump implantation, the left CCA was injured using an intravascular balloon embolectomy catheter (2F Fogarty). Systolic blood pressure was monitored by tail cuff. Fourteen days after injury, CCAs were harvested and analyzed by digital morphometry. Rats in both groups remained normotensive, with no significant differences in systolic blood pressure. Reactive oxygen species measurements after injury indicated a significant reduction in vascular O 2 ·− in rats infused with gp91ds-tat, and the neointima/media area and thickness ratios were significantly lower in their arteries compared with control. On the contrary, no significant change in overall CCA diameter was observed in any group. Our data indicate that in response to balloon injury of the rat carotid artery, NAD(P)H oxidase activity contributes to neointimal hyperplasia and is involved in vascular cell proliferation and migration during restenosis.
Polymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitis
Authors: Julien Taı̈eb, Charlotte Delarche, Valérie Paradis, Philippe Mathurin, Alain Grenier, Bruno Crestani, Monique Dehoux, Dominique Thabut, Marie-Anne Gougerot-Pocidalo, Thierry Poynard, Sylvie Chollet-Martin
Journal: Journal of Hepatology (2002)
Gender Differences in the Salaries of Physician Researchers
Authors: Reshma Jagsi, Kent A Griffith, Abigail Stewart, Dana Sambuco, Rochelle DeCastro, Peter A Ubel
Journal: JAMA (2012)

It is unclear whether male and female physician researchers who perform similar work are currently paid equally.To determine whether salaries differ by gender in a relatively homogeneous cohort of physician researchers and, if so, to determine if these differences are explained by differences in specialization, productivity, or other factors.A US nationwide postal survey was sent in 2009-2010 to assess the salary and other characteristics of a relatively homogeneous population of physicians. From all 1853 recipients of National Institutes of Health (NIH) K08 and K23 awards in 2000-2003, we contacted the 1729 who were alive and for whom we could identify a mailing address.The survey achieved a 71% response rate. Eligibility for the present analysis was limited to the 800 physicians who continued to practice at US academic institutions and reported their current annual salary.A linear regression model of self-reported current annual salary was constructed considering the following characteristics: gender, age, race, marital status, parental status, additional graduate degree, academic rank, leadership position, specialty, institution type, region, institution NIH funding rank, change of institution since K award, K award type, K award funding institute, years since K award, grant funding, publications, work hours, and time spent in research.The mean salary within our cohort was $167,669 (95% CI, $158,417-$176,922) for women and $200,433 (95% CI, $194,249-$206,617) for men. Male gender was associated with higher salary (+$13,399; P = .001) even after adjustment in the final model for specialty, academic rank, leadership positions, publications, and research time. Peters-Belson analysis (use of coefficients derived from regression model for men applied to women) indicated that the expected mean salary for women, if they retained their other measured characteristics but their gender was male, would be $12,194 higher than observed.Gender differences in salary exist in this select, homogeneous cohort of mid-career academic physicians, even after adjustment for differences in specialty, institutional characteristics, academic productivity, academic rank, work hours, and other factors.
Anti-Platelet Factor 4/Heparin Antibodies
Authors: R. Taylor Williams, Lakshmi V. Damaraju, Mary Ann Mascelli, Elliot S. Barnathan, Robert M. Califf, Maarten L. Simoons, Efthymios N. Deliargyris, David C. Sane
Journal: Circulation (2003)

Background— We postulated that antibodies to platelet factor 4/heparin complex might contribute to recurrent ischemic events in patients with acute coronary syndrome. Methods and Results— We analyzed serum from patients enrolled in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had high likelihood of prior heparin exposure. We selected 109 patients without thrombocytopenia with the 30-day primary end point (death, myocardial infarction [MI], or revascularization) and 109 age-, gender-, and race-matched controls who did not achieve the primary end point. An ELISA for anti-platelet factor 4/heparin antibodies was performed using 48-hour serum samples. The analyses were done by blinded investigators, and the results were correlated with clinical outcomes. Twenty-three of 218 patients (10.6%) had anti-PF4/heparin antibodies. Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% versus 11.3%, P =0.011) or MI (21.7% versus 6.2%, P =0.008) than patients who were negative for the antibody. After multiple logistic regression analysis, anti-PF4/heparin antibodies remained a predictor of 30-day death or MI (odds ratio, 4.0; 95% CI, 1.4 to 11.3; P =0.0093) and MI (odds ratio, 4.6; 95% CI, 1.4 to 15.0; P =0.0108). The antibody was not associated with the composite end point (death, MI, or revascularization) or with death or revascularization alone. Conclusions— Antibodies to the platelet factor 4/heparin complex are a novel, independent predictor of myocardial infarction at 30 days in patients presenting with acute coronary ischemic syndromes. This finding may explain the previous association between thrombocytopenia and adverse events in patients with acute coronary syndrome and may have important implications for the choice of anticoagulant regimens.
Prenatal Exposure to Maternal Infection and Executive Dysfunction in Adult Schizophrenia
Authors: Alan S Brown, Sophia Vinogradov, William S Kremen, John H Poole, Raymond F Deicken, Justin D Penner, Ian W McKeague, Anna Kochetkova, David Kern, Catherine A Schaefer
Journal: American Journal of Psychiatry (2009)

Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with schizophrenia.The authors assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort.Patients who were exposed to infection in utero committed significantly more total errors on the Wisconsin Card Sorting Test and took significantly more time to complete the Trails B than unexposed patients. Exposed patients also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span.Prenatal infections previously associated with schizophrenia are related to impaired performance on the Wisconsin Card Sorting Test and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is needed to elucidate the specificity of prenatal infection to these executive function measures and to examine correlates with neuroanatomic and neurophysiologic anomalies.