tbuckley/cabot-search huggingface dataset:
Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling
Authors: Fabio Conforti, Yisong Wang, Jose A. Rodriguez, Anna Teresa Alberobello, Yu-Wen Zhang, Giuseppe Giaccone
Journal: Clinical Cancer Research (2015)

A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, KPT-330 (Selinexor), which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.
The Role of Depression in the Treatment of Aggressive Personality Disorders
Authors: JOHN R. LION
Journal: American Journal of Psychiatry (1972)

The author believes that patients with aggressive personality disorders can be successfully treated in an outpatient setting. One important aspect of the treatment is getting the patient to confront, understand, and handle the depression ensuing from frustration without acting out. The therapist can help the patient by focusing on the daily frustrations of living and by getting him to fantasize about the possible consequences of his aggressive behavior.
A Behavioral-Biochemical Study of Lithium Treatment
Authors: WILLIAM E. BUNNEY, FREDERICK K. GOODWIN, JOHN M. DAVIS, JAN A. FAWCETT
Journal: American Journal of Psychiatry (1968)

A longitudinal double-blind study of two manic patients treated in a random fashion with lithium carbonate and placebo is reported. Daily ratings of mania were recorded independently by a trained psychiatric nursing team and by a psychiatrist. The major finding was a definite increase in mania, reflected in the daily ratings, during placebo periods within 24 hours of the withdrawal of lithium, even when the placebo period lasted only one day. The rapidity and predictability of the response to withdrawal of lithium offers important advantages both in the clinical use of this drug and in its use as a research tool.
FGFR4 Promotes Stroma-Induced Epithelial-to-Mesenchymal Transition in Colorectal Cancer
Authors: Rui Liu, Jingyi Li, Ke Xie, Tao Zhang, Yunlong Lei, Yi Chen, Lu Zhang, Kai Huang, Kui Wang, Hong Wu, Min Wu, Edouard C. Nice, Canhua Huang, Yuquan Wei
Journal: Cancer Research (2013)

Tumor cells evolve by interacting with the local microenvironment; however, the tumor-stroma interactions that govern tumor metastasis are poorly understood. In this study, proteomic analyses reveal that coculture with tumor-associated fibroblasts (TAF) induces significant overexpression of FGFR4, but not other FGFRs, in colorectal cancer cell lines. Mechanistic study shows that FGFR4 plays crucial roles in TAF-induced epithelial-to-mesenchymal transition (EMT) in colorectal cancer cell lines. Accumulated FGFR4 in cell membrane phosphorylates β-catenin, leading to translocation of β-catenin into the nucleus. Further, TAF-derived CCL2 and its downstream transcription factor, Ets-1, are prerequisites for TAF-induced FGFR4 upregulation. Furthermore, FGFR4-associated pathways are shown to be preferentially activated in colorectal tumor samples, and direct tumor metastasis in a mouse metastasis model. Our study shows a pivotal role of FGFR4 in tumor-stroma interactions during colorectal cancer metastasis, and suggests novel therapeutic opportunities for the treatment of colorectal cancer.
Cancers converge at 2-HG
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2010)

Gender-biased vessel growthA man's male hormones may ward off heart damage by helping vessels around the heart regenerate, suggest Sieveking and colleagues.Although studies have shown that estrogen helps regenerate blood vessels, both in the uterus after menstruation and around the heart after wear and tear, little is known about whether or not men make up for a lack of the female hormone.Some researchers have theorized that this disparity accounts for why men tend to suffer worse heart attacks more often and earlier in life than women.However, Sieveking and colleagues find that this trend may be due to a drop in androgens, a collective term for male hormones, as men age.Angiogenic activities like cell migration ensued after the authors treated human cells derived from the umbilical cord of a male fetus with the androgen DHT.Meanwhile, female cells failed to respond to the androgen, unless they were supplied with extra androgen receptors.In this case, angiogenic activities increased slightly, indicating that hormone sensitivity accounts for some of the gender difference.Castrated mice produced fewer androgens and fared poorly after the researchers inflicted vessel damage intended to resemble injuries that occur during a heart attack or a stroke.And treating the castrated mice with DHT hastened their recovery.Therefore, the authors suggest that androgen replacement therapy might one day be used to treat men at risk for heart disease.The therapy currently receives attention for possibly inducing other rejuvenating benefits, such as increased energy and muscle mass.However, it's been approached with caution as androgens have been shown to assist in tumor growth in prostate cancer-perhaps by stimulating cancer-promoting angiogenesis.Androgen treatments correlated with spikes in the growth factor VEGF, and blocking VEGF interrupted androgen-induced angiogenesis.However, androgens may also modulate angiogenesis by mobilizing progenitor cells known to be critical for vessel repair; the authors found that castrated mice had fewer progenitor cells in circulation after injury than those with their organs intact.
Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients
Authors: B A Johnson, J D Roache, M A Javors, C C DiClemente, C R Cloninger, T J Prihoda, P S Bordnick, N Ait-Daoud, J Hensler
Journal: JAMA (2000)

ContextEarly-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent.ObjectiveTo test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT3 (serotonin) antagonist ondansetron.DesignDouble-blind, randomized, placebo-controlled clinical trial.SettingsUniversity of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999).ParticipantsA total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization.InterventionsAfter 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 µg/kg (n = 67), 4 µg/kg (n = 77), or 16 µg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy.Main Outcome MeasuresSelf-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption.ResultsPatients with early-onset alcoholism who received ondansetron (1, 4, and 16 µg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P = .03, P = .01, and P = .02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P = .03, P = .004, and P = .03, respectively). Ondansetron, 4 µg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P = .02) and total days abstinent per study week (6.74 vs 5.92; P = .03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 µg/kg twice per day) compared with those who received the placebo (−0.17 and −0.19 vs 0.12; P = .03 and P = .01, respectively).ConclusionOur results suggest that ondansetron (particularly the 4 µg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality.
Oxygen uptake efficiency slope: A new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise
Authors: Reizo Baba, Masami Nagashima, Masahiko Goto, Yoshiko Nagano, Mitsuhiro Yokota, Nobuo Tauchi, Kenji Nishibata
Journal: Journal of the American College of Cardiology (1996)
Minimum package for cross-border TB control and care in the WHO European region: a Wolfheze consensus statement
Authors: Masoud Dara, Pierpaolo de Colombani, Roumyana Petrova-Benedict, Rosella Centis, Jean-Pierre Zellweger, Andreas Sandgren, Einar Heldal, Giovanni Sotgiu, Niesje Jansen, Rankica Bahtijarevic, Giovanni Battista Migliori
Journal: European Respiratory Journal (2012)

The World Health Organization (WHO) European region estimates that more than 400,000 tuberculosis (TB) cases occur in Europe, a large proportion of them among migrants. A coordinated public health mechanism to guarantee TB prevention, diagnosis, treatment and care across borders is not in place. A consensus paper describing the minimum package of cross-border TB control and care was prepared by a task force following a literature review, and with input from the national TB control programme managers of the WHO European region and the Wolfheze 2011 conference. A literature review focused on the subject of TB in migrants was carried out, selecting documents published during the 11-yr period 2001–2011. Several issues were identified in cross-border TB control and care, varying from the limited access to early TB diagnosis, to the lack of continuity of care and information during migration, and the availability of, and access to, health services in the new country. The recommended minimum package addresses the current shortcomings and intends to improve the situation by covering several areas: political commitment (including the implementation of a legal framework for TB cross-border collaboration), financial mechanisms and adequate health service delivery (prevention, infection control, contact management, diagnosis and treatment, and psychosocial support).
Enhancement of 5-Fluorouracil-induced <i>In Vitro</i> and <i>In Vivo</i> Radiosensitization with MEK Inhibition
Authors: Mary Ellen Urick, Eun Joo Chung, William P. Shield, Naamit Gerber, Ayla White, Anastasia Sowers, Angela Thetford, Kevin Camphausen, James Mitchell, Deborah E. Citrin
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. Experimental Design: Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. Results: Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone. Conclusion: These data suggest that selumetinib can be used with 5-FU to augment radiation response. Clin Cancer Res; 17(15); 5038–47. ©2011 AACR.
Anticardiolipin, anti- 2-glycoprotein I and antiprothrombin antibodies in black South African patients with infectious disease
Authors: S Loizou
Journal: Annals of the Rheumatic Diseases (2003)

To investigate IgG, IgM, and IgA, antiphospholipid antibodies (aPL), against cardiolipin (aCL), beta(2)-glycoprotein I (anti-beta(2)GPI), and prothrombin (anti-PT), in black South African patients with infectious disease. Unlike patients with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS), raised levels of aPL in infectious diseases are not usually associated with thrombotic complications.Serum samples from 272 patients with a variety of infectious diseases (100 HIV positive, 112 leprosy, 25 syphilis, 25 malaria, and 10 HCV patients) were studied and compared with autoantibody levels in 100 normal controls. All three aPL were measured using commercial enzyme linked immunosorbent assay (ELISA) kits.Raised levels of all three aPL were found in all patient groups studied: aCL in 7%, anti-beta(2)GPI in 6%, and aPT in 43% of 100 HIV patients, in 29%, 89%, and 21% of 112 patients with leprosy, in 8%, 8%, and 28% of 25 patients with syphilis, in 12%, 8%, and 28% of 25 patients with malaria, and in 20%, 30%, and 30% of 10 HCV patients studied, respectively.The prevalence of aCL and anti-beta(2)GPI in black South African HIV positive patients, or those with syphilis, malaria, or hepatitis C virus is lower than reported for mixed race or white populations. aPT were the most prevalent aPL detected in these patient groups, except in patients with leprosy, for whom anti-beta(2)GPI was the most prevalent, and where the spectrum of aPL was similar to that seen in patients with SLE and APS.
CD4 <sup>+</sup> T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants
Authors: Mohammad A. Khan, Xinguo Jiang, Gundeep Dhillon, Joshua Beilke, V. Michael Holers, Carl Atkinson, Stephen Tomlinson, Mark R. Nicolls
Journal: Circulation Research (2011)

While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated.We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants.Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4(+) and CD8(+) T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4(+) T cells and complement are independently sufficient to cause graft ischemia. CD8(+) T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia×time duration) and the development of subsequent airway remodeling.These studies demonstrated that CD4(+) T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.
Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1
Authors: G. Ferretti, T. Bacchetti, A. Campanati, O. Simonetti, G. Liberati, A. Offidani
Journal: British Journal of Dermatology (2011)

Psoriasis is a chronic, inflammatory skin disease associated with abnormal plasma lipid metabolism and with a high frequency of cardiovascular events. Modifications of plasma lipids and an increase in the levels of biochemical markers of lipid peroxidation have been reported in subjects with psoriasis, suggesting a relationship between psoriasis, lipoproteins and oxidative damage.To investigate further the relationship between lipoproteins and oxidative stress in psoriasis.The levels of plasma lipids, lipoprotein(a) [Lp(a)] and markers of lipid peroxidation were evaluated in subjects with psoriasis (n=23) and in controls (n=25). In the same subjects, the activity of paraoxonase-1 (PON1), an antioxidant and an anti-inflammatory enzyme associated with high-density lipoproteins, was investigated.The results showed higher levels of Lp(a) in the serum of patients with psoriasis compared with controls (P<0·001). Higher levels of lipid hydroperoxides (P<0·001) and lower PON1 activity were observed in the serum of patients compared with healthy subjects, confirming that psoriasis is associated with oxidative stress. The imbalance between oxidative stress and antioxidant enzymes, and the increase of Lp(a) serum levels was related to the extent and severity of psoriasis. Finally, our results demonstrated that Lp(a) levels were positively correlated with markers of lipid peroxidation and negatively related to PON1 activity, suggesting that subjects with higher levels of Lp(a) are more exposed to oxidative damage.Our results provide further evidence that oxidative stress and impairment of the antioxidant system in the plasma of patients may play a role in pathogenesis and progression of psoriasis and related complications.
Radiographic progression of hospital referred osteoarthritis of the hip.
Authors: J Ledingham, S Dawson, B Preston, G Milligan, M Doherty
Journal: Annals of the Rheumatic Diseases (1993)

Various factors have been considered important in the rate of progression of osteoarthritis of the hip, though few data are available from large longitudinal studies. One hundred and thirty six patients referred to hospital (85 women, 51 men; mean age 65 years, range 29-86 years) with osteoarthritis of the hip (192 affected hips) were followed up for a median of 27 (range 3-72) months. One hundred and six patients (144 affected hips) were reviewed for a minimum of one year (median 28, range 12-72 months). Fifty three per cent of all osteoarthritic hips required an operation at a median of 14 (range 3-48) months from entry. All radiographs before and after entry were examined (median four films for each patient over a median of three years, range 0.5-19 years). Hips showing rapid radiographic progression on prospective films more often had superior migration, or an atrophic bone response; those with no progression more often had an indeterminate, medial, or axial migration pattern, protrusio or mild osteoarthritis at presentation. A higher occurrence of rapid progression was seen in women, in those of older age at symptom onset, and in hips with a higher Kellgren grade at entry; men more often showed no progression. Age at presentation, body mass index, symptom duration, or presence of chondrocalcinosis, hand osteoarthritis/nodes, or Forestier9s disease did not influence progression. This study supports the contention that, at the time of hospital referral, certain patient characteristics and radiographic features at the hip may help to identify those at high risk of rapidly progressive hip osteoarthritis.
Tau deletion impairs intracellular β-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models
Authors: Irina Lonskaya, Michaeline Hebron, Wenqiang Chen, Joel Schachter, Charbel Moussa
Journal: Molecular Neurodegeneration (2014)

Tau is an axonal protein that binds to and regulates microtubule function. Hyper-phosphorylation of Tau reduces its binding to microtubules and it is associated with β-amyloid deposition in Alzheimer's disease. Paradoxically, Tau reduction may prevent β-amyloid pathology, raising the possibility that Tau mediates intracellular Aβ clearance. The current studies investigated the role of Tau in autophagic and proteasomal intracellular Aβ1-42 clearance and the subsequent effect on plaque deposition. Tau deletion impaired Aβ clearance via autophagy, but not the proteasome, while introduction of wild type human Tau into Tau−/− mice partially restored autophagic clearance of Aβ1-42, suggesting that exogenous Tau expression can support autophagic Aβ1-42 clearance. Tau deletion impaired autophagic flux and resulted in Aβ1-42 accumulation in pre-lysosomal autophagic vacuoles, affecting Aβ1-42 deposition into the lysosome. This autophagic defect was associated with decreased intracellular Aβ1-42 and increased plaque load in Tau−/− mice, which displayed less cell death. Nilotinib, an Abl tyrosine kinase inhibitor that promotes autophagic clearance mechanisms, reduced Aβ1-42 only when exogenous human Tau was expressed in Tau−/− mice. These studies demonstrate that Tau deletion affects intracellular Aβ1-42 clearance, leading to extracellular plaque.