tbuckley/cabot-search huggingface dataset:
Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity
Authors: Tae-Min Kim, Seung-Hyun Jung, Chang Hyeok An, Sung Hak Lee, In-Pyo Baek, Min Sung Kim, Sung-Won Park, Je-Keun Rhee, Sug-Hyung Lee, Yeun-Jun Chung
Journal: Clinical Cancer Research (2015)

The intratumoral heterogeneity (ITH) and the evolution of genomic architectures associated with the development of distant metastases are not well understood in colorectal cancers.We performed multiregion biopsies of primary and liver metastatic regions from five colorectal cancers with whole-exome sequencing and copy number profiling.In addition to a substantial level of genetic ITH, multiregion genetic profiling identifies the subclonal mutational architecture, leading to the region-based or spatial categorization of somatic mutations and the inference of intratumoral evolutionary history of cancers. The universal mutations (those observed in all the regional biopsies) are enriched in known cancer genes such as APC and TP53 with distinct mutational spectra compared with biopsy- or region-specific mutations, suggesting that major operative mutational mechanisms and their selective pressures are not constant across the metastatic progression. The phylogenies inferred from genomic data show branching evolutionary patterns where some primary biopsies are often segregated with metastastic lesions. Our analyses also revealed that copy number changes such as the chromosomal gains of c-MYC and chromothripsis can be region specific and the potential source of genetic ITH.Our data show that the genetic ITH is prevalent in colorectal cancer serving as a potential driving force to generate metastasis-initiating clones and also as a means to infer the intratumoral evolutionary history of cancers. The paucity of recurrent metastasis-clonal events suggests that colorectal cancer distant metastases may not follow a uniform course of genomic evolution, which should be considered in the genetic diagnosis and the selection of therapeutic targets for the advanced colorectal cancer.
Estrogen-Related Receptor Gamma Promotes Mesenchymal-to-Epithelial Transition and Suppresses Breast Tumor Growth
Authors: Claire Tiraby, Bethany C. Hazen, Marin L. Gantner, Anastasia Kralli
Journal: Cancer Research (2011)

Abstract Estrogen-related receptors (ERR), ERR alpha (ERRα) and ERR gamma (ERRγ), are orphan nuclear receptors implicated in breast cancer that function similarly in the regulation of oxidative metabolism genes. Paradoxically, in clinical studies, high levels of ERRα are associated with poor outcomes whereas high levels of ERRγ are associated with a favorable course. Recent studies suggest that ERRα may indeed promote breast tumor growth. The roles of ERRγ in breast cancer progression and how ERRα and ERRγ may differentially affect cancer growth are unclear. In mammary carcinoma cells that do not express endogenous ERRγ, we found that ectopic expression of ERRγ enhanced oxidative metabolism in vitro and inhibited the growth of tumor xenografts in vivo. In contrast, ectopic expression of the ERRα coactivator PGC-1α enhanced oxidative metabolism but did not affect tumor growth. Notably, ERRγ activated expression of a genetic program characteristic of mesenchymal-to-epithelial transition (MET). This program was apparent by changes in cellular morphology, upregulation of epithelial cell markers, downregulation of mesenchymal markers, and decreased cellular invasiveness. We determined that this program was also associated with upregulation of E-cadherin, which is activated directly by ERRγ. In contrast, PGC-1α activated only a subset of genes characteristic of the MET program and, unlike ERRγ, did not upregulate E-cadherin. In conclusion, these results show that ERRγ induces E-cadherin, promotes MET, and suppresses breast cancer growth. Our findings suggest that ERRγ agonists may have applications in the treatment of breast cancer. Cancer Res; 71(7); 2518–28. ©2011 AACR.
Large differences in cost of illness and wellbeing between patients with fibromyalgia, chronic low back pain, or ankylosing spondylitis
Authors: A.E.R.C.H. Boonen, R. van den Heuvel, A.M. van Tubergen, M. Goossens, J.L. Severens, D.M.F.M. van der Heijde, S. van der Linden
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To compare the cost of illness of three musculoskeletal conditions in relation to general wellbeing. <b>Methods:</b> Patients with fibromyalgia, chronic low back pain (CLBP), and ankylosing spondylitis who were referred to a specialist and participated in three randomised trials completed a cost diary for the duration of the study, comprising direct medical and non-medical resource utilisation and inability to perform paid and unpaid work. Patients rated perceived wellbeing (0–100) at baseline. Univariate differences in costs between the groups were estimated by bootstrapping. Regression analyses assessed which variables, in addition to the condition, contributed to costs and wellbeing. <b>Results:</b> 70 patients with fibromyalgia, 110 with chronic low back pain, and 111 with ankylosing spondylitis provided data for the cost analyses. Average annual disease related total societal costs per patient were €7813 for fibromyalgia, €8533 for CLBP, and €3205 for ankylosing spondylitis. Total costs were higher for fibromyalgia and CLBP than for ankylosing spondylitis, mainly because of cost of formal and informal care, aids and adaptations, and work days lost. Wellbeing was lower in fibromyalgia (mean, 48) and low back pain (mean, 42) than in ankylosing spondylitis (mean, 67). No variables other than diagnostic group contributed to differences in costs or wellbeing. <b>Conclusions:</b> In patients under the care of a specialist, there were marked differences in costs and wellbeing between those with fibromyalgia or CLBP and those with ankylosing spondylitis. In particular, direct non-medical costs and productivity costs were higher in fibromyalgia and CLBP.
PRENATAL DIAGNOSIS OF CHRONIC GRANULOMATOUS DISEASE
Authors: Niels Borregaard, Jens Bang, JørgenG. Berthelsen, KirstenStaehr Johansen, Christian Koch, John Philip, Kirsten Rasmussen, Marianne Schwartz, AgeJ. Therkelsen, NielsHenrik Valerius
Journal: The Lancet (1982)
Abstract 575: A subset of small cell lung cancer (SCLC) cell lines are Mcl-1-dependent and undergo apoptosis in response to Flavopiridol-mediated inhibition of cyclin-dependent kinase (cdk) 9
Authors: Li Qi, Geoffrey I. Shapiro
Journal: Cancer Research (2010)

Abstract Small cell lung cancer (SCLC) accounts for approximately 13% of lung cancer cases. Although SCLC is initially a chemosensitive disease, the development of resistance is a major obstacle. Recently, multiple SCLC cell lines have been found to be responsive to a Bcl-2/Bcl-xL inhibitor, ABT-737, both in vitro and in vivo (Oltersdorf T et al. Nature. 2005 Jun 2; 435(7042): 677-81). Clinical trials of the related orally-available compound ABT-263 have shown promising activity in SCLC patients. However, a subset of SCLC cell lines that express Mcl-1, another anti-apoptotic protein, are resistant to ABT-737 treatment. Furthermore, SCLC lines have elevated expression of Mcl-1 when they become resistant to ABT-737 (Tahir SK et al. Cancer Res. 2007 Feb 1; 67(3): 1176-83). Therefore drugs targeting Mcl-1 may be particularly useful in this disease. Here, we have investigated dependence of a panel of SCLC cell lines on Mcl-1 for survival, using Mcl-1 knockdown achieved by lentiviral-based shRNA technology. Several SCLC cell lines expressing Mcl-1, including NCI-H82 and SHP77 cells, demonstrate apoptosis by TUNEL assay and reduced viability by MTS assay in response to Mcl-1 depletion. However, other SCLC cell lines, including NCI-H69 and SW1271, are not responsive to Mcl-1 knockdown. We have also investigated the efficacy of Flavopiridol, a potent inhibitor of cdk9, against a panel of SCLC cell lines. Flavopiridol acutely down-regulates Mcl-1 expression in NCI-H82, SHP77, H69 and SW1271 cells. Mcl-1-dependent cell lines, including H82 and SHP77, undergo abrupt apoptosis in response to Flavopiridol. In contrast, H69 and SW1271 cells, which were not found to be Mcl-1-dependent, were not effectively killed by Flavopiridol. These data suggest that Mcl-1-dependent SCLC cells may be particularly sensitive to Flavopiridol treatment to overcome ABT-737 resistance. Finally, we have demonstrated that the combination of Flavopiridol and ABT-737 can synergistically kill both Mcl-1-dependent and -independent SCLC cells, with significantly reduced viability in SHP77 and SW1271 cells compared to treatment with either drug alone. Taken together, our studies suggest Flavopiridol-mediated cdk9 inhibition may effectively target Mcl-1 dependent SCLCs, including those resistant to Bcl-2/Bcl-xL inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 575.
An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression
Authors: Suresh Durgam, Willie Earley, Alan Lipschitz, Hua Guo, István Laszlovszky, György Németh, Eduard Vieta, Joseph R. Calabrese, Lakshmi N. Yatham
Journal: American Journal of Psychiatry (2015)

Objective: The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression. Method: This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population. Results: The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was −4.0 (95% CI=−6.3, −1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (−2.5, 95% CI=−4.9, −0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=−0.4, 95% CI=−0.6, −0.1; 3.0 mg/day: −0.3, 95% CI=−0.5, −0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo. Conclusions: Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.
Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth
Authors: Hideki Amano, Izumi Hayashi, Hirahito Endo, Hidero Kitasato, Shohei Yamashina, Takayuki Maruyama, Michiyoshi Kobayashi, Kazutoyo Satoh, Masami Narita, Yukihiko Sugimoto, Takahiko Murata, Hirokuni Yoshimura, Shuh Narumiya, Masataka Majima
Journal: The Journal of Experimental Medicine (2003)

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3−/−) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3−/−, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3−/−, compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3−/−. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.
Orphan targets for reperfusion injury
Authors: J. Inserte, J. A. Barrabes, V. Hernando, D. Garcia-Dorado
Journal: Cardiovascular Research (2009)

Cardiomyocyte death secondary to transient ischaemia occurs mainly during the first minutes of reperfusion in the form of contraction band necrosis. Research on the mechanisms leading to sarcolemmal rupture and necrosis during initial reperfusion identified several promising pharmacological targets directed either to correct the alterations in Ca2+ handling occurring during this period (Na+/H+-exchanger, reverse mode of Na+/Ca2+-exchanger, sarcoplasmic reticulum) or to interfere with its consequences [hypercontracture, calpain activation, and mitochondrial permeability transition pore (mPTP) opening]. However, despite the fact that pharmacological tools against some of these targets have consistently demonstrated that it is possible to reduce infarct size in experimental studies by interventions applied at the time of reperfusion, the translation of these approaches to clinical practice has failed due in part to the lack of drugs able to be tested in humans. Recently, the benefits of both post-conditioning and inhibition of mPTP have been supported by proof-of-concept trials demonstrating the clinical applicability of strategies aimed at preventing lethal reperfusion injury. These promising results should stimulate efforts to develop drugs testable in humans against known, unexploited targets involved in reperfusion injury and to identify and validate additional ones.
HLA-DR expression in human fetal intestinal epithelium.
Authors: T T MacDonald, A Weinel, J Spencer
Journal: Gut (1988)

Villus epithelial cells in fetal human small intestine are HLA-DR- until 17 weeks gestation. At 18 weeks HLA-DR begins to be expressed in the epithelial cells, usually at the villus tips. Of 13 specimens examined between 18 and 22 weeks gestation, two were HLD-DR-, seven had HLA-DR expressed only at the villus tips and in four most of the villus epithelial cells were HLA-DR+. The epithelium overlying the Peyer9s patches in fetal intestine was also HLA-DR+. T cells in explant cultures of fetal intestine were activated in situ using pokeweed mitogen. The local cell mediated immune reaction increased expression of HLA-DR on the villus and crypt epithelial cells. Organ culture supernatants from explants treated with pokeweed mitogen induced HLA-DR expression on the HT-29 epithelial cell line; an effect inhibited by antibody against human interferon gamma.
Duodenal juice total protein and pancreatic enzyme synthesis, turnover, and secretion in patients after acute pancreatitis.
Authors: J M Ogden, S J O'Keefe, J A Louw, G Adams, I N Marks
Journal: Gut (1993)

It is controversial whether acute pancreatitis has longterm effects on pancreatic function. Pancreatic enzyme synthesis, turnover, and secretion were measured in 10 patients in clinical remission who had had one or more (one to six) attacks of acute alcoholic pancreatitis. The studies were done between two and 29 months after the most recent attack. A control group included five patients with no evidence of pancreatic disease. A four hour primed/continuous intravenous infusion of [14C]L-leucine tracer was given with secretin (2 U/kg/h) and cholecystokinin (0.5 U/kg/h) and secreted duodenal juice aspirated. Amylase and trypsin were extracted from duodenal juice by affinity chromatography, permitting measurement of the rate of isotope incorporation into total protein, amylase, and trypsin. The results showed non-parallel changes in enzyme synthesis and turnover with decreases in total enzyme protein and amylase synthesis and turnover but preservation of trypsin synthesis and turnover. The low turnover rates may be ascribed to continuing pancreatic cell malfunction after recovery from acute alcoholic pancreatitis and suggest that the decreased amylase secretion rates are partly a consequence of impaired amylase synthesis and not simply because of loss of pancreatic tissue.
A case of lymphoid interstitial pneumonia associated with common variable immunodeficiency
Authors: Martin Schreder, Marianne Hubner, Wolfgang Sperr, Thomas Staudinger, Ingrid Simonitsch-Klupp, Gerhard Mostbeck, Meinhard Kneussl
Journal: European Respiratory Journal (2012)

Introduction : Lymphoid interstitial pneumonia (LIP) represents a rare disease that typically occurs in association with autoimmune diseases and dysproteinemia. We report a case of LIP in a patient with common variable immunodeficiency (CVID).   Case Report : In October 2009, a 51 year old woman presented with a 12-months history of recurrent pyrexia and was subsequently diagnosed with CVID. CT scans showed bilateral pulmonary consolidations, while bronchoscopy revealed acute inflammation of the bronchial mucosa and purulent secretion. The patient received antibiotic treatment and immunoglobulin replacement. She remained asymptomatic until January 2012, when she was readmitted with increasing dyspnea and fatigue for 2 weeks prior to admission. CT scans showed progressive opacities mainly in the lower zones. Despite immediate treatment with broad-spectrum antibiotics, the patient developed acute respiratory failure requiring invasive mandatory ventilation and, ultimately, extracorporeal membrane oxygenation. Open lung biopsy was performed 5 days after admission. Histologic workup showed diffuse interstitial infiltration of T lymphocytes, plasma cells and histiocytes, consistent with a diagnosis of LIP. Treatment with prednisone (1mg/kg) resulted in rapid clinical and radiological improvement. The patient was discharged 4 weeks after admission. At present, she remains clinically stable at a steroid dose of 0.25mg/kg.   Discussion : The finding of bilateral ground-glass infiltrates in a patient with CVID should raise suspicion of LIP. Open lung biopsy is required to establish the diagnosis. Treatment is primarily based on corticosteroids, which resulted in excellent response in this patient.
Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease
Authors: Rex L. Jamison, Pamela Hartigan, James S. Kaufman, David S. Goldfarb, Stuart R. Warren, Peter D. Guarino, J. Michael Gaziano, For the Veterans Affairs Site Investigators
Journal: JAMA (2007)

High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown.To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease.Double-blind randomized controlled trial (2001-2006) in 36 US Department of Veterans Affairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease (estimated creatinine clearance < or =30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/L).Participants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo.The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients.Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8%; P < .001) in the vitamin group and 0.4 micromol/L (1.7%; P = .14) in the placebo group at 3 months, but there was no significant effect on mortality (448 vitamin group deaths vs 436 placebo group deaths) (hazard ratio [HR], 1.04; 95% CI, 0.91-1.18). No significant effects were demonstrated for secondary outcomes or adverse events: there were 129 MIs in the vitamin group vs 150 for placebo (HR, 0.86; 95% CI, 0.67-1.08), 37 strokes in the vitamin group vs 41 for placebo (HR, 0.90; 95% CI, 0.58-1.40), and 60 amputations in the vitamin group vs 53 for placebo (HR, 1.14; 95% CI, 0.79-1.64). In addition, the composite of MI, stroke, and amputations plus mortality (P = .85), time to dialysis (P = .38), and time to thrombosis in hemodialysis patients (P = .97) did not differ between the vitamin and placebo groups.Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease.clinicaltrials.gov Identifier: NCT00032435.
So how much do doctors really earn?
Authors: Michael Day
Journal: BMJ (2007)

The rumbling political row over debt in the NHS means that the vexed issue of doctors' pay is not going to go away any time soon. 

Are doctors in the United Kingdom overpaid? An obvious way to address the question is to compare the earnings of UK medics with those of their overseas colleagues. That is easier said than done, though: few if any direct comparisons exist, and any comparison is made difficult by different contractual agreements and working conditions. The UK Treasury has, however, made an attempt, in its latest 2007 comprehensive spending review for the NHS. 

The report contains estimates of average earnings of GPs and hospital doctors in 2003-4 in 16 countries, including the UK's major competitors. The figures are based on research gathered by British embassies. It should be emphasised that the figures are estimates. 

Nevertheless, a few things leap out from the data, including the large (and, in the case of hospital salaries, huge) lead that US doctors enjoy in pay terms. The second is the very large advantage that UK doctors have over their continental colleagues. GPs in Italy have remarkably low average earnings—the result of the marketplace being flooded with too …