tbuckley/cabot-search huggingface dataset:
Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity
Authors: Shiwei Duan, Wasim K. Bleibel, Rong Stephanie Huang, Sunita J. Shukla, Xiaolin Wu, Judith A. Badner, M. Eileen Dolan
Journal: Cancer Research (2007)

Abstract Daunorubicin is an anthracycline antibiotic agent used in the treatment of hematopoietic malignancies. Toxicities associated with this agent include myelosuppression and cardiotoxicity; however, the genes or genetic determinants that contribute to these toxicities are unknown. We present an unbiased genome-wide approach that incorporates heritability, whole-genome linkage analysis, and linkage-directed association to uncover genetic variants contributing to the sensitivity to daunorubicin-induced cytotoxicity. Cell growth inhibition in 324 Centre d' Etude du Polymorphisme Humain lymphoblastoid cell lines (24 pedigrees) was evaluated following treatment with daunorubicin for 72 h. Heritability analysis showed a significant genetic component contributing to the cytotoxic phenotypes (h2 = 0.18–0.63 at 0.0125, 0.025, 0.05, 0.1, 0.2, and 1.0 μmol/L daunorubicin and at the IC50, the dose required to inhibit 50% cell growth). Whole-genome linkage scans at all drug concentrations and IC50 uncovered 11 regions with moderate peak LOD scores (&amp;gt;1.5), including 4q28.2 to 4q32.3 with a maximum LOD score of 3.18. The quantitative transmission disequilibrium tests were done using 31,312 high-frequency single-nucleotide polymorphisms (SNP) located in the 1 LOD confidence interval of these 11 regions. Thirty genes were identified as significantly associated with daunorubicin-induced cytotoxicity (P ≤ 2.0 × 10−4, false discovery rate ≤ 0.1). Pathway and functional gene ontology analysis showed that these genes were overrepresented in the phosphatidylinositol signaling system, axon guidance pathway, and GPI-anchored proteins family. Our findings suggest that a proportion of susceptibility to daunorubicin-induced cytotoxicity may be controlled by genetic determinants and that analysis using linkage-directed association studies with dense SNP markers can be used to identify the genetic variants contributing to cytotoxicity. [Cancer Res 2007;67(11):5425–33]
Evidence of Improving Prognosis in Heart Failure
Authors: K. MacIntyre, S. Capewell, S. Stewart, J.W.T. Chalmers, J. Boyd, A. Finlayson, A. Redpath, J.P. Pell, J.J.V. McMurray
Journal: Circulation (2000)

Background —Contemporary survival in unselected patients with heart failure and the population impact of newer therapies have not been widely studied. Therefore, we have documented case-fatality rates (CFRs) over a recent 10-year period. Methods and Results —In Scotland, all hospitalizations and deaths are captured on a single database. We have studied case fatality in all patients admitted with a principal diagnosis of heart failure from 1986 to 1995. A total of 66 547 patients (47% male) were studied. Median age was 72 years in men and 78 years in women. Crude CFRs at 30 days and at 1, 5, and 10 years were 19.9%, 44.5%, 76.5%, and 87.6%, respectively. Median survival was 1.47 years in men and 1.39 years in women (2.47 and 2.36 years, respectively, in those surviving 30 days). Age had a powerful effect on survival, and sex, comorbidity, and deprivation had modest effects. One-year CF was 24.2% in those aged &lt;55 years and 58.1% in those aged &gt;84 years. After adjustment, 30-day CFRs fell between 1986 and 1995, by 26% (95% CI 15 to 35, P &lt;0.0001) in men and 17% (95% CI 6 to 26, P &lt;0.0001) in women. Longer term CFRs fell by 18% (95% CI 13 to 24, P &lt;0.0001) in men and 15% (95% CI 10 to 20, P &lt;0.0001) in women. Median survival increased from 1.23 to 1.64 years. Conclusions —Heart failure CF is much higher in the general population than in clinical trials, especially in the elderly. Although survival has increased significantly over the last decade, there is still much room for improvement.
The jejunal cellular infiltrate in coeliac disease complicated by lymphoma
Authors: R. Ferguson, P. Asquith, W. T. Cooke
Journal: Gut (1974)

Lymphocytes and plasma cells in the lamina propria and lymphocyte in the epithelium have been quantitated in jejunal biopsies from 18 patients with coeliac disease who developed lymphoma. In six patients two or more serial biopsies were available for study. Counts were compared with those obtained in 15 healthy controls and 30 other coeliacs, 15 of whom have been on a gluten-free diet for more than 12 months. Results showed that although the lymphoma patients have abnormal counts compared with controls, they differed from untreated coeliacs in that they had lower plasma cell and higher lymphocyte counts in the lamina propria and lower lymphocyte counts in the epithelium. Such changes tended to be present for up to five years before the diagnosis of lymphoma was made. The results suggest that the immunological status of coeliac patients with lymphoma differs from that of other coeliacs and it could represent a primary abnormality and also be relevant to the development of lymphoma.
Bone Marrow Transplantation Generates Immature Oocytes and Rescues Long-Term Fertility in a Preclinical Mouse Model of Chemotherapy-Induced Premature Ovarian Failure
Authors: Ho-Joon Lee, Kaisa Selesniemi, Yuichi Niikura, Teruko Niikura, Rachael Klein, David M. Dombkowski, Jonathan L. Tilly
Journal: Journal of Clinical Oncology (2007)

Purpose Although early menopause frequently occurs in female cancer patients after chemotherapy (CTx), bone marrow (BM) transplantation (BMT) has been linked to an unexplained return of ovarian function and fertility in some survivors. Studies modeling this in mice have shown that BMT generates donor-derived oocytes in CTx-treated recipients. However, a subsequent report claimed that ovulated eggs are not derived from BM and that BM-derived oocytes reported previously are misidentified immune cells. This study was conducted to further clarify the impact of BMT on female reproductive function after CTx using a preclinical mouse model. Methods Female mice were administered CTx followed by BMT using coat color-mismatched female donors. After housing with males, the number of pregnancies and offspring genotype were recorded. For cell tracking, BM from germline-specific green fluorescent protein-transgenic mice was transplanted into CTx-treated wild-type recipients. Immune cells were sorted from blood and analyzed for germline markers. Results BMT rescued long-term fertility in CTx-treated females, but all offspring were derived from the recipient germline. Cell tracking showed that donor-derived oocytes were generated in ovaries of recipients after BMT, and two lines of evidence dispelled the claim that these oocytes are misidentified immune cells. Conclusion These data from a preclinical mouse model validate a testable clinical strategy for preserving or resurrecting ovarian function and fertility in female cancer patients after CTx, thus aligning with recommendations of the 2005 National Cancer Institute Breast Cancer Progress Review Group and President's Cancer Panel to prioritize research efforts aimed at improving the quality of life in cancer survivors.
Disagreement between skin prick test and specific IgE in young children
Authors: A.-M. M. Schoos, B. L. K. Chawes, N. V. Følsgaard, N. Samandari, K. Bønnelykke, H. Bisgaard
Journal: Allergy (2014)

Background Skin prick test (SPT) and measurement of serum-specific IgE (sIgE) level are important tools for the clinician to diagnose allergic sensitization. However, little is known about the agreement between the two methods in young children. Methods SPT and sIgE levels were assessed simultaneously for 16 common inhalant and food allergens at age ½, 1½, 4, and 6 years in 389 children from the Copenhagen Prospective Study on Asthma in Childhood2000 (COPSAC2000) at-risk birth cohort. Agreement between the two methods for diagnosing inhalant and food allergic sensitization at the four age points was analyzed using kappa statistics. Results The prevalence of inhalant allergen sensitization increased during childhood diagnosed by both sIgE levels (0.6% to 4.2% to 18.1% to 24.8%, P < 0.0001) and SPT results (1.5% to 3.8% to 8.4% to 15.4%, P < 0.0001). In contrast, the prevalence of food sensitization increased during childhood when diagnosed from sIgE (7.8% to 12.1% to 15.0% to 18.9%, P < 0.0001), but decreased when diagnosed from SPT (5.3% to 5.1% to 3.7% to 3.0%, P = 0.05). Overall, the agreement between SPT and sIgE levels was poor to moderate (all κ-coefficients≤0.60) and decreased from moderate to slight for food allergens by increasing age (κ-coefficients: 0.46 to 0.31 to 0.16 to 0.14). Conclusion There is a substantial disagreement between SPT and sIgE for diagnosing allergic sensitization in young children, which increases with age for food sensitization. Choice of assessment method therefore has major impact on results with wide implications for both clinical practice and research.
Natural History of Dysplasia of the Uterine Cervix
Authors: P Holowaty, A B Miller, T Rohan, T To
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: A historical cohort of Toronto (Ontario, Canada) women whose Pap smear histories were recorded at a major cytopathology laboratory provided the opportunity to study progression and regression of cervical dysplasia in an era (1962-1980) during which cervical squamous lesions were managed conservatively. METHODS: Actuarial and Cox's survival analyses were used to estimate the rates and relative risks of progression and regression of mild (cervical intraepithelial neoplasia 1 [CIN1]) and moderate (CIN2) dysplasias. In addition, more than 17 000 women with a history of Pap smears between 1970 and 1980 inclusive and who were diagnosed as having mild, moderate, or severe dysplasia were linked to the Ontario Cancer Registry for the outcome of any subsequent cervical cancers occurring through 1989. RESULTS: Both mild and moderate dysplasias were more likely to regress than to progress. The risk of progression from mild to severe dysplasia or worse was only 1% per year, but the risk of progression from moderate dysplasia was 16% within 2 years and 25% within 5 years. Most of the excess risk of cervical cancer for severe and moderate dysplasias occurred within 2 years of the initial dysplastic smear. After 2 years, in comparison with mild dysplasia, the relative risks for progression from severe or moderate dysplasia to cervical cancer in situ or worse was 4.2 (95% confidence interval [CI] = 3.0-5.7) and 2.5 (95% CI = 2.2-3.0), respectively. CONCLUSION: The risk of progression for moderate dysplasia was intermediate between the risks for mild and severe dysplasia; thus, the moderate category may represent a clinically useful distinction. The majority of untreated mild dysplasias were recorded as regressing to yield a normal smear within 2 years.
Deactivation of peroxisome proliferator–activated receptor-α during cardiac hypertrophic growth
Authors: Philip M. Barger, Jon M. Brandt, Teresa C. Leone, Carla J. Weinheimer, Daniel P. Kelly
Journal: Journal of Clinical Investigation (2000)

We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth. alpha(1)-adrenergic agonist-induced hypertrophy of cardiac myocytes in culture resulted in a significant decrease in palmitate oxidation rates and a reduction in the expression of the gene encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme involved in mitochondrial fatty acid uptake. Cardiac myocyte transfection studies demonstrated that M-CPT I promoter activity is repressed during cardiac myocyte hypertrophic growth, an effect that mapped to a peroxisome proliferator-activated receptor-alpha (PPARalpha) response element. Ventricular pressure overload studies in mice, together with PPARalpha overexpression studies in cardiac myocytes, demonstrated that, during hypertrophic growth, cardiac PPARalpha gene expression falls and its activity is altered at the posttranscriptional level via the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. Hypertrophied myocytes exhibited reduced capacity for cellular lipid homeostasis, as evidenced by intracellular fat accumulation in response to oleate loading. These results indicate that during cardiac hypertrophic growth, PPARalpha is deactivated at several levels, leading to diminished capacity for myocardial lipid and energy homeostasis.
The association between increased alanine aminotransferase activity and metabolic factors in nonalcoholic fatty liver disease
Authors: Se-Yong Oh, Yong-Kyun Cho, Mun-Su Kang, Tae-Woo Yoo, Jung-Ho Park, Hong-Joo Kim, Dong-Il Park, Chong-Il Sohn, Woo-Kyu Jeon, Byung-Ik Kim, Byung-Ho Son, Jun-Ho Shin
Journal: Metabolism (2006)
Smac Mimetic Increases Chemotherapy Response and Improves Survival in Mice with Pancreatic Cancer
Authors: Sean P. Dineen, Christina L. Roland, Rachel Greer, Juliet G. Carbon, Jason E. Toombs, Puja Gupta, Nabeel Bardeesy, Haizhou Sun, Noelle Williams, John D. Minna, Rolf A. Brekken
Journal: Cancer Research (2010)

Failure of chemotherapy in the treatment of pancreatic cancer is often due to resistance to therapy-induced apoptosis. A major mechanism for such resistance is the expression and activity of inhibitors of apoptosis proteins (IAP). Smac (second mitochondria-derived activator of caspase) is a mitochondrial protein that inhibits IAPs. We show that JP1201, a Smac mimetic, is a potent enhancer of chemotherapy in robust mouse models of pancreatic cancer. Combination of JP1201 with gemcitabine reduced primary and metastatic tumor burden in orthotopic xenograft and syngenic tumor models, induced regression of established tumors, and prolonged survival in xenograft and transgenic models of pancreatic cancer. The effect of JP1201 was phenocopied by XIAP small interfering RNA in vitro and correlated with elevated levels of tumor necrosis factor alpha protein in vivo. The continued development of JP1201 and other strategies designed to enhance therapy-induced apoptosis in pancreatic cancer is warranted.
Moisture damage and childhood asthma: a population-based incident case-control study
Authors: J. Pekkanen, A. Hyvärinen, U. Haverinen-Shaughnessy, M. Korppi, T. Putus, A. Nevalainen
Journal: European Respiratory Journal (2006)

Most previous studies on the association between moisture damage and asthma have been cross-sectional and relied on self-reported exposure and health. The present authors studied the association by carrying out careful home inspections among new, clinically determined cases of asthma and controls. New cases of asthma aged 12–84 months (n = 121) were recruited prospectively and matched for year of birth, sex and living area with two randomly selected population controls (n = 241). Trained engineers visited all homes. Both cases and controls had lived ≥75% of their lifetime or the past 2 yrs in their current home. Risk of asthma increased with severity of moisture damage and presence of visible mould in the main living quarters but not in other areas of the house. Cases more often had damage in their bedroom. Associations were comparable for atopic and nonatopic asthma and for children aged &gt;30 months or ≤30 months. The present results, using standardised assessment of exposure and asthma, suggest that moisture damage and mould growth in the main living quarters are associated with the development of asthma in early childhood.
Molecular Beacons Illuminate Subcellular Events
Authors: Robert O. Bonow
Journal: Circulation (2005)

uilding on decades of technological advances and imaging experience, during which noninvasive imaging of cardiac structure and function, myocardial perfusion and viability, and noncoronary vascular pathology have become intimately entwined in routine clinical practice, advanced imaging techniques are now poised to deliver noninvasive coronary arteriograms and to delineate the coronary artery wall in exquisite detail.At the same time that these highly promising methods for anatomic imaging at the macroscopic level are creating great excitement among physicians, their patients, and the public, a quieter imaging revolution is underway with steady progress in detecting and tracking fundamental biological processes at the cellular and subcellular levels.In the era of genomic research, molecular biology, and stem cell therapies, these methods have great potential to accelerate understanding of basic pathophysiological processes in animals and humans and to develop new tools for early diagnosis and drug development.Cardiovascular molecular imaging is taking hold.
Acute distal colitis impairs gastric emptying in rats via an extrinsic neuronal reflex pathway involving the pelvic nerve
Authors: H U De Schepper, J G De Man, L Van Nassauw, J-P Timmermans, A G Herman, P A Pelckmans, B Y De Winter
Journal: Gut (2006)

<b>Background and aims:</b> Patients with inflammatory bowel disease often present with abnormal gut motility away from the inflammatory site. We studied remote motility disturbances and their pathophysiology in a rat model of colitis. <b>Methods:</b> Colitis was induced 72 h prior to experiments using trinitrobenzene sulphate (TNBS) instillation. Inflammation was verified using histology and myeloperoxidase (MPO) measurements. To assess gut motility, we determined gastric emptying, distal front and geometric centre (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. The effects of hexamethonium (20 mg/kg), capsaicin (125 mg/kg) and pelvic nerve section on colitis induced motility changes were evaluated. c-Fos expression was studied in the pelvic nerve dorsal root ganglion (DRG) S1. <b>Results:</b> Colitis reduced gastric emptying from 38.4 (3.6)% in controls to 22.7 (4.4)% in TNBS treated rats in the absence of local gastric inflammation. Colitis had no effect on the distal front or on the geometric centre of small intestinal transit. Hexamethonium reduced gastric emptying in controls to 26.3 (4.1)% but restored it to 35.8 (4.4)% in TNBS treated rats. Capsaicin significantly impaired gastric emptying in controls from 33.1 (5.2)% to 9.5 (3.3)% while this effect was less pronounced in TNBS treated rats (from 19.2 (2.3)% to 11.5 (3.8)%; NS). In TNBS treated rats, pelvic nerve section completely restored gastric emptying from 19.8 (5.3)% to 52.5 (6.3)% without any effect on gastric emptying in control rats. TNBS colitis induced de novo c-Fos expression in the DRG S1. <b>Conclusions:</b> Experimental colitis in rats delays gastric emptying via a neuronal pathway involving pelvic afferent nerve hyperactivity.
526The role of endothelial Dicer in atherosclerosis
Authors: P Hartmann, Z Zhou, Y Wei, ML Iruela-Arispe, C Weber, A Schober
Journal: Cardiovascular Research (2014)

Background: Increased monocyte adhesion to dysfunctional endothelial cells (ECs) orchestrated by chemokines plays an important role in atherosclerosis. Endothelial microRNAs (miRNAs) processed by the RNase Dicer determine the phenotype of ECs by posttranscriptional regulation of gene expression. However, the impact of endothelial miRNAs on endothelial inflammation and atherosclerosis is currently unclear.

Methods: VE-Cadherin-CreERT2/Dicerflox/flox/Apoe-/- (EC-Dicerflox) and VE-Cadherin-CreERT2/DicerWT/WT/Apoe-/- (EC-DicerWT) mice were treated with tamoxifen to induce the activity of Cre-recombinase and fed with a high fat diet for 4 or 12 weeks (wks). The plaque area in aortic roots was analyzed by morphometry in Elasic Van Gieson stained sections. The lipid deposition was determined in en face prepared thoracoabdominal aortas by Oil-Red-O staining. To study monocyte adhesion to the endothelium, left carotid arteries of EC-Dicerflox and EC-DicerWT were ex vivo perfused with calcein-AM labeled monocytic MonoMac6 cells at a flow rate of 0.1 ml/min. Differentially expressed miRNAs in EC-Dicerflox and EC-DicerWT aortas were identified by qRT-PCR microRNA arrays.

Results: In EC-Dicerflox mice, the adhesion of monocytes and expression of chemokines, such as CXCL1, was reduced in carotid arteries after 4wks HFD feeding (n=5-6; p<0.01; p<0.05). Atherosclerosis in aortic roots (by 58%) and lipid depositions in thoracoabdominal aortas (by 41%) were diminished in EC-Dicerflox compared to EC-DicerWT mice after 12wks HFD feeding (n=8-9; p<0.05; p<0.01). Moreover, the lesional macrophage content in the aorta was reduced in EC-Dicerflox (n=8-9; p<0.01). Mir103, -301b, -433, and -652 were permanently down-regulated after 4 and 12wks of the HFD in arteries of EC-Dicerflox mice (n=3; p<0.05). In vitro, only the expression of Mir103 was correlated with the expression of chemokines in human aortic ECs (HAoECs) and Mir103 regulated CXCL1 expression in HAoECs by targeting the anti-inflammatory transcription factor Kruppel-like factor (KLF) 4 (n=5; p<0.05). Accordingly, treatment of HAoECs with Mir103 enhanced monocyte adhesion in a CXCR2-dependent manner (n=3; p<0.001).

Conclusion: Our findings indicate that endothelial Dicer promotes atherosclerosis by enhancing monocyte recruitment to the endothelium. This effect is at least partly due to endothelial Mir103, which up-regulates CXCL1 by targeting KLF4. Therefore, inhibition of Mir103 might be a promising therapeutic approach to treat atherosclerosis.
JACKSON, FREUD AND SHERRINGTON ON THE RELATION OF BRAIN AND MIND
Authors: RONALD W. ANGEL
Journal: American Journal of Psychiatry (1961)

Hughlings Jackson, Sigmund Freud and Sir Charles Sherrington held similar views concerning the relation of brain and mind. Jackson and Freud believed that physical and mental processes comprise two distinct series of events, which are closely related but do not interact. Both men objected to the prevalent confusion of psychology with the physiology of the nervous system. Sherrington agreed that physical and mental processes are "incommensurable," but he believed that interaction is possible. When contrasted with rival theories, the doctrines of these men appear to be more acceptable, both logically and as a rationale for experiments on the neural basis of mind.
Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study
Authors: E. Van Cutsem, F. Rivera, S. Berry, A. Kretzschmar, M. Michael, M. DiBartolomeo, M.-A. Mazier, J.-L. Canon, V. Georgoulias, M. Peeters, J. Bridgewater, D. Cunningham
Journal: Annals of Oncology (2009)
The liver in adolescents with α-antitrypsin deficiency
Authors: Tomas Sveger, Sten Eriksson
Journal: Hepatology (1995)

Of 200,000 Swedish infants screened for alpha 1-antitrypsin deficiency (alpha 1 ATD), 184 (127 PiZ, 2 PiZ-, 54 PiSZ, and 1 PiS-) children have been followed prospectively, of whom 1 PiSZ and 5 PiZ children died in early childhood. We now report clinical and biochemical signs of liver disease in adolescence and the prognosis of neonatal liver disease up to the age of 18 years. The alpha 1 ATD subjects were offered a clinical checkup and liver tests at 16 and 18 years of age, 150 of 178 alpha 1ATD subjects undergoing checkups at age 16 and 166 at age 18. Liver tests were performed in 121 adolescents at both the 16- and 18-year checkups. None of the PiZ and PiSZ subjects checked at the age of 16 and 18 years had any clinical signs of liver disease. Abnormalities of serum alanine aminotransferase (S-ALAT) or gamma-glutamyl transferase (S-GT) were found at the 16-year checkup (all PiZ and PiSZ subjects tested included) in 17% of PiZ and 8% of PiSZ adolescents, and at the age of 18 years in 12% of PiZ and 15% of PiSZ subjects. In only two cases were both S-ALAT and S-GT concentrations abnormal at both the 16-year and 18-year follow-ups. Serum procollagen III peptide concentrations were normal in all those with abnormal liver test results. Of 127 PiZ subjects, 22 had manifested clinical signs of liver disease in infancy. Of these 22, two died early in life of cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)