tbuckley/cabot-search huggingface dataset:
A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases
Authors: Neil A. Miller, Emily G. Farrow, Margaret Gibson, Laurel K. Willig, Greyson Twist, Byunggil Yoo, Tyler Marrs, Shane Corder, Lisa Krivohlavek, Adam Walter, Josh E. Petrikin, Carol J. Saunders, Isabelle Thiffault, Sarah E. Soden, Laurie D. Smith, Darrell L. Dinwiddie, Suzanne Herd, Julie A. Cakici, Severine Catreux, Mike Ruehle, Stephen F. Kingsmore
Journal: Genome Medicine (2015)

While the cost of whole genome sequencing (WGS) is approaching the realm of routine medical tests, it remains too tardy to help guide the management of many acute medical conditions. Rapid WGS is imperative in light of growing evidence of its utility in acute care, such as in diagnosis of genetic diseases in very ill infants, and genotype-guided choice of chemotherapy at cancer relapse. In such situations, delayed, empiric, or phenotype-based clinical decisions may meet with substantial morbidity or mortality. We previously described a rapid WGS method, STATseq, with a sensitivity of >96 % for nucleotide variants that allowed a provisional diagnosis of a genetic disease in 50 h. Here improvements in sequencing run time, read alignment, and variant calling are described that enable 26-h time to provisional molecular diagnosis with >99.5 % sensitivity and specificity of genotypes. STATseq appears to be an appropriate strategy for acutely ill patients with potentially actionable genetic diseases.
Cellular Mechanisms of Depressed Atrial Contractility in Patients With Chronic Atrial Fibrillation
Authors: Ulrich Schotten, Jannie Ausma, Christoph Stellbrink, Ingo Sabatschus, Miriam Vogel, Dirk Frechen, Friedrich Schoendube, Peter Hanrath, Maurits A. Allessie
Journal: Circulation (2001)

Background —After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. Methods and Results —Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (≥3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. β-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca 2+ , isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca 2+ was maintained, and the postrest potentiation was preserved. β-Adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. Conclusions —After prolonged AF, atrial contractility was reduced by 75%. The impairment of β-adrenergic modulation of contractile force cannot be explained by downregulation of β-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca 2+ channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca 2+ shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.
Marrow Transplantation for Severe Aplastic Anemia
Authors: CLAUDIO ANASETTI
Journal: Annals of Internal Medicine (1986)

Fifty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. Of the 50, 42 are still alive 1 to 12 years after transplantation (median, 7 years). By actuarial standards, the 10-year probability of survival is 82%. Of the 42 surviving patients, 37 have Karnofsky performance status scores of 100% and 5 with chronic graft-versus-host disease have scores ranging from 50% to 90% (median, 80%). The 8 deaths were caused by early infection in 1, graft rejection in 1, acute graft-versus-host disease in 3, and chronic graft-versus-host disease in 3. All deaths occurred within two years after transplantation. The incidence of graft failure was 10%. Acute graft-versus-host disease developed in 14 of 44 patients at risk and chronic graft-versus-host disease, in 15 of 41. Risk factors for development of chronic graft-versus-host disease included increased age (p = 0.008) and presence of acute graft-versus-host disease (p = 0.001). The only factor associated with increased risk of death was development of acute graft-versus-host disease (p = 0.05). Results of this study extend our previous finding that patients with severe aplastic anemia who have transplants before the onset of transfusion-induced sensitization have an excellent probability of long-term survival and a normal life.
<i>KIT</i> Mutations and Imatinib Dose Effects in Patients With Gastrointestinal Stromal Tumors
Authors: Ugo De Giorgi
Journal: Journal of Clinical Oncology (2007)

their molecular signatures, probably a result of the varying carcinogenic processes within the different parts of the biliary tree.It is possible that those mutations may vary in the different locations within the biliary system, as was suggested by Gwak et al. 2 Second, testing the hypotheses relating the known and yet undiscovered EGFR gene mutations to clinical response to therapy will be limited by the relatively small number of patients within individual clinical trials who received or who are currently receiving EGFR tyrosine kinase (TK) inhibitors.This underscores the need for national and international collaborative efforts to ensure the pooling of tumor specimens and clinical data from different studies, as it would allow for more definitive statistical analyses to determine the correlations between specific gene mutations and therapy outcome.In addition, performing prospective trials of EGFR-TK inhibitors in patients with prespecified gene mutations will require major collaborations given the small number of eligible patients.Considerations should also be given to define the role of other molecular events that relate to EGFR signaling, such as the expression of the ligands, HER-2 activity, downstream molecules (eg, BRAF), and other survival pathways as suggested by Leone et al. 3 Analyses and quantifications focused on protein expression and phosphorylation status are challenged by the need for fresh tissue and the performance of assays for phosphorylated proteins.
<i>FGFR2</i>-Amplified Gastric Cancer Cell Lines Require FGFR2 and Erbb3 Signaling for Growth and Survival
Authors: Kaiko Kunii, Lenora Davis, Julie Gorenstein, Harold Hatch, Masakazu Yashiro, Alessandra Di Bacco, Cem Elbi, Bart Lutterbach
Journal: Cancer Research (2008)

We have identified a critical role for amplified FGFR2 in gastric cancer cell proliferation and survival. In a panel of gastric cancer cell lines, fibroblast growth factor receptor 2 (FGFR2) was overexpressed and tyrosine phosphorylated selectively in FGFR2-amplified cell lines KatoIII, Snu16, and OCUM-2M. FGFR2 kinase inhibition by a specific small-molecule inhibitor resulted in selective and potent growth inhibition in FGFR2-amplified cell lines, resulting in growth arrest in KatoIII cells and prominent induction of apoptosis in both Snu16 and OCUM-2M cells. FGFR2-amplified cell lines also contained elevated phosphotyrosine in EGFR, Her2, and Erbb3, but the elevated phosphorylation in EGFR could not be inhibited by gefitinib or erlotinib. We show that the elevated EGFR, Her2, and Erbb3 phosphotyrosine is dependent on FGFR2, revealing EGFR family kinases to be downstream targets of amplified FGFR2. Moreover, shRNA to Erbb3 resulted in a loss of proliferation, confirming a functional role for the activated EGFR signaling pathway. These results reveal that both the FGFR2 and EGFR family signaling pathways are activated in FGFR2-amplified gastric cancer cell lines to drive cell proliferation and survival. Inhibitors of FGFR2 or Erbb3 signaling may have therapeutic efficacy in the subset of gastric cancers containing FGFR2 amplification.
Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature
Authors: James D. Murphy, Aaron C. Spalding, Yash R. Somnay, Sonja Markwart, Michael E. Ray, Daniel A. Hamstra
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The PI3K/Akt/mTOR prosurvival pathway is frequently up-regulated in soft tissue sarcoma. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, have recently shown clinical benefit in soft tissue sarcoma, and mTOR inhibition has also been associated with radiosensitization of carcinoma and endothelial cells. This study tested the hypothesis that rapamycin radiosensitizes soft tissue sarcoma and endothelial cells in vitro and in vivo through the inhibition of mTOR. Experimental Design: Colony formation assays were done to determine the radiosensitizing properties of rapamycin on three human soft tissue sarcoma cell lines (SK-LMS-1, SW-872, and HT-1080) and human dermal microvascular endothelial cells (HDMEC). The functional effects of rapamycin and radiation on the endothelial compartment were evaluated with microvascular sprouting assays. The in vivo radiosensitizing activity of rapamycin was assessed with s.c. SK-LMS-1 nude mice xenografts treated with concurrent daily rapamycin, radiation, or both for three weeks. Results: In vitro radiosensitization was shown in all three soft tissue sarcoma cell lines with minimally cytotoxic doses of rapamycin. SK-LMS-1 xenografts displayed significant tumor growth delay with rapamycin and radiation compared with either treatment alone. Radiation resulted in transient increased mTOR function, whereas rapamycin abolished this signaling in irradiated and unirradiated samples. In HDMEC, rapamycin and radiation reduced microvessel sprouting, but did not alter colony formation. Conclusions: Minimally cytotoxic concentrations of rapamycin inhibited the mTOR cascade in culture and in vivo while radiosensitizing soft tissue sarcoma, and produced synergistic effects with radiation on HDMEC microvessel formation. By targeting both tumor and endothelial compartments, rapamycin produced potent radiosensitization of soft tissue sarcoma xenografts. Clinical trials combining rapamycin and radiotherapy in soft tissue sarcoma are warranted.
Activation of Apoptosis by 1-Hydroxy-5,7-Dimethoxy-2-Naphthalene-Carboxaldehyde, a Novel Compound from <i>Aegle marmelos</i>
Authors: Dharmalingam Subramaniam, Periyasamy Giridharan, Nabendu Murmu, Nallakandy P. Shankaranarayanan, Randal May, Courtney W. Houchen, Rama P. Ramanujam, Arun Balakrishnan, Ram A. Vishwakarma, Shrikant Anant
Journal: Cancer Research (2008)

Abstract We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-α (TNF-α), TNF receptor (TNFR)-associated death domain (TRADD), and caspases. The molecule 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC, marmelin) was isolated and characterized from ethyl acetate fraction of extracts of Aegle marmelos. HDNC treatment inhibited the growth of HCT-116 colon cancer tumor xenografts in vivo. Immunostaining for CD31 showed that there was a significant reduction in microvessels in the HDNC-treated animals, coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA. Using hexoseaminidase assay, we determined that HDNC inhibits proliferation of HCT-116 colon and HEp-2 alveolar epithelial carcinoma cells. Furthermore, the cancer cells showed increased levels of activated caspase-3 and induced G1 cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-α, TNFR1, and TRADD mRNA and protein expression. Moreover, caspase-8 and Bid activation, and cytochrome c release, were observed, suggesting the existence of a cross-talk between death receptor and the mitochondrial pathways. HDNC inhibited AKT and extracellular signal-regulated kinase phosphorylation both in cells in culture and in tumor xenografts. In addition, electrophoretic mobility shift assay and luciferase reporter assays showed that HDNC significantly suppressed TNF-α–mediated activation and translocation of nuclear factor-κB (NF-κB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-κB, were significantly less in cells treated with HDNC. Together, the data suggest that the novel compound HDNC (marmelin) is a potent anticancer agent that induces apoptosis during G1 phase of the cell cycle and could be a potential chemotherapeutic candidate. [Cancer Res 2008;68(20):8573–81]
Human Embryo Research and the Language of Moral Uncertainty
Authors: William P. Cheshire
Journal: The American Journal of Bioethics (2004)

In bioethics as in the sciences, enormous discussions often concern the very small. Central to public debate over emerging reproductive and regenerative biotechnologies is the question of the moral status of the human embryo. Because news media have played a prominent role in framing the vocabulary of the debate, this study surveyed the use of language reporting on human embryo research in news articles spanning a two-year period. Terminology that devalued moral status—for example, the descriptors things, property, tissue, or experimental material —was found to outnumber fivefold those that affirmed any degree of moral status above that of inanimate cellular matter; for example, living, human life, or human being. A quarter of the articles failed to note that the embryos under discussion were human. These findings confirm that even among scientific and philosophical experts a diversity of opinion exists on society's moral obligations to nascent human life. The skewed linguistic distribution also indicates a distinct bias. Concerned readers should take notice when any category of humanity becomes subject to prejudicial and disparaging language and the value of vulnerable human life is trivialized alongside sensational assertions of anticipated medical cures. The responsibility for holding the media to a higher standard of truth and fairness falls to us all.
Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study
Authors: S.R. Alberts, P.M. Townley, R.M. Goldberg, S.S. Cha, D.F. Moore, J.E. Krook, H.C. Pitot, T.R. Fitch, M. Wiesenfeld, J.A. Mailliard, D.J. Sargent
Journal: Annals of Oncology (2002)
The Scavenger Receptor Class B Type I Adaptor Protein PDZK1 Maintains Endothelial Monolayer Integrity
Authors: Weifei Zhu, Sonika Saddar, Divya Seetharam, Ken L. Chambliss, Christopher Longoria, David L. Silver, Ivan S. Yuhanna, Philip W. Shaul, Chieko Mineo
Journal: Circulation Research (2008)

Circulating levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease, and HDL and the HDL receptor scavenger receptor class B type I (SR-BI) initiate signaling in endothelium through src that promotes endothelial NO synthase activity and cell migration. Such signaling requires the C-terminal PDZ-interacting domain of SR-BI. Here we show that the PDZ domain–containing protein PDZK1 is expressed in endothelium and required for HDL activation of endothelial NO synthase and cell migration; in contrast, endothelial cell responses to other stimuli, including vascular endothelial growth factor, are PDZK1-independent. Coimmunoprecipitation experiments reveal that Src interacts with SR-BI, and this process is PDZK1-independent. PDZK1 also does not regulate SR-BI abundance or plasma membrane localization in endothelium or HDL binding or cholesterol efflux. Alternatively, PDZK1 is required for HDL/SR-BI to induce Src phosphorylation. Paralleling the in vitro findings, carotid artery reendothelialization following perivascular electric injury is absent in PDZK1 −/− mice, and this phenotype persists in PDZK1 −/− mice with genetic reconstitution of PDZK1 expression in liver, where PDZK1 modifies SR-BI abundance. Thus, PDZK1 is uniquely required for HDL/SR-BI signaling in endothelium, and through these mechanisms, it is critically involved in the maintenance of endothelial monolayer integrity.
Prolonged Chronic Inflammation Progresses to Dysplasia in a Novel Rat Model of Colitis-Associated Colon Cancer
Authors: Cariluz Santiago, Beatriz Pagán, Angel A. Isidro, Caroline B. Appleyard
Journal: Cancer Research (2007)

Abstract Inflammatory bowel disease (IBD) is a gastrointestinal disorder of unknown etiology or cure. One complication of IBD is an increased risk for development of colon cancer. The aims of this study were to use a previously established rat model of colitis to develop a new model of colitis-associated colon cancer and ascertain the involvement of three cancer-related genes: K-ras, adenomatous polyposis coli (APC), and p53. Four groups of rats were used: reactivated 1,2-dimethylhydrazine [DMH; trinitrobenzene sulfonic acid (TNBS) was used to induce colitis followed by a weekly s.c. dose of DMH], prolonged reactivation (inflammation was induced with TNBS, then maintained twice a week), saline-DMH (animals received saline instead of TNBS followed by a weekly dose of DMH), and normal (received no treatment). Animals were sacrificed at 5, 10, or 15 weeks, and colon samples were taken for pathologic analysis and gene mutation detection. No dysplasia was found in the normal group. The highest incidences of dysplasia were as follows: prolonged reactivation group at 5 weeks (60%), reactivated DMH group at 10 weeks (83%), and saline-DMH group at 15 weeks (67%). Carcinoma was found in both the prolonged reactivation and saline-DMH groups. No mutations were found in the K-ras oncogene; however 62% of the APC samples (exon 15 at nucleotide 2778) and 76% of p53 (exon 6 at nucleotide 1327) showed substitutions. The prolonged reactivation group may be considered a new model of colitis-associated colon cancer, offering the potential to study cancer prevention strategies for patients with IBD. [Cancer Res 2007;67(22):10766–73]
TM-04 * A TRANSGENIC ZEBRAFISH MODEL FOR GLIOMAS WITH MUTATIONS IN ISOCITRATE DEHYDROGENASE 1
Authors: Y. D. Gao, H. C. Z. van der Linde, E. A. Struys, V. van Breugel, M. de Wit, L. Erdem, J. V. M. G. Bovee, M. L. M. Lamfers, P. A. E. Silleviss Smitt, G. S. Salomons, R. Willemsen, P. J. French
Journal: Neuro-Oncology (2014)

Isocitrate dehydrogenase 1 (IDH1) is a gene that is mutated in about 70-90% of grade II/III glioma patients. Unfortunately, there are very few good model systems for IDH-mutated tumors to functionally examine effects of IDH1 mutations and to test candidate inhibitors. We have therefore generated a transgenic zebrafish (Danio rerio) model expressing mutant IDH1 to create an in-vivo model system for studying IDH1 mutated tumors. IDH1R132H and IDH1wildtype constructs driven by a Nestin promoter were generated. These constructs were injected into fertilized zebrafish eggs at the one-cell stage. The generated transgenic fish were characterized at the transcriptional, proteomic, enzymatic and metabolomics level. All transgenic fish lines appeared healthy and produced offspring. Thus far, no tumors were observed. Introduced IDH1 wildtype and mutant expression was detected in a subset of cells in the mid-and hindbrain of central nerve system by immunohistochemistry in 1-5 dpf embryos. This temporal expression is consistent with activity of the Nestin promoter. Even though only a subset of cells (i.e. the Nestin+ cells) expressed mutant IDH1, D2-HG levels were approximately 4-10 fold higher than in the wildtype. The effect was specific for D2-HG as L2-HG in both transgenic zebrafish lines remained similar. No differences in collagen maturation or DNA methylation were observed. Treatment of the transgenic zebrafish with an IDH1 mutant inhibitor, AGI-5198, for up to three days resulted in a ∼2 fold reduction in the D2-HG level in the mutant zebrafish. The L2-HG level was not affected by lines for the use of drug screening. We have generated a transgenic zebrafish model system for IDH1 mutated tumors that can be used to examine pathway activation and be used for drug screening.
Testosterone Concentrations in Diabetic and Nondiabetic Obese Men
Authors: Sandeep Dhindsa, Michael G. Miller, Cecilia L. McWhirter, Donald E. Mager, Husam Ghanim, Ajay Chaudhuri, Paresh Dandona
Journal: Diabetes Care (2010)

OBJECTIVE To determine the prevalence of subnormal testosterone concentrations in patients with obesity and with type 2 diabetes in a primary care clinic population. RESEARCH DESIGN AND METHODS Free testosterone concentrations of 1,849 men (1,451 nondiabetic and 398 diabetic) in the Hypogonadism In Males (HIM) study were analyzed. The HIM study was a U.S.-based cross-sectional study designed to define the prevalence of hypogonadism in men aged &amp;gt;45 years. Free testosterone was measured by equilibrium dialysis. RESULTS The prevalence of subnormal free testosterone concentrations in lean, overweight, and obese nondiabetic men was 26% (n = 275), 29% (n = 687), and 40% (n = 489), respectively (P &amp;lt; 0.001 for trend), and 44% (n = 36), 44% (n = 135), and 50% (n = 227), respectively, in diabetic men (P = 0.46 for trend within group and P &amp;lt; 0.05 compared with nondiabetic men). The mean free testosterone concentration of diabetic men was significantly lower than that of nondiabetic men. Free testosterone concentrations were negatively and significantly (P &amp;lt; 0.001) related to age (r = −0.37), BMI (r = −0.18), and sex hormone–binding globulin (r = −0.11) in multiple regression analysis. The average decline of free testosterone concentrations was 7.8 pg/ml per decade in nondiabetic men and 8.4 pg/ml per decade in diabetic men. CONCLUSIONS Forty percent of obese nondiabetic men and 50% of obese diabetic men aged ≥45 years have subnormal free testosterone concentrations. In view of its high prevalence, obesity is probably the condition most frequently associated with subnormal free testosterone concentrations in males. The concomitant presence of diabetes is associated with an additional increase in the prevalence of subnormal free testosterone concentrations.