tbuckley/cabot-search huggingface dataset:
Alzheimer's Disease with Prominent Visual Symptoms
Authors: Motohiro Kiyosawa, Thomas M. Bosley, John Chawluk, Dara Jamieson, Norman J. Schatz, Peter J. Savino, Robert C. Sergott, Martin Reivich, Abass Alavi
Journal: Ophthalmology (1989)

The authors examined eight patients with dementia of the Alzheimer's type (DAT), five with prominent visual symptoms early in the illness (VS) and three with no visual symptoms (NVS). Results of neuro-ophthalmologic examinations on VS patients showed relatively consistent abnormalities in figure copying, color vision tested by isochromatic plates, and stereopsis. Cerebral glucose metabolism determined by 18F-fluoro-2-deoxyglucose positron emission tomography (PET) was unchanged in primary visual cortex of VS and NVS patients compared with 12 normal volunteers of similar age and sex. Glucose metabolism in VS patients was decreased by 45 and 34% in left and right visual association cortex (P < 0.01 and P < 0.05, respectively) and 34 and 37% in left and right inferior parietal cortex (P < 0.05) compared with controls; NVS patients had no significant metabolic alteration in these areas. Symptoms, physical examination, and metabolic imaging imply that these patients are a heterogenous but distinct clinical subgroup of DAT often with mild dementia who have visual symptoms due primarily to visual agnosia.
Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia
Authors: M Blink, T D Buitenkamp, M M van den Heuvel-Eibrink, A A Danen-van Oorschot, V de Haas, D Reinhardt, J-H Klusmann, M Zimmermann, M Devidas, A J Carroll, G Basso, A Pession, H Hasle, R Pieters, K R Rabin, S Izraeli, C M Zwaan
Journal: Leukemia (2011)
Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study
Authors: Isabelle Cleynen, Gabrielle Boucher, Luke Jostins, L Philip Schumm, Sebastian Zeissig, Tariq Ahmad, Vibeke Andersen, Jane M Andrews, Vito Annese, Stephan Brand, Steven R Brant, Judy H Cho, Mark J Daly, Marla Dubinsky, Richard H Duerr, Lynnette R Ferguson, Andre Franke, Richard B Gearry, Philippe Goyette, Hakon Hakonarson, Jonas Halfvarson, Johannes R Hov, Hailang Huang, Nicholas A Kennedy, Limas Kupcinskas, Ian C Lawrance, James C Lee, Jack Satsangi, Stephan Schreiber, Emilie Théâtre, Andrea E van der Meulen-de Jong, Rinse K Weersma, David C Wilson, Miles Parkes, Severine Vermeire, John D Rioux, John Mansfield, Mark S Silverberg, Graham Radford-Smith, Dermot P B McGovern, Jeffrey C Barrett, Charlie W Lees
Journal: The Lancet (2015)

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
The association of family history of liver cancer with hepatocellular carcinoma: A case-control study in the United States
Authors: Manal M. Hassan, Margret R. Spitz, Melanie B. Thomas, Steven A. Curley, Yehuda Z. Patt, Jean-Nicolas Vauthey, Katrina Y. Glover, Ahmed Kaseb, Richard D. Lozano, Adel S. El-Deeb, Nga T. Nguyen, Steven H. Wei, Wenyaw Chan, James L. Abbruzzese, Donghui Li
Journal: Journal of Hepatology (2008)
Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways
Authors: Ymera Pignochino, Giovanni Grignani, Giuliana Cavalloni, Manuela Motta, Marta Tapparo, Stefania Bruno, Alessia Bottos, Loretta Gammaitoni, Giorgia Migliardi, Giovanni Camussi, Marco Alberghini, Bruno Torchio, Stefano Ferrari, Federico Bussolino, Franca Fagioli, Piero Picci, Massimo Aglietta
Journal: Molecular Cancer (2009)

Osteosarcoma (OS) is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory.We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice.In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.
THE RENAL CLEARANCE OF HEMOGLOBIN IN THE DOG
Authors: J. Victor Monke, Charles L. Yuile
Journal: The Journal of Experimental Medicine (1940)

Simultaneous hemoglobin and creatinine renal clearance studies have been presented which indicate that hemoglobin is eliminated by the kidney at a rate which is 3 per cent of the creatinine clearance, above a plasma hemoglobin concentration of approximately 250 mg. per 100 cc. In dogs whose average glomerular filtration rate is 66 cc. per minute, about 2 cc. of plasma are cleared of hemoglobin per minute. A definite renal threshold exists for hemoglobin at a plasma concentration of about 100 mg. per 100 cc., below which hemoglobinuria does not occur. The uniformity of the process indicates that hemoglobinuria is not the result of a transient glomerular injury induced by the hemoglobin. It is tentatively suggested that the experimental results obtained may be interpreted in terms of the following concept. The glomerulus permits the filtration of hemoglobin in amounts directly dependent upon plasma concentration. However, only 3 per cent of all the pores of the membrane are electrostatically large enough to permit the passage of an undissociated hemoglobin molecule. Of that hemoglobin which passes down the tubule, a relatively constant though small amount is recovered by the tubules by a process not unlike that of phagocytosis found elsewhere in the body. An average value for this "athrocytic" capacity in a medium-sized dog is 2 mg. of hemoglobin per minute. This pattern of renal hemoglobin excretion is in agreement with the principles of the modern theory of kidney function.
Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
Authors: A Santoro, T Tursz, H Mouridsen, J Verweij, W Steward, R Somers, J Buesa, P Casali, D Spooner, E Rankin
Journal: Journal of Clinical Oncology (1995)

PURPOSE The aim of this trial was to compare the activity and toxicity of single-agent doxorubicin with that of two multidrug regimens in the treatment of patients with adult advanced soft tissue sarcomas. PATIENTS AND METHODS This was a prospective randomized phase III trial performed by 35 cancer centers within the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer (EORTC). Six hundred sixty-three eligible patients were randomly allocated to receive either doxorubicin 75 mg/m2 (arm A), cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC) (arm B), or ifosfamide 5 g/m2 plus doxorubicin 50 mg/m2 (arm C). RESULTS The overall response rate was 24% (95% confidence interval, 20.7% to 27.3%) among eligible patients and 26% among assessable patients. No statistically significant difference was detected among the three study arms in terms of response rate (arm A, 23.3%; arm B, 28.4%; and arm C, 28.1%), remission duration (median, 46 weeks on arm A, 48 weeks on arm B, and 44 weeks on arm C), or overall survival (median, 52 weeks on arm A, 51 weeks on arm B, and 55 weeks on arm C). The degree of myelosuppression was significantly greater for the combination of ifosfamide and doxorubicin than for the other two regimens. Cardiotoxicity was also more frequent in this arm, but other toxicities were similar. CONCLUSION In advanced soft tissue sarcomas of adults, single-agent doxorubicin is still the standard chemotherapy against which more intensive or new drug treatments should be compared. Combination chemotherapy cannot be recommended outside a controlled clinical trial with the exclusion of some subsets of sarcoma patients for whom significant tumor volume reduction may be an important end point of a chemotherapy regimen.
Adrenergic regulation of myocardial apoptosis
Authors: K Singh
Journal: Cardiovascular Research (2000)

Increased sympathetic nerve activity to the myocardium is a central feature in patients with heart failure. Norepinephrine, the primary transmitter of the sympathetic nervous system, signals via binding to α- and β-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac myocytes in vitro demonstrate that β-AR can stimulate apoptosis. Likewise, in transgenic mice overexpression of β1-AR or Gαs is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Whereas β1-AR stimulate apoptosis in vitro and in vivo, β2-AR may either stimulate or inhibit apoptosis and myocardial failure depending on the level of expression. Receptors coupling to Gi and Gq may also be able to mediate or modulate apoptosis and the development of myocardial failure, suggesting the potential for interactions between the β-AR system and numerous remodeling stimuli that act through Gi or Gq signaling pathways. It appears likely that the mitogen-activated protein kinase superfamily plays a key role in mediating the actions of adrenergic pathways on myocyte apoptosis. These observations suggest that the adrenergic nervous system plays an important role in the regulation of myocyte apoptosis, and may thus contribute to the development of myocardial failure.
Activation of p53 by MDM2 Antagonists Can Protect Proliferating Cells from Mitotic Inhibitors
Authors: Daisy Carvajal, Christian Tovar, Hong Yang, Binh T. Vu, David C. Heimbrook, Lyubomir T. Vassilev
Journal: Cancer Research (2005)

Abstract Recent studies have shown that activation of cell cycle checkpoints can protect normal proliferating cells from mitotic inhibitors by preventing their entry into mitosis. These studies have used genotoxic agents that act, at least in part, by activation of the p53 pathway. However, genotoxic drugs are known also to have p53-independent activities and could affect the sensitivity of tumor cells to antimitotic agents. Recently, we have developed the first potent and selective small-molecule inhibitors of the p53-MDM2 interaction, the nutlins, which activate the p53 pathway only in cells with wild-type but not mutant p53. Using these compounds, we show that p53 activation leads to G1 and G2 phase arrest and can protect cells from mitotic block and apoptosis caused by paclitaxel. Pretreatment of HCT116 and RKO colon cancer cells (wild-type p53) or primary human fibroblasts (1043SK) with nutlins for 24 hours followed by incubation with paclitaxel for additional 48 hours did not increase significantly their mitotic index and protected the cells from the cytotoxicity of paclitaxel. Cancer cells with mutant p53 (MDA-MB-435) responded to the same treatment with mitotic arrest and massive apoptosis. These results have two major implications for cancer therapy. First, p53-activating therapies may have antagonistic effect when combined with mitotic poisons. Second, pretreatment with MDM2 antagonists before chemotherapy of tumors with mutant p53 may offer a partial protection to proliferating normal tissues.
A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.
Authors: J C Brackett, H F Sims, R D Steiner, M Nunge, E M Zimmerman, B deMartinville, P Rinaldo, R Slaugh, A W Strauss
Journal: Journal of Clinical Investigation (1994)

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common known genetic disorder of fatty acid oxidation. Most (approximately 80%) cases are homozygous for a single mutation: A to G replacement at nucleotide 985 (A985G). MCAD deficiency typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Prompt diagnosis and management may prevent long-term sequelae. MCAD deficiency was verified by analysis of urinary acylglycine and serum acylcarnitine species from two neonates referred for diagnosis. Full-length cDNA and MCAD exon 7 and 11 genomic clones were prepared for sequence analysis. Normal and mutant cDNAs were expressed in bacteria, and enzymatic activity was assayed by the ferricenium hexaflurophosphate method. Four compound heterozygote individuals from two unrelated families with A985G on one allele and a novel G to A mutation at nucleotide 583 (G583A) as the second mutant allele presented with MCAD deficiency in the first week of life. The expressed G583A mutant protein lacks enzymatic activity. This novel mutation, G583A, is associated with severe MCAD deficiency causing hypoglycemia or sudden, unexpected neonatal death. This previously unrecognized phenotype of MCAD deficiency may contribute significantly to preventable infant deaths.
Measurement of anterior-posterior diameter of inferior vena cava by ultrasonography: a new non-invasive method to assess acute changes in vascular filling state
Authors: J. J Duvekot, E. C Cheriex, W. D. Tan, G. A K Heidendal, L. L H Peeters
Journal: Cardiovascular Research (1994)

Objective: The aim was to determine whether measurement of the anterior-posterior diameter of the inferior vena cava (IVC) by ultrasonography, before and during deep inspiration, allows indirect information on baseline blood volume and changes in vascular filling state to be obtained in healthy subjects. Methods: Blood volume was measured in 12 volunteers by a standard radioactive isotope method. The IVC dimensions were measured by ultrasound in various positions. In addition, in 10 male subjects the effect on the IVC dimensions of volume loading was evaluated by rapid infusion of plasma expander. During and immediately following volume loading, the IVC dimensions and blood volume were remeasured. Results: Neither the baseline IVC diameters nor any combination of these variables correlated with the concomitant blood volume. Volume loading increased the anterior-posterior IVC dimensions linearly, the largest increase being observed with the maximum IVC diameter and the subject in supine position. Conclusions: It follows that ultrasonic IVC indices cannot be used as accurate indirect estimate of baseline blood volume, but provide reliable information on acute changes of the subjects' vascular filling state. Cardiovascular Research 1994;28:1269-1272
Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer
Authors: Paul P Anglim, Janice S Galler, Michael N Koss, Jeffrey A Hagen, Sally Turla, Mihaela Campan, Daniel J Weisenberger, Peter W Laird, Kimberly D Siegmund, Ite A Laird-Offringa
Journal: Molecular Cancer (2008)

Lung cancer is the leading cause of cancer death in men and women in the United States and Western Europe. Over 160,000 Americans die of this disease every year. The five-year survival rate is 15% - significantly lower than that of other major cancers. Early detection is a key factor in increasing lung cancer patient survival. DNA hypermethylation is recognized as an important mechanism for tumor suppressor gene inactivation in cancer and could yield powerful biomarkers for early detection of lung cancer. Here we focused on developing DNA methylation markers for squamous cell carcinoma of the lung. Using the sensitive, high-throughput DNA methylation analysis technique MethyLight, we examined the methylation profile of 42 loci in a collection of 45 squamous cell lung cancer samples and adjacent non-tumor lung tissues from the same patients.We identified 22 loci showing significantly higher DNA methylation levels in tumor tissue than adjacent non-tumor lung. Of these, eight showed highly significant hypermethylation in tumor tissue (p < 0.0001): GDNF, MTHFR, OPCML, TNFRSF25, TCF21, PAX8, PTPRN2 and PITX2. Used in combination on our specimen collection, this eight-locus panel showed 95.6% sensitivity and specificity.We have identified 22 DNA methylation markers for squamous cell lung cancer, several of which have not previously been reported to be methylated in any type of human cancer. The top eight markers show great promise as a sensitive and specific DNA methylation marker panel for squamous cell lung cancer.
Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus
Authors: Yukio Horikawa, Naohisa Oda, Nancy J. Cox, Xiangquan Li, Marju Orho-Melander, Manami Hara, Yoshinori Hinokio, Tom H. Lindner, Hirosato Mashima, Peter E.H. Schwarz, Laura del Bosque-Plata, Yohko Horikawa, Yukie Oda, Issei Yoshiuchi, Susan Colilla, Kenneth S. Polonsky, Shan Wei, Patrick Concannon, Naoko Iwasaki, Jan Schulze, Leslie J. Baier, Clifton Bogardus, Leif Groop, Eric Boerwinkle, Craig L. Hanis, Graeme I. Bell
Journal: Nature Genetics (2000)
IS HEMOGLOBIN AN ESSENTIAL STRUCTURAL COMPONENT OF HUMAN ERYTHROCYTE MEMBRANES?*
Authors: Robert I. Weed, Claude F. Reed, George Berg
Journal: Journal of Clinical Investigation (1963)

This investigation of human red cell membranes was undertaken in order to determine whether the presence of hemoglobin in the membrane is es- sential for maintenance of the membrane's struc- tural integrity, which has been evaluated by stud- ies of the shape, lipid content and composition, protein content, osmotic responsiveness, and certain enzymic activities of erythrocyte ghosts from which virtually all of the cellular hemoglobin had been removed.Many studies have been done with red cell "ghosts," or posthemolytic residues, because such preparations offer the possibility of analyzing certain physiological, biochemical, electron micro- scopic, and immunologic properties attributable to the membranes themselves, apart from the intracel- lular contents.Representative techniques for preparation of red cell ghosts include hemolysis in distilled water, the effects of which were stud- ied first by Bernstein and his associates (1), the freeze-thaw method described by Jorpes (2), the use of chemical lysins such as digitonin and sa- ponin (3) and the use of 0.1%o sodium chloride saturated with CO2 (4), both as described by Ponder, and the method of successive osmotic hemolysis proposed by Hillier and Hoffman (5).Recently, Danon, Nevo, and Marikovsky (6) have described a modification of the technique of Hil- lier and Hoffman which they have termed "gradual osmotic lysis."This method provides a high yield of ghosts that bear a remarkable resemblance
A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non–Small Cell Lung Cancer with a <i>KRAS</i> Mutation
Authors: Anne-Marie C. Dingemans, Wouter W. Mellema, Harry J.M. Groen, Atie van Wijk, Sjaak A. Burgers, Peter W.A. Kunst, Erik Thunnissen, Danielle A.M. Heideman, Egbert F. Smit
Journal: Clinical Cancer Research (2012)

Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib.In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks.Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%).Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.