tbuckley/cabot-search huggingface dataset:
Genetic and Pharmacological Strategies to Refunctionalize the von Hippel Lindau R167Q Mutant Protein
Authors: Zhiyong Ding, Peter German, Shanshan Bai, A. Srinivas Reddy, Xian-De Liu, Mianen Sun, Lijun Zhou, Xiaohua Chen, Xiaobei Zhao, Chengbiao Wu, Shuxing Zhang, Gordon B. Mills, Eric Jonasch
Journal: Cancer Research (2014)

Abstract Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations. Cancer Res; 74(11); 3127–36. ©2014 AACR.
Lesson of the week: Tonic seizures are a particular risk factor for drowning in people with epilepsy
Authors: F. M C Besag
Journal: BMJ (2001)

<h3>Background</h3> Biomarkers of a number of pathophysiological processes might improve the clinical diagnosis of stroke and transient ischaemic attack (TIA). <h3>Methods</h3> We recruited symptomatic patients with suspected stroke or TIA &lt;24 h after onset. We measured markers of inflammation, thrombosis; thrombolysis, cardiac dysfunction and cerebral damage. A panel of stroke physicians, neurologists and neuro-radiologists reviewed the clinical features, brain imaging and subsequent course of each patient to make the gold standard diagnosis. We constructed multivariate logistic models to analyse the data. <h3>Results</h3> We recruited 405 patients with suspected stroke (285 stroke or TIA, 180 mimics) at a median of 7 h (IQR 3–19 h) after symptom onset. Higher levels of Ln NT pro-BNP (OR 2.2 (95% CI 1.5 to 3.0) 75th to 25th centile) and t-PA (OR 1.6 (1.2 to 2.2)) were associated with a diagnosis of TIA or stroke. Adjustment for neurological impairment and age attenuated these associations. The associations of higher levels of adiponectin (OR 1.8 (1.2 to 2.4)) and IL-10 (OR 1.1 (1.0 to 1.1)) with a diagnosis of mimic were robust to adjustment for neurological impairment, age and infection. A model with eight markers from systematic review had no better diagnostic performance than an emergency department clinician. <h3>Conclusion</h3> We found no single marker or combination of markers that positively predicted a diagnosis of stroke or TIA independently of neurological impairment and age, or added usefully to the clinical diagnosis.
Preemployment Medical Examinations-Reply
Authors: Jermyn McCahan
Journal: JAMA (1982)

In Reply.—  Physicians who perform preplacement medical examinations for industry or business at the time of hire or job transfer should be aware of the legal obligations placed on management by the EEOC regulations; §503 and §504 of the Rehabilitation Act of 1973; and the Vietnam Era Veterans Readjustment Act of 1974. This can be accomplished by consulting with the personnel and legal departments or consultants of the company for whom the physician is performing the medical evaluations.  I agree with Dr Lerner's advice to physicians expressed in the second paragraph of his response to Dr Fisher.  A physician who accepts responsibility for this type of examination is urged to review carefully an article published in the Journal of Occupational Medicine , 1 as well as the reference listed by Dr Lerner.
1194 CHARACTERIZATION OF VIRAL ESCAPE IN HCV GENOTYPE 1-INFECTED PATIENTS TREATED WITH BMS-791325 AND PEGYLATED INTERFERON-ALFA AND RIBAVIRIN
Authors: D. McPhee, P. Falk, P. Fracasso, J. Lemm, M. Liu, M. Kirk, D. Hernandez, E. Cooney, E. Hughes, M. Gao
Journal: Journal of Hepatology (2012)
The Distribution of the Human Blood Groups and Other Polymorphisms
Authors: Frances K. Widmann
Journal: JAMA (1977)

In publishing this monumental reference, Oxford Press and Professor Mourant and his associates have saved many researchers countless hours of literature search. There are 661 pages of tabulated data and 68 pages of bibliography, not including the republication of the complete monograph<i>The ABO Blood Groups</i>by the same authors, first published by Blackwell's in 1958. Most readers will head first for Mourant's pithy summaries of all these numbers. Superb on blood groups, competent on proteins and enzymes, Mourant puts isolated and featureless population studies into a working framework. There is a separate chapter for each major blood group system and protein polymorphism, followed by chapters considering the blood group distributions in different geographic and population categories. Red cell blood groups are the major focus, especially ABO and Rh; haptoglobulins, transferrins, lipoproteins, and enzyme systems occupy a decidedly secondary position. Histocompatibility antigens and hemoglobin variants have been deliberately omitted. Essential
Expression of a constitutive NF-kappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells.
Authors: R E Bellas, J S Lee, G E Sonenshein
Journal: Journal of Clinical Investigation (1995)

We have recently discovered bovine and human vascular smooth muscle cells (SMCs) express a novel constitutive Nuclear Factor-kappa B (NF-kappa B)/Rel-like activity (Lawrence, R., L.-J. Chang, U. Siebenlist, P. Bressler, and G.E. Sonenshein. 1994. J. Biol. Chem. 269:28913-28918), here termed SMC-Rel. Since cytomegalovirus (CMV) infection of human vascular SMCs has been implicated in aberrant SMC proliferation during post-angioplasty restenosis, we tested the role of NF-kappa B/Rel activity in transactivation of the CMV immediate early (ie) promoter. The basal CMV ie promoter linked to three wild-type, but not mutant, copies of its NF-kappa B element was active in bovine aortic SMCs. The anti-oxidants N-acetyl cysteine (NAC) or pentoxifylline (PTX), which are used clinically to reduce NF-kappa B/Rel activity, inhibited NF-kappa B driven promoter transactivation, and SMC-Rel binding activity. Treatment with either NAC or PTX was observed to slow the growth of the SMCs in a dose dependent fashion. Microinjection of either purified I kappa B-alpha, a naturally occurring specific inhibitor of NF-kappa B/Rel activity, or double-stranded oligonucleotides harboring wild type, but not non-binding mutants of NF-kappa B elements selectively inhibited SMC proliferation. Thus constitutive NF-kappa B/Rel activity appears essential for proliferation of vascular SMCs and might be a novel target for therapeutic intervention for restenosis.
Genetically InFormed Therapies—A “GIFT” for Children with Cancer
Authors: Carol J. Thiele, Susan L. Cohn
Journal: Clinical Cancer Research (2012)

Abstract The national investment that was made in oncology research with the passage of the National Cancer Act in 1971 is now coming to fruition. Nowhere is this more apparent than in the exciting prospects for genetically informed precision medicine as applied to the treatment of children with cancer. The wealth of information gleaned from intensive genetic analyses and NexGen sequencing studies has identified a number of viable targets in leukemias and solid tumors. Our rapidly evolving understanding of the enzymatic controls that regulate chromatin dynamics during normal differentiation of stem cells and their mutation or dysregulation in tumor cells is leading to a new library of therapeutically tractable tumor targets. The recent identification of germline variants associated with toxicity and/or response to therapy has further enhanced our ability to deliver individualized treatments for pediatric cancer patients. Our challenge today is to determine how best to use genomic data and integrate it into evolving clinical protocols to provide more efficacious therapies and a better quality of life for children with cancer. Clin Cancer Res; 18(10); 2735–9. ©2012 AACR.
341 PREVALENCE OF TRANSAMINASE ABNORMALITIES IN GENERAL POPULATION IN XXI CENTURY: THE BAGNACAVALLO STUDY
Authors: P. Giacomoni, F.G. Foschi, M. Domenicali, S. Savini, F. Dazzani, A.C. Dall'Aglio, G. Saini, G. Re, T. Casetti, P. Andreone, M. Bernardi, G.F. Stefanini
Journal: Journal of Hepatology (2010)
rho, a Small GTP-Binding Protein, Is Essential for <i>Shigella</i> Invasion of Epithelial Cells
Authors: Masahisa Watarai, Yoichi Kamata, Shunji Kozaki, Chihiro Sasakawa
Journal: The Journal of Experimental Medicine (1997)

Shigella, the causative agents of bacillary dysentery, are capable of invading mammalian cells that are not normally phagocytic. Uptake of bacteria by the mammalian cells is directed by bacterial factors named IpaB, IpaC, and IpaD invasins, in which Ipa invasins secreted into the bacterial environment can interact with alpha5beta1 integrin. We report here that Shigella invasion of epithelial cells requires rho activity, a ras-related GTP-binding protein. The invasive capacity of Shigella flexneri for Chinese hamister ovary (CHO) cells and other epithelial cells were greatly reduced when treated with Clostridium botulinum exoenzyme C3 transferase. Conversely, uptake of bacteria by CHO cells was promoted upon microinjection of an activated rho variant, Val14RhoA. Attachment of S. flexneri to CHO cells can elicit tyrosine phosphorylation of pp125FAK and paxillin, localized accumulation of F-actin, vinculin, and talin, and activation of protein kinase C, which were all blocked by the treatment with C3 transferase. Our results indicate that cellular signal transduction regulated by rho is essential for Shigella invasion of epithelial cells.
Eosinophilic Meningitis Following Myelography
Authors: A. A. McBeath
Journal: JAMA (1980)

<h3>To the Editor.—</h3> If the recently reported case of eosinophilic meningitis following myelography (242:2432, 1979) is only the third reported such case, it appears reasonable to report a fourth case. <h3>Report of a Case.—</h3> Our patient was a 32-year-old woman who had undergone an uneventful iophendylate injection (Pantopaque) myelogram and an L5-S1 diskectomy. Her postoperative course was uneventful until 30 days after the myelogram was performed. She then had an acuteonset of headache and anterior thigh pain. She was afebrile and exhibited a positive Kernig sign, and the straight-leg raising test was normal bilaterally at 20 degrees. Analysis of CSF showed an elevated eosinophil count and an increased protein level (Table). Culture yields for bacteria, viruses, and fungi were all negative. Her blood sample showed a WBC count of 5,500/cu mm, with 45% segmented neutrophils, 6% eosinophils, and 49% lymphocytes. An unsuccessful attempt to remove a small amount of
Percutaneous endoscopic gastrostomy feeding in patients with cystic fibrosis
Authors: S G J Williams, F Ashworth, A McAlweenie, S Poole, M E Hodson, D Westaby
Journal: Gut (1999)

Malnutrition is a common management problem in patients with cystic fibrosis (CF). Various approaches to supplemental nutrition by both parenteral and enteral routes have been used.To analyse the efficacy and acceptability of supplemental overnight feeding using a percutaneous endoscopic gastrostomy (PEG) in patients with CF.53 patients with CF (43 adults; age >17 years) with severe pulmonary disease.The technical success and complications of PEG insertion were documented together with changes in nutritional and pulmonary status of the cohort.PEG tubes were successfully inserted in all patients, with immediate complications (respiratory depression) in two (4%) and late complications in 13 (25%). Feeding was well tolerated by 50/51 (98%) of the cohort during a mean (SEM) follow up of 14.5 (2.1) months. The adult cohort had a significant increase in weight and body mass index at six months which was maintained at 12 months. Serum albumin concentration remained stable at six months but had fallen by 12 months, although the differences were not statistically significant. These results were reflected in the paediatric cohort. Pulmonary function in those followed up for one year had apparently stabilised, but the number of admissions to hospital over the year before and the year after PEG did not change. Half of the cohort were accepted for heart-lung/lung transplantation, the improvement in nutritional status being a prerequisite for this.Supplemental PEG tube feeding is well tolerated and results in a significant improvement in nutritional status and an apparent stabilisation of pulmonary function in severely malnourished CF patients with advanced pulmonary disease
Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study
Authors: Heyder Omran, Harald Schmidt, Matthias Hackenbroch, Stefan Illien, Peter Bernhardt, Giso von der Recke, Rolf Fimmers, Sebastian Flacke, Günter Layer, Christoph Pohl, Berndt Lüderitz, Hans Schild, Torsten Sommer
Journal: The Lancet (2003)
1063-61 Angiomax versus heparin as an antithrombotic agent in patients undergoing percutaneous coronary intervention in saphenous vein bypass grafts
Authors: Seung-Woon Rha, Ron Waksman, George Aggrey, Afework GebreEyesus, Rebecca Torguson, Mohan Nandalur, Pramod K Kuchulakanti, Rajbabu Pakala, Ellen E Pinnow, Joseph Lindsay
Journal: Journal of the American College of Cardiology (2004)
Influence of Social Class on Obesity and Thinness in Children
Authors: Albert Stunkard
Journal: JAMA (1972)

Several social factors have been closely linked to obesity and thinness in adults. This study, based on 3,344 measurements of triceps skin-fold thickness found similar relationships in white urban children. Obesity was far more prevalent in the lower-class girls than in those of the upper class—nine times as prevalent by age 6. Similar though less striking differences were found between boys of upper and lower socioeconomic status. The pattern of thinness among girls was similar to that previously reported in women, with significantly more thinness in the upper-class group. Among boys, as among men, there were no such differences. The remarkably early onset of class-linked differences in prevalence of obesity underlines the importance of attempts to prevent the disorder in childhood. These attempts should be directed particularly toward those at high risk because of their lower socioeconomic status.
Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction
Authors: Ulrich Meinzer, Frederick Barreau, Sophie Esmiol-Welterlin, Camille Jung, Claude Villard, Thibaut Léger, Sanah Ben-Mkaddem, Dominique Berrebi, Monique Dussaillant, Ziad Alnabhani, Maryline Roy, Stéphane Bonacorsi, Hans Wolf-Watz, Julie Perroy, Vincent Ollendorff, Jean-Pierre Hugot
Journal: Cell Host & Microbe (2012)
832. Efficient Readministration of Adenovectors to the Inner Ear
Authors: Hinrich Staecker, Mark Praetorius, Chi Hsu, Douglas E. Brough
Journal: Molecular Therapy (2006)

Adenovectors have been extensively studied and provide one of the most flexible vehicles for gene delivery to a wide variety of cells. A number of studies have demonstrated the ability of Ad5 adenovectors to deliver genes to the inner ear without any associated loss of auditory function. We have previously shown that delivery of the atonal gene with an adenovirus vector to deaf inner ears can restore hearing and balance function by restoring functional sensory cells. Given the potential utility of adenovectors for these and other diseases of the inner ear, we have explored the repeated delivery of Ad5 capsid vectors in the inner ear. In this study we have evaluated and compared the host immune response on the efficiency of delivery. In these studies we show that preimmunization with Ad 5 or repeat delivery of vector to the inner ear using 2 different delivery routes resulted in efficient transduction of inner ear tissues and did not result in hearing loss due to the repeated delivery. These data suggest that by using an E1, E3, E4 deleted Ad5 based adenovector we can readminister adenovector in the inner ear. In addition, our studies with adenovectors based on alternative serotypes show the ability of these vectors to efficiently transduce cells within the inner ear. Alternative serotyped adenovectors were evaluated that have low pre-existing neutralizing antibody titers in the human population. Interestingly, Ad35 based vectors effectively deliver GFP to both hair cells and the spiral ganglion. In conclusion, both Ad5 based vectors and Ad35 based vectors were found to be well tolerated in the inner ear of the mouse and can form the basis of developing flexible drug delivery systems for the inner ear. Douglas E Brough and Chi Hsu are employees of GenVec Inc.
Abstract 530: Contribution of fibroblasts isolated from primary lung cancers and normal lung tissue to tumor growth
Authors: Francesca Andriani, Giulia Bertolini, Roberto Caserini, Sara Bursomanno, Patrizia Gasparini, Ugo Pastorino, Gabriella Sozzi, Luca Roz
Journal: Cancer Research (2011)

Abstract Fibroblasts isolated from cancer specimens have been shown to possess pro-tumorigenic properties, often associated with traits reminiscent of myofibroblasts found at sites of wound healing, but little is known about the mediators of the interaction between fibroblasts and cancer cells especially in lung cancer. To evaluate the contribution of fibroblasts to lung cancer development we established 60 fibroblast cultures from cancerous and normal lung tissue from primary lung cancer patients, including 18 pairs of normal (NF) and cancer-associated fibroblasts (CAF) from the same patient. The mesenchymal nature of the cultures was confirmed by expression of surface markers CD90, CD166, CD105 and CD73 and negativity for epithelial and hematopoietic markers (ESA and CD45). Further immunophenotyping with markers specific for fibroblasts subpopulations (FSP, vimentin, alpha-SMA, FAP) identified frequent expression of activation markers, with up to 50% of alpha-SMA+ cells. Interestingly activation properties were identified also in cultures derived from normal lung tissue. Co-mingling of fibroblasts (NF or CAF) with A549 lung cancer cells generally resulted in increased tumor size after injection in nude mice and 2/4 of the CAF cultures tested also increased tumor take when cancer cells were injected at low doses. Human cells were identified by HLA staining in the stroma of tumors grown after co-injection confirming the contribution of the mixed fibroblasts to tumor development. Furthermore medium conditioned by fibroblasts promoted growth of lung cancer cells or immortalized bronchial epithelial cells. All the cultures tested displayed a normal karyotype suggesting that the functional properties of fibroblasts are likely to be the result of epigenetic changes.These results indicate that lung fibroblasts might play a central role in the growth and progression of lung neoplasia. Consistently with their activated phenotype also cultures from normal lung tissue of heavy smokers displayed pro-tumorigenic activity, indicating that the microenvironment of lungs heavily exposed to damage from carcinogenic substances might already be predisposed to foster the growth of transformed epithelial cells. The full dissection of this complex picture might reveal mediators of the cross-talk between stroma and cancer cells and provide novel therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 530. doi:10.1158/1538-7445.AM2011-530
Detection of platelet‐derived microparticles in patients with diabetes
Authors: Shosaku Nomura, Yasuhiko Miyazaki, Tetsuya Miyake, Masahko Suzuki, Toshihiro Kawakatsu, Hirofumi Kido, Kazuyuki Yamaguchi, Tsutomu Fukuroi, Hideo Kagawa, Mutsumasa Yanabu
Journal: American Journal of Hematology (1993)

increased significantly ( P < 0.01).A positive correlation existed between the detection of MP and the value of fasting blood sugar (r = 0.62, P < 0.05).and the rate of detection of MP increased at a high fasting blood sugar level.The functional significance of platelet-derived MP is of considerable interest.because they are rich in membrane receptors for coagulation factor Va and provide a catalytic surface for the prothrombinase reaction [ 3 ] .It is
Radiology as a Diagnostic Aid in Clinical Surgery
Authors: Fred O. Coe
Journal: JAMA (1960)

The author states that this book is intended for surgeons. In the introduction it is made clear that the surgeon can receive the greatest help from the radiologist by mutual co-operation. Clinical findings are often important in radiological interpretation. The chapter on emergency work contains material with which every surgeon, resident, and intern should be familiar. Much unnecessary radiological work could be eliminated if the doctor requesting the examination had sufficient clinical experience to recognize the necessity of an immediate examination. There is a fine balance between indicated examinations and those that are unnecessary. To err on the more conservative side may be just as disastrous for the patient as to order unnecessary examinations. The x-ray examinations which should be considered emergency measures are well selected. These include certain fractures; dislocation of the shoulder, elbow, and hip; swallowed or aspirated foreign bodies; rupture of the kidney; intussusception; perforation of a