tbuckley/cabot-search huggingface dataset:
Selective and Potent Akt Inhibition Triggers Anti-Myeloma Activities and Enhances Fatal Endoplasmic Reticulum Stress Induced by Proteasome Inhibition
Authors: Naoya Mimura, Teru Hideshima, Toshiyasu Shimomura, Rikio Suzuki, Hiroto Ohguchi, Ola Rizq, Shohei Kikuchi, Yasuhiro Yoshida, Francesca Cottini, Jana Jakubikova, Diana Cirstea, Gullu Gorgun, Jiro Minami, Yu-Tzu Tai, Paul G. Richardson, Teruhiro Utsugi, Atsushi Iwama, Kenneth C. Anderson
Journal: Cancer Research (2014)

The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM.
On covering one's mouth (when yawning)
Authors: George Dunea
Journal: BMJ (2004)

A simple observational study recently found that 67.5% of medical students attending morning conference did not cover their mouth while yawning.

The data are still with the statisticians, who raised several problems. Could the extreme boredom of attending these conferences have induced excessive yawning and biased the results? Were genders and races adequately represented in the study? Can the results be extrapolated to livelier conferences? Was there a …
Endoscopic Diagnosis of 115 Cases of Early Esophageal Carcinoma
Authors: Yang Guanrei, Huang He, Qui Sungliang, Chang Yuming
Journal: Endoscopy (1982)

Mass surveys of a population of 28,139 people in high-risk areas for esophageal carcinoma in Henan Province were carried out using the methods of esophageal exfoliative cytology, reontgenology and fiberendoscopy, between January 1978 and May 1981. 115 cases of early esophageal cancer comprising 64 males and 51 females were found. This paper reports on the results of the fiberendoscopic examination of these 115 cases of early esophageal carcinoma followed-up at regular intervals. On the basis of clinical, laboratory, and endoscopic findings, esophageal carcinoma of early stage can be divided into four types including the congestive type, erosive type, plaque-like type and polypoid type. All results were obtained on the basis of a follow-up observation period of 19-42 months. It was shown that the evolution of esophageal cancer in situ to an advanced cancer probably takes 3-4 years. Therefore, esophageal carcinoma could be reasonably considered to be a chronic disease of relatively slow growth. In order to make complete cure of such a "poor-prognosis" disease possible, early diagnosis established in good time using all the methods mentioned, is essential.
Abstract 3934: Identification of novel cancer DNA sequence variants in human sarcomas
Authors: Ogan D. Abaan, Princy Francis, Marbin Pineda, Robert Walker, Sven Bilke, Sean R. Davis, Paul S. Meltzer
Journal: Cancer Research (2011)

Abstract Understanding of the genetic basis of cancer initiation and progression is a fundamental goal of cancer research. Identification of cancer variants is of profound importance for both understanding disease mechanism and for developing novel therapies. Soft-tissue sarcomas are multiple uncommon histotypes with features of diverse connective tissue lineages. Although some of their underlying genetic changes have been elucidated, for example in those types which contain etiologic chromosome translocations, in general, the genetics of these tumors is incompletely described. Adult soft tissue sarcomas often exhibit highly complex genomic rearrangements. To search for novel variants in these tumors, we utilized a custom “targeted-resequencing” approach to sequence coding exons from over 1300 known cancer-related genes and candidate gene families in 65 soft-tissue sarcoma patient samples covering several subtypes and their matching normal tissues where available. We used the previously published method of “In-solution capture” to enrich for regions of interest and sequenced both the normals and the tumors using the Illumina GAII platform. The variant calls reveal the distribution of mutations affecting the exons of the targeted regions across histotypes, and reveal the role of critical functional pathways in sarcoma genesis. Preliminary data suggest that TP53 single nucleotide variants are mostly confined to one histotype. This work is an important step in cataloging novel cancer mutations in these cancers, with potential implications for understanding their biology and the development of new therapies. 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 3934. doi:10.1158/1538-7445.AM2011-3934
Abstract 681: Knockdown of connective tissue growth factor and treatment with temozolomide inhibited invasion, angiogenesis, and tumorigenesis of human glioblastomas
Authors: Joseph George, Naren L. Banik, Swapan K. Ray
Journal: Cancer Research (2010)

Abstract Connective tissue growth factor (CTGF) is a putative proto-oncogene and plays a crucial role in endothelial cell migration and tumor angiogenesis. CTGF is highly upregulated in proliferating endothelial cells and glioblastoma cells. In this investigation, we examined whether knockdown of CTGF at the mRNA level and treatment with temozolomide (TMZ) could inhibit cell invasion, angiogenesis, and growth of human glioblastoma SNB-19 and T98G cells in vivo. The cells were stably transfected with a plasmid vector carrying the human CTGF siRNA cDNA and then treated with 10 μM TMZ for 48 h. Semiquantitative PCR, Western blotting, and immunohistochemical staining demonstrated 80% downregulation of CTGF both at mRNA and protein levels after stable transfection. Matrigel invasion, cell migration from spheroids, and cell proliferation studies demonstrated significant inhibition of cell invasion, migration, and proliferation, respectively, of both cell lines after downregulation of CTGF and treatment with TMZ. In vitro and in vivo angiogenesis assays demonstrated inhibition of network formation of endothelial cells and neovascularization under the dorsal skin of nude mice, respectively, after knockdown of CTGF and treatment with TMZ. Both subcutaneous and intracerebral tumorigenesis in nude mice was markedly reduced in CTGF downregulated cells after TMZ treatment. Mechanistic studies demonstrated significant reduction of PCNA, VEGF, c-Myc, CDK2, CDK4, and cyclin D1 and upregulation of the cell cycle inhibitors p21Waf1 and p27Kip1. Flow cytometric analysis showed cell cycle arrest at G2/M phase in both cell lines after CTGF knockdown and TMZ treatment. Taken together, our study indicates that the CTGF knockdown and TMZ treatment effectively prevents cell invasion, migration, angiogenesis, and growth of glioblastomas in vivo. Therefore, CTGF knockdown during TMZ treatment offers a novel and potential therapeutic strategy for controlling the growth of glioblastomas. This investigation was supported in part by the R01 grants (CA-91460 and NS-57811) from the National Institutes of Health (Bethesda, MD). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 681.
Donald Campbell's doubt: Cultural difference or failure of communication?
Authors: Richard A. Shweder
Journal: Behavioral and Brain Sciences (2010)

The objection, rightfully noted but then dismissed by Henrich et al., that the observed variation across populations "may be due to various methodological artifacts that arise from translating experiments across contexts" is a theoretically profound and potentially constructive criticism. It parallels Donald Campbell's concern that many cultural differences reported by psychologists "come from failures of communication misreported as differences." Ironically, Campbell's doubt is a good foundation for investigations in cultural psychology.
Brief Communication: Preoperative Anticoagulant Activity after Bridging Low-Molecular-Weight Heparin for Temporary Interruption of Warfarin
Authors: Martin J. O'Donnell, Clive Kearon, Judy Johnson, Marlene Robinson, Michelle Zondag, Irene Turpie, Alexander G. Turpie
Journal: Annals of Internal Medicine (2007)

Background: Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. Objective: To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. Design: Prospective cohort study. Setting: Single university hospital. Patients: Consecutive patients who had warfarin therapy interrupted before an invasive procedure. Intervention: Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. Measurements: Blood anti–factor Xa heparin levels measured shortly before surgery. Results: Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. Limitations: The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. Conclusions: Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.
The Emerging Role of Innate Immunity in the Heart and Vascular System
Authors: Douglas L. Mann
Journal: Circulation Research (2011)

Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses, within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive; in which case, the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein, the biology of innate immune signaling in the heart is reviewed, as well as the literature suggesting that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia/reperfusion injury, and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system.
Comparative Analysis of Transcription Start Sites Using Mutual Information
Authors: D. Ashok Reddy, Chanchal K. Mitra
Journal: Genomics Proteomics & Bioinformatics (2006)

Abstract The transcription start site (TSS) region shows greater variability compared with other promoter elements. We are interested to search for its variability by using information content as a measure. We note in this study that the variability is significant in the block of 5 nucleotides (nt) surrounding the TSS region compared with the block of 15 nt. This suggests that the actual region that may be involved is in the range of 5–10 nt in size. For Escherichia coli, we note that the information content from dinucleotide substitution matrices clearly shows a better discrimination, suggesting the presence of some correlations. However, for human this effect is much less, and for mouse it is practically absent. We can conclude that the presence of short-range correlations within the TSS region is species-dependent and is not universal. We further observe that there are other variable regions in the mitochondrial control element apart from TSS. It is also noted that effective comparisons can only be made on blocks, while single nucleotide comparisons do not give us any detectable signals.
Snoring, Intermittent Hypoxia and Academic Performance in Primary School Children
Authors: Michael S. Urschitz, Anke Guenther, Esther Eggebrecht, Judith Wolff, Pilar M. Urschitz-Duprat, Martin Schlaud, Christian F. Poets
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Sleep-disordered breathing is associated with impaired attention and neurocognitive deficits. We assessed the association of snoring and intermittent hypoxia with poor academic performance in third grade school children (1,144 children). Snoring frequency and intermittent hypoxia were investigated using parental questionnaire and nocturnal home pulse oximetry. Intermittent hypoxia was specified as desaturation events of 90% or less pulse oximeter saturation. Poor academic performance was defined as grade 4-6 on a six-point scale (i.e., approximately the lowest quintile grades) in mathematics, science, reading, spelling, and/or handwriting in the most recent school report. Snoring "always" was significantly associated with poor academic performance in mathematics (odds ratio; 95% confidence interval: 3.6; 1.3-10.1), science (4.3; 1.3-14.6), and spelling (3.5; 1.2-10.3). Snoring "frequently" was also significantly associated with poor academic performance in mathematics (2.4; 1.3-4.7) and spelling (2.0; 1.04-3.8). A significant relationship between snoring and poor academic performance was also found in children without intermittent hypoxia, whereas intermittent hypoxia did not show an independent association with poor academic performance. Thus, habitual snoring (i.e., snoring frequently or always) was associated with poor academic performance in these primary school children.
Social costs of smoking are triple those of illicit drugs
Authors: C. Zinn
Journal: BMJ (2003)

The financial impact of tobacco and alcohol far outweigh the impact of illicit drugs, with smoking costing the community almost three times as much as any other category of drug, according to a study on the social costs of drug use in Australia.

The report, produced for the federal government's national drug strategy, estimates that tobacco accounted for 61.2% of the costs to society of drugs, or $A21bn (£7.6bn; $12.4bn; ‡11.5bn). For the first time the cost calculations included an estimate of the impact of passive smoking and newly available data to assess the effect on the Australian …
938. Ceramide May Have a Role in Sensitizing ACHN Renal Cancer Cells (RCC) to Fas Induced Apoptosis
Authors: Ahmed M. El-Zawahry, David Holman, Xiang Liu, Saeed ElOjeimy, Sunil Sudarshan, Nabil K. Bissada, Hashim Rashwan, Zdzislaw Szulc, Alicjia Bielwaska, Thomas Keane, Yusuf Hannun, James Norris
Journal: Molecular Therapy (2006)

INTRODUCTION AND OBJECTIVE: RCC is the sixth leading cause of cancer death in USA. One third of patients present with metastatic disease. Current systemic therapies have limited results. Gene therapy including pro-apoptotic gene therapy is a promising tool under investigation for treatment of RCC. However, inability to deliver lethal genes to all tumor cells is a problem. FasL is a pro- apoptotic gene that is a member of the Tumor Necrosis Factor family. Although ACHN cells were resistant to convention Fas monoclonal Ab (CH-11), we were able to induce apoptosis by AdGFPFasLTET gene therapy.
Renal cell carcinoma
Authors: E. Jonasch, J. Gao, W. K. Rathmell
Journal: BMJ (2014)

The treatment of renal cell carcinoma (RCC) has changed greatly over the past 15 years. Progress in the surgical management of the primary tumor and increased understanding of the molecular biology and genomics of the disease have led to the development of new therapeutic agents. The management of the primary tumor has changed owing to the realization that clean margins around the primary lesion are sufficient to prevent local recurrence, as well as the development of more sophisticated tools and techniques that increase the safety of partial nephrectomy. The management of advanced disease has altered even more dramatically as a result of new agents that target the tumor vasculature or that attenuate the activation of intracellular oncogenic pathways. This review summarizes data from prospective randomized phase III studies on the surgical management and systemic treatment of RCC, and provides an up to date summary of the histology, genomics, staging, and prognosis of RCC. It describes the management of the primary tumor and offers an overview of systemic agents that form the mainstay of treatment for advanced disease. The review concludes with an introduction to the exciting new class of immunomodulatory agents that are currently in clinical trials and may form the basis of a new therapeutic approach for patients with advanced RCC.
Bilateral Ureteral Obstruction
Authors: Melvin E. Clouse
Journal: JAMA (1964)

Dr. Dale E. Wenlund: This 63-year-old man was well until about one and a half years prior to the present admission, when he had a cholecystectomy. He subsequently noted a painful bulge in the region of the subcostal scar. Because of pain and anorexia, he lost 30 lb (1.36 kg) during the next 18 months and was unable to work. He entered the emergency ward with an obvious ventral hernia. Approximately 30 years prior to the present admission he had undergone a laparotomy for intestinal obstruction. There was no history of postoperative difficulty. Physical examination revealed an intelligent, cooperative male in good physical condition. His blood pressure level was 140/90 mm Hg; pulse, 82; and temperature, 99 F ( 210 C). He had no urinary symptoms. The abdomen was unremarkable except for an obvious ventral hernia. The hematocrit value was 32%. The white blood count and serum electrolyte levels were normal.
Restoration of immune responses of aging hamsters by treatment with isoprinosine.
Authors: K Y Tsang, H H Fudenberg, M J Gnagy
Journal: Journal of Clinical Investigation (1983)

Immune competence declines with advanced age in hamsters, as in other laboratory mammals and in humans. We found significant alterations in the functional parameters of different populations of immunocytes (natural killer cells, T cells, monocytes, and suppressor cells) in aging hamsters, beginning at approximately 14 mo of age. Natural killer cytotoxicity, phytohemagglutinin-induced lymphocyte stimulation, and monocyte chemotaxis were decreased in aging Lak:LvG(Syr) outbred hamsters. When old hamsters were given a single injection (5 mg/kg body wt) of isoprinosine, a chemical immune potentiator, these three immune parameters increased almost to the levels found in young adult hamsters but returned to pretreatment levels after 7 d. Suppressor cell activity for the lymphocyte response to phytohemagglutinin, which increased with age, was decreased after treatment. In old hamsters treated with weekly injections of isoprinosine, these four immunological parameters remained at or near the levels found in young adults.
Effect of Carotid Sinus Stimulation on the Electrocardiograms of Clinically Normal Individuals
Authors: G. H. HEIDORN, A. P. MCNAMARA
Journal: Circulation (1956)

The cardioinhibitory effects of carotid sinus stimulation were studied by electrocardiographic means in 40 clinically normal, adult males. Although the carotid sinus reflex is of clinical importance, the measure of its effects in normal individuals is little known. Electrocardiographic changes were varied and occurred in nearly all. Almost one fourth of the patients developed ventricularasystole, and symptoms were induced in another fourth. The wide range of effects emphasizes the importance of this reflex even in normal persons and underscores the need for rigid criteria in the diagnosis of the hypersensitive carotid sinus syndrome.
Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B
Authors: Paquita Nurden, Giuliana Gobbi, Alan Nurden, Jocelyne Enouf, Ibtissam Youlyouz-Marfak, Cecilia Carubbi, Silvia La Marca, Margherita Punzo, Luciano Baronciani, Luigi De Marco, Marco Vitale, Augusto B. Federici
Journal: Blood (2010)
Reaching Out to the Depressed Physician
Authors: Thomas E. Bittker
Journal: JAMA (1976)

Many of the character traits that contribute to physician success can become risk factors for depression when amplified. Only reluctantly do some physicians attend to and express personal needs. The preemptory desire to satisfy the demands of his patients and colleagues may further subvert selfawareness and appropriate self-indulgence. Ultimately, frank depression emerges. Too often, depression remains unrecognized or untreated until the physician's self-destructive pattern compromises his capacity to care for his patients. The author discusses clues to the early recognition of depression as well as strategies in the prevention and treatment of the depressed physician. (<i>JAMA</i>236:1713-1716, 1976)
Production of Common Colds in Human Volunteers by Influenza C Virus
Authors: A. C. C. Joosting, B. Head, M. L. Bynoe, D. A. J. Tyrrell
Journal: BMJ (1968)

Influenza C virus was intranasally administered to volunteers; most were infected and nine developed symptoms of common cold. Increasing titres of serum haemagglutination-inhibiting antibody and complement-fixing antibody were detected. Virus neutralizing activity in nasal secretion was not correlated with either resistance to infection or the occurrence of overt illness. Interferon was detected in the nasal secretions of some subjects.
Antibodies to tissue-type plasminogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in 2 patients
Authors: Massimo Cugno, Mara Cabibbe, Monica Galli, Pier Luigi Meroni, Sonia Caccia, Rosaria Russo, Bianca Bottasso, Pier Mannuccio Mannucci
Journal: Blood (2003)