tbuckley/cabot-search huggingface dataset:
Mitochondrial control of nuclear apoptosis.
Authors: N Zamzami, S A Susin, P Marchetti, T Hirsch, I Gómez-Monterrey, M Castedo, G Kroemer
Journal: The Journal of Experimental Medicine (1996)

Anucleate cells can be induced to undergo programmed cell death (PCD), indicating the existence of a cytoplasmic PCD pathway that functions independently from the nucleus. Cytoplasmic structures including mitochondria have been shown to participate in the control of apoptotic nuclear disintegration. Before cells exhibit common signs of nuclear apoptosis (chromatin condensation and endonuclease-mediated DNA fragmentation), they undergo a reduction of the mitochondrial transmembrane potential (delta psi m) that may be due to the opening of mitochondrial permeability transition (PT) pores. Here, we present direct evidence indicating that mitochondrial PT constitutes a critical early event of the apoptotic process. In a cell-free system combining purified mitochondria and nuclei, mitochondria undergoing PT suffice to induce chromatin condensation and DNA fragmentation. Induction of PT by pharmacological agents augments the apoptosis-inducing potential of mitochondria. In contrast, prevention of PT by pharmacological agents impedes nuclear apoptosis, both in vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing apoptosis, but not those from normal cells, induce disintegration of isolated Hela nuclei. A specific ligand of the mitochondrial adenine nucleotide translocator (ANT), bongkreik acid, inhibits PT and reduces apoptosis induction by mitochondria in a cell-free system. Moreover, it inhibits the induction of apoptosis in intact cells. Several pieces of evidence suggest that the proto-oncogene product Bcl-2 inhibits apoptosis by preventing mitochondrial PT. First, to inhibit nuclear apoptosis, Bcl-2 must be localized in mitochondrial but not nuclear membranes. Second, transfection-enforced hyperexpression of Bcl-2 directly abolishes the induction of mitochondrial PT in response to a protonophore, a pro-oxidant, as well as to the ANT ligand atractyloside, correlating with its apoptosis-inhibitory effect. In conclusion, mitochondrial PT appears to be a critical step of the apoptotic cascade.
The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation.
Authors: G P Browman, M N Levine, E A Mohide, R S Hayward, K I Pritchard, A Gafni, A Laupacis
Journal: Journal of Clinical Oncology (1995)

PURPOSE To develop a conceptual tool for the systematic development of cancer treatment practice guidelines. MATERIALS AND METHODS The guidelines development tool, the Practice Guidelines Development Cycle, was derived from observing an evidence-based practice guidelines initiative at a comprehensive cancer center in Ontario, Canada, and from a literature review that uncovered barriers to guidelines development and implementation. Based on the literature findings and direct observations of how clinicians struggled with evidence-based guidelines development, we evolved a framework to incorporate clinical and administrative factors (eg, costs) into evidence-based guidelines. Use of the Practice Guidelines Development Cycle is illustrated with a clinical example (the use of adjuvant systemic therapy in good-risk, node-negative premenopausal breast cancer patients). RESULTS The result is the Practice Guidelines Development Cycle, which consists of eight sequential steps, from topic selection to policy formulation. Independent validation of guidelines is included. The cycle products are the evidence-based recommendation, the practice guideline, and the practice policy. The main features of the cycle are emphasis on scientific evidence, acknowledgment of the roles of clinical experience and nonclinical (administrative) factors through consensus, and explicit separation of clinical and cost considerations in guidelines development. Twenty guidelines are currently in development. CONCLUSION Attention to the barriers of guidelines development and the sociocultural nature of clinical practice, and respect for clinical experience, can lead to improved strategies for guidelines development.
Metastasis-Associated Protein 1 Short Form Stimulates Wnt1 Pathway in Mammary Epithelial and Cancer Cells
Authors: Rakesh Kumar, Seetharaman Balasenthil, Suresh B. Pakala, Suresh K. Rayala, Aysegul A. Sahin, Kazufumi Ohshiro
Journal: Cancer Research (2010)

Abstract Although Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antigen 1 short form (MTA1s) are elevated in human breast cancer, it remains unknown whether a regulatory cross-talk exists between these two pathways. Here, we provide evidence of a remarkable correlation between the levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabilization of β-catenin and stimulation of Wnt1 target genes in the murine mammary epithelial and human breast cancer cells. We found that MTA1s influences Wnt1 pathway through extracellular signal-regulated kinase (ERK) signaling as selective silencing of the endogenous MTA1s or ERK, or its target glycogen synthase kinase 3β resulted in a substantial decrease in β-catenin expression, leading to the inhibition of Wnt1 target genes. Furthermore, downregulation of β-catenin in cells with elevated MTA1s level was accompanied by a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role for the ERK/glycogen synthase kinase 3β/β-catenin pathway in the stimulation of the Wnt1 target genes by MTA1s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice mimicked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivation of the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of β-catenin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal carcinoma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells. Cancer Res; 70(16); 6598–608. ©2010 AACR.
Effect of Alpha Particle Hypophysectomy on Disseminated Cancer of Male Breast
Authors: John D. Constable
Journal: JAMA (1960)

Although great strides have been made in furthering our understanding of the origin of cancer, the chief forms of therapy continue to be surgery, irradiation, and treatment with hormonal methods. Advances have been made in endocrine therapy, notably by Huggins and others in the control of prostate cancer and male and female breast cancer through endocrine manipulation.<sup>1-5</sup> In the modern era, with the advent of nuclear energy, investigators throughout the world have been on the lookout for new types and sources of irradiation for use in the treatment of patients with cancer. For over 10 years our group has been interested in a special type of radiation generated by the 184-inch cyclotron—particulate radiation, such as protons, deuterons, and alpha particles, accelerated to exceedingly high energies. These radiations have unusual characteristics in their great powers of penetration and their small degree of scatter compared with the conventional x- and gamma-radiation.
Various rheumatic syndromes in adult patients associated with high antistreptolysin O titres and their differential diagnosis with rheumatic fever.
Authors: J M Valtonen, S Koskimies, A Miettinen, V V Valtonen
Journal: Annals of the Rheumatic Diseases (1993)

The purpose of this study was to analyse retrospectively adult patients with acute joint or muscle symptoms and a high antistreptolysin O (ASO) titre to find out which syndromes of clinical arthritis are associated with serological evidence of streptococcal infection.Seventy six adult patients with an acute arthritis syndrome or an exacerbation in their chronic rheumatic disease and simultaneously a high ASO titre (> or = 500 Todd units) were examined in two time periods in the 1980s.Twenty six patients had arthritis associated with a known rheumatic disease, 25 had non-specific arthralgia/myalgia, 20 had reactive arthritis, and five had septic arthritis. No case of classic rheumatic fever classified by two major criteria was found. Six patients fulfilled one major and at least two minor criteria. The frequency of HLA-B27 was significantly higher in the whole patient group than in the healthy Finnish population (30 v 14%).It is concluded that classic rheumatic fever is now rare, even in patients with arthritis with a high ASO titre. These results support the suggestion that beta haemolytic streptococci may trigger reactive arthritis as well as rheumatic fever.
Fluidity, adaptivity, and self-organization
Authors: Elpida S. Tzafestas
Journal: Behavioral and Brain Sciences (2006)

I propose a neuroscience and animat research-inspired model and a thought experiment to test the hypothesis of a developmental relation between fluid and crystallized intelligence. I propose that crystallized intelligence is the result of well-defined activities and structures, whereas fluid intelligence is the physiological catalytic adaptation mechanism responsible for coordinating and regulating the crystallized structures. We can design experiments to reproduce exemplified normal and anomalous phenomena, especially disorders, and study possible cognitive treatments.
Adenovirus tumor-specific transplantation antigen is a function of the E1A early region.
Authors: Y Sawada, D Urbanelli, J Raskova, T E Shenk, K Raska
Journal: The Journal of Experimental Medicine (1986)

Viable recombinant adenoviruses that carry a portion of the type 12 E1A and E1B transcription units in a type 5 background were used to identify genes controlling expression of the adenovirus tumor-specific transplantation antigen (TSTA). The TSTA immunity is not crossreacting between the group A and group C adenovirus serotypes. Viruses carrying the E1A region (sub370-12E1A), or both E1A and E1B (sub370-12E1AB) regions of Ad12, induce a strong transplantation immunity against tumors induced by syngeneic cells transformed with adenovirus 12, but fail to induce any protection against syngeneic cells transformed with adenovirus 2. Immunization with the virus carrying only the E1B region (sub370-12E1B) of adenovirus 12 induces no immunity to adenovirus 12 transformed cell line, but confers a strong protection against cells transformed with adenovirus 2. These results provide strong evidence that the adenovirus tumor-specific transplantation antigen is a function of the E1A early region.
Pasteurella multocida. Infections after domestic animal bites and scratches
Authors: D. P. Francis
Journal: JAMA (1975)

Pasteurella multocida is a common cause of infection followingbites or scratches caused by dogs and cats. However, it is rarely reported and appar-ently often overlooked as a pathogen. It causes the typical clinical manifestationsof a rapidly developing cellulitis at the site of injury. The infection is potentiallydangerous and can cause a chronic local infection of deep tissues and septicemia. However, it responds well to several antimicrobials, with penicillin being the drug ofchoice
Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions
Authors: Weihong Yin, Satish Cheepala, Jennifer N Roberts, Keith Syson-Chan, John DiGiovanni, John L Clifford
Journal: Molecular Cancer (2006)

Abstract Background Squamous cell carcinoma (SCC) of the skin is the most aggressive form of non-melanoma skin cancer (NMSC), and is the single most commonly diagnosed cancer in the U.S., with over one million new cases reported each year. Recent studies have revealed an oncogenic role of activated signal transducer and activator of transcription 3 (Stat3) in many human tumors, especially in those of epithelial origin, including skin SCC. Stat3 is a mediator of numerous growth factor and cytokine signaling pathways, all of which activate it through phosphorylation of tyrosine 705. Results To further address the role of Stat3 in skin SCC tumorigenesis, we have analyzed a panel of human skin-derived cell lines ranging from normal human epidermal keratinocytes (NHEK), to non-tumorigenic transformed skin cells (HaCaT), to highly tumorigenic cells (SRB1-m7 and SRB12-p9) and observed a positive correlation between Stat3 phosphorylation and SCC malignancy. We next determined the role of Stat3 activity in cell proliferation and viability under serum-free culture conditions. This was accomplished by suppressing Stat3 activity in the SRB12-p9 cells through stable expression of a dominant negative acting form of Stat3β, which contains a tyrosine 705 to phenylalanine mutation (S3DN). The S3DN cells behaved similar to parental SRB12-p9 cells when cultured in optimal growth conditions, in the presence of 10% fetal calf serum. However, unlike the SRB12-p9 cells, S3DN cells underwent apoptotic cell death when cultured in serum-free medium (SFM). This was evidenced by multiple criteria, including accumulation of sub-G1 particles, induced PARP cleavage, and acquisition of the characteristic morphological changes associated with apoptosis. Conclusion This study provides direct evidence for a role for Stat3 in maintaining cell survival in the conditions of exogenous growth factor deprivation produced by culture in SFM. We also propose that delivery of the S3DN gene or protein to tumor cells could induce apoptosis and/or sensitize those cells to the apoptotic effects of cancer therapeutic agents, raising the possibility of using S3DN as an adjunct for treatment of skin SCC.
Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors
Authors: P.A. Zucali, M.G. Ruiz, E. Giovannetti, A. Destro, M. Varella-Garcia, K. Floor, G.L. Ceresoli, J.A. Rodriguez, I. Garassino, P. Comoglio, M. Roncalli, A. Santoro, G. Giaccone
Journal: Annals of Oncology (2008)
Getting Knit-PI3Ky: PIK3CA Mutation Status to Direct Multimodality Therapy?
Authors: Andrea P. Myers, Jeffrey A. Meyerhardt, Lewis C. Cantley
Journal: Clinical Cancer Research (2009)

Abstract There is high morbidity associated with local recurrence of rectal cancer. However, the adjuvant therapies given to prevent such recurrences also have significant side effects and associated risks. The ability to select patients with the highest risk of recurrence and greatest therapeutic response will improve rectal cancer care. (Clin Cancer Res 2009;15(22):674850)
T cell receptor V beta gene usage in a human alloreactive response. Shared structural features among HLA-B27-specific T cell clones.
Authors: R Bragado, P Lauzurica, D López, J A López de Castro
Journal: The Journal of Experimental Medicine (1990)

A strategy, based on using V beta family-specific oligonucleotides, was developed for specific amplification and direct sequencing of human TCR V beta genes. With this strategy, it was possible to undertake a structural analysis of TCRs from human T cell clones in specific responses. 12 HLA-B27-specific cytotoxic clones were examined. The results reveal a nonrandom use of V beta gene diversity in this alloreactive response in that: (a) the clones express a restricted number of V beta segments, including a subset of V beta families that are significantly more related to one another than to most other V beta families; (b) five of seven clones having a particular reaction pattern with HLA-B27 subtypes possess Alanine at the D-J junction; and (c) identical J beta segments are found associated in several instances with identical or highly homologous V beta gene segments. In addition, two new V beta 13 members are reported.
Reduced renal medullary water channel expression in puromycin aminonucleoside--induced nephrotic syndrome.
Authors: E Apostol, C A Ecelbarger, J Terris, A D Bradford, P Andrews, M A Knepper
Journal: Journal of the American Society of Nephrology (1997)

The aquaporins are molecular water channels that mediate transcellular water transport across water-permeable epithelia. To investigate the cause of the concentrating defect in the nephrotic syndrome, immunoblotting using membrane fractions from inner medulla was utilized to assess the level of expression of four aquaporin water channels in vehicle-treated versus puromycin aminonucleoside (PAN)-treated rats. Scanning electron microscopy demonstrating loss of glomerular foot processes and measurements of urinary protein excretion confirmed the efficacy of the PAN treatment. In rats receiving PAN, there was an increase in plasma vasopressin, without a change in plasma sodium concentration. Inner medullary tissue hypertonicity was sustained in PAN-treated rats while the urinary osmolality was low, pointing to defective osmotic equilibration across the collecting ducts in PAN-nephrosis. Among collecting duct aquaporins, there was an 87% decrease in aquaporin-2 expression and a 70% decrease in aquaporin-3 expression in the inner medulla, whereas aquaporin-4 expression was unaltered. Transmission electron microscopy of the inner medullary collecting ducts of PAN-treated rats showed normal-appearing cells. Thus, PAN-nephrosis is associated with an extensive downregulation of collecting duct water channel expression despite increased circulating vasopressin, providing an explanation for the concentrating defect associated with the nephrotic syndrome.
Extensive identification and analysis of conserved small ORFs in animals
Authors: Sebastian D. Mackowiak, Henrik Zauber, Chris Bielow, Denise Thiel, Kamila Kutz, Lorenzo Calviello, Guido Mastrobuoni, Nikolaus Rajewsky, Stefan Kempa, Matthias Selbach, Benedikt Obermayer
Journal: Genome biology (2015)

There is increasing evidence that transcripts or transcript regions annotated as non-coding can harbor functional short open reading frames (sORFs). Loss-of-function experiments have identified essential developmental or physiological roles for a few of the encoded peptides (micropeptides), but genome-wide experimental or computational identification of functional sORFs remains challenging. Here, we expand our previously developed method and present results of an integrated computational pipeline for the identification of conserved sORFs in human, mouse, zebrafish, fruit fly, and the nematode C. elegans. Isolating specific conservation signatures indicative of purifying selection on amino acid (rather than nucleotide) sequence, we identify about 2,000 novel small ORFs located in the untranslated regions of canonical mRNAs or on transcripts annotated as non-coding. Predicted sORFs show stronger conservation signatures than those identified in previous studies and are sometimes conserved over large evolutionary distances. The encoded peptides have little homology to known proteins and are enriched in disordered regions and short linear interaction motifs. Published ribosome profiling data indicate translation of more than 100 novel sORFs, and mass spectrometry data provide evidence for more than 70 novel candidates. Taken together, we identify hundreds of previously unknown conserved sORFs in major model organisms. Our computational analyses and integration with experimental data show that these sORFs are expressed, often translated, and sometimes widely conserved, in some cases even between vertebrates and invertebrates. We thus provide an integrated resource of putatively functional micropeptides for functional validation in vivo.
Implementation and outcome of thrombolysis with alteplase 3–4·5 h after an acute stroke: an updated analysis from SITS-ISTR
Authors: Niaz Ahmed, Nils Wahlgren, Martin Grond, Michael Hennerici, Kennedy R Lees, Robert Mikulik, Mark Parsons, Risto O Roine, Danilo Toni, Peter Ringleb
Journal: The Lancet Neurology (2010)
P205 Smoking Prevalence and Smoking Cessation Amongst Acute Medical Admissions
Authors: R Harrison, P Preston, C Bucur, SV Fletcher
Journal: Thorax (2012)

<h3>Introduction and Objectives</h3> In 2009/10 there were 1.5 million hospital admissions in adults aged &gt;35yrs with a smoking related illness. Smoking cessation is a cost effective clinical intervention, producing better health outcomes for patients and saving NHS resources. In 2010/11 total expenditure on ‘NHS Stop Smoking Services’ in England excluding prescriptions was £84.3million. NICE guidelines recommend that every smoker should be offered smoking cessation advice and prescription of nicotine replacement therapy (NRT). The purpose of this study was to identify smoking prevalence in a general medical inpatient population at the time of admission and evaluating the hospital’s provision of smoking cessation advice and NRT prescription. <h3>Methods</h3> Using a cross-sectional study design, contemporaneous data was collected from the Acute Medical Unit (AMU) on 6 separate days. All admitted patients were eligible and interviewed using a standardised questionnaire. Three interviewers agreed a standard approach to questioning. Contemporaneous hospital notes and drug charts were reviewed. Exclusions to the study included cognitive impairment, language, not being present on the ward, being significantly clinically unwell and patient refusal. <h3>Results</h3> Figure 1. 185 patients were reviewed and 23 excluded. 85% of patients had their smoking status clearly documented. Only 30% of smokers were provided with cessation advice and 7% were referred to Quitters. 69.5% of smokers did not have NRT prescribed but only 19.5% not wish to receive NRT. <h3>Conclusions</h3> The medical impatient population has a higher prevalence of smokers (28%) when compared to the national average of 21%. Our results for smoking cessation service provision compare poorly with NICE guidelines which target 100% of smokers receiving smoking cessation guidance. Awareness needs to be raised amongst the medical staff in order to optimise the provision of advice, referral to quitters and NRT prescription rate in order to achieve the targets set by NICE and the DOH. We are currently embarking upon a series of educational sessions and a ward round ‘checklist’ is under development which will include a prompt for smoking cessation.
ADAPTIVE ROLES OF PROGRAMMED CELL DEATH DURING NERVOUS SYSTEM DEVELOPMENT
Authors: Robert R. Buss, Woong Sun, Ronald W. Oppenheim
Journal: Annual Review of Neuroscience (2006)

The programmed cell death (PCD) of developing cells is considered an essential adaptive process that evolved to serve diverse roles. We review the putative adaptive functions of PCD in the animal kingdom with a major focus on PCD in the developing nervous system. Considerable evidence is consistent with the role of PCD in events ranging from neurulation and synaptogenesis to the elimination of adult-generated CNS cells. The remarkable recent progress in our understanding of the genetic regulation of PCD has made it possible to perturb (inhibit) PCD and determine the possible repercussions for nervous system development and function. Although still in their infancy, these studies have so far revealed few striking behavioral or functional phenotypes.
THE NOVEL TECHNIQUE TO EVALUATE THE AREA OF FAT PAD ABLATED DURING ATRIAL FIBRILLATION ABLATION: THE APPROACH USING LATE GADOLINIUM ENHANCEMENT MRI
Authors: Koji Higuchi, Mehmet AkkayA, Josh Blauer, Damal Kavitha, Chankevin Tek, Nathan Burgon, Eugene Kholmovski, Rob MacLeod, Nassir Marrouche
Journal: Journal of the American College of Cardiology (2012)
HIV Treatment as Prevention: Debate and Commentary—Will Early Infection Compromise Treatment-as-Prevention Strategies?
Authors: Myron S. Cohen, Christopher Dye, Christophe Fraser, William C. Miller, Kimberly A. Powers, Brian G. Williams
Journal: PLoS Medicine (2012)

Universal HIV testing and immediate antiretroviral therapy for infected individuals has been proposed as a way of reducing the transmission of HIV and thereby bringing the HIV epidemic under control. It is unclear whether transmission during early HIV infection—before individuals are likely to have been diagnosed with HIV and started on antiretroviral therapy—will compromise the effectiveness of treatment as prevention. This article presents two opposing viewpoints by Powers, Miller, and Cohen, and Williams and Dye, followed by a commentary by Fraser.