tbuckley/cabot-search huggingface dataset:
Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion.
Authors: C Noviello, F Courjal, C Theillet
Journal: Clinical Cancer Research (1996)

Deletions and rearrangements involving chromosome 6q have been reported in a number of human cancers such as ovarian and breast tumors as well as melanoma and hemopoietic malignancies. To gain insight into the regions undergoing deletions on the long arm of chromosome 6, we performed a survey of loss of heterozygosity (LOH) at 11 CA repeat markers, mapping from 6q13 to 6q27 in 83 matched sets of tumor and blood DNAs from breast tumor patients. LOH was observed at all tested markers with frequencies ranging from 11.4 to 39.8% of the informative cases, whereas D2S123, a marker linked to the HMSH2 gene mapping in a region rarely presenting allele losses, showed 3.2%. LOH patterns were often complex, with a number of tumors presenting multiple interstitial losses, thus indicating that chromosome 6q can be severely rearranged in breast cancer. Patterns of losses and correlation between LOH occurring at adjacent markers suggested the existence of three (possibly four) distinct regions of allele losses. These were defined by: D6S251-D6S434 (6q13), D6S292-D6S310-D6S314-D6S311 (6q24-q25), and D6S441-D6S281 (6q27). The fourth and more hypothetical region was in the 6q21 region and defined by D6S287-D6S407. Interestingly, the region at 6q24-q25 defined by D6S292-D6S310-D6S314-D6S311 was predominantly observed in evolved and aggressive breast tumors. LOH at D6S314 was correlated with PR- tumors. All together, our data suggest the possible presence of several genes on 6q whose alteration may play a role in breast cancer formation and development.
Fact or fiction - identifying the elusive multiple myeloma stem cell
Authors: Joshua Kellner, Bei Liu, Yubin Kang, Zihai Li
Journal: Journal of Hematology & Oncology (2013)

Multiple Myeloma (MM) is a debilitating disease of proliferating and malignant plasma cells that is currently incurable. The ability of monoclonal recurrence of disease suggests it might arise from a stem cell-like population capable of self-renewal. The difficulty to isolate the cancer stem-like cell in MM has introduced confusion toward this hypothesis. However, recent evidence has suggested that MM originates from the B cell lineage with memory-B cell like features, allowing for self-renewal of the progenitor-like status and differentiation to a monoclonal plasma cell population. Furthermore, this tumor-initiating cell uses signaling pathways and microenvironment similar to the hematopoietic stem cell, though hijacking these mechanisms to create and favor a more tumorigenic environment. The bone marrow niche allows for pertinent evasion, either through avoiding immunosurveillance or through direct interaction with the stroma, inducing quiescence and thus drug resistance. Understanding the interaction of the MM stem cell to the microenvironment and the mechanisms utilized by various stem cell-like populations to allow persistence and therapy-resistance can enable for better targeting of this cell population and potential eradication of the disease.
Acute Ischemic Stroke: Overview of Recent Therapeutic Developments
Authors: Nijasri Suwanwela, Walter J. Koroshetz
Journal: Annual Review of Medicine (2007)

Stroke, a disorder encompassing all cerebrovascular accidents, is a public health problem of immense proportions across the globe. Therapeutic efforts are directed at three aspects: prevention, acute treatment, and rehabilitation. Preventative measures, which in many instances mirror those for cardiovascular disease, can achieve the greatest public health impact. Measures that enhance the recovery of neurologic function and reduce neurologic disability after stroke can also affect a large population of handicapped stroke survivors. In the past 10 years, the greatest changes have occurred in the field of acute stroke treatment. Ultra-early-stage therapies with the potential to dramatically reverse severe neurologic deficits, or halt their progression, have caused a restructuring of the emergency care of neurologic patients. The parallels with the evolution of emergency treatment of acute coronary syndromes after 1970 are striking. This review focuses on aspects of stroke therapy that are either just entering, or soon to enter, current practice.
Abstract 4802: Cat eye syndrome chromosome region, candidate 1 (CECR1) is overexpressed and hypomethylated in salivary gland adenoid cystic carcinoma
Authors: Chunbo Shao, Marietta Tan, Chad A. Glazer, Sheetal Bhan, Xiaofei Chang, Mamoru Uemura, Myoung S. Kim, Christopher Moskaluk, David Sidransky, Joseph A. Califano, Patrick K. Ha
Journal: Cancer Research (2011)

Abstract BACKGROUND and PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. It is characterized by a heterogeneous morphology, perineural invasion, and a variable clinical course. The molecular mechanisms underlying ACC are still unknown. We previously developed a high-throughput integrative epigenomic screening method to discover novel proto-oncogene candidates in ACC. With this screening method, we found that cat eye syndrome chromosome region, candidate 1 (CECR1) was a promising oncogene candidate for ACC. CECR1 encodes a member of a subfamily of the adenosine deaminase protein family and acts as a growth factor through its adenosine deaminase activity. No previous studies have correlated CECR1 in human cancers. In the current study, we validated several features of CECR1 in primary ACC samples, including promoter methylation status and expression levels. METHODS and RESULTS: Bisulfite genomic sequencing was first employed to analyze the DNA methylation levels in the promoter of CECR1 in four ACC samples and four normal salivary gland tissues. Decreased methylation in CECR1 was found in three out of four ACC samples compared to zero out of four normal tissues. Secondly, quantitative methylation specific PCR (qMSP) was performed in a larger ACC cohort including 15 ACCs and 18 normal tissues. Consistent with the bisulfite genomic sequencing results, significant demethylation of CECR1 was detected in ACC samples (methylation levels ranged from 0.1 to 300.1; median, 19.8) compared to normal tissues (range from 10.2 to 600.0; median, 235.6), p &amp;lt; 0.05. Thirdly, we induced global demethylation in an ACC cell line, ACC83, by 5-aza-2′-deoxycytidine/ trichostatin A (5 Aza dC/TSA) treatment. Quantitative reverse transcription PCR (qRT-PCR) showed that CECR1 was significantly re-expressed in 5 Aza dC/TSA treated cell lines. Lastly, we analyzed the expression levels of CECR1 by qRT-PCR in the same ACC cohort. We found significant overexpression of CECR1 in ACCs compared to normal salivary tissue, p &amp;lt; 0.05. CONCLUSIONS: This is the first study to associate elevated CECR1 levels with salivary gland ACC. The transcription of CECR1 appears to be upregulated by promoter demethylation. Both overexpression and promoter hypomethylation of CECR1 are hallmarks of ACC. CECR1 might play an important role in salivary gland ACC. FUTURE DIRECTIONS: Functional studies of CECR1's role(s) in the carcinogenesis of salivary gland ACC are underway. 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 4802. doi:10.1158/1538-7445.AM2011-4802
Differences in bronchoalveolar cell response to nitrogen dioxide exposure between smokers and nonsmokers
Authors: R Helleday, T Sandstrom, N Stjernberg
Journal: European Respiratory Journal (1994)

We have previously reported on the bronchoalveolar inflammatory effects of the common air pollutant NO2 in nonsmokers. In this study, we have investigated these effects in tobacco smokers. Eight young nonbronchitic smokers and, as a reference group, eight healthy life-time nonsmokers were exposed to 3.5 ppm NO2 for 20 min. Bronchoalveolar lavage (BAL) was performed 3 weeks before and 24 h after exposure. The first recovered 20 ml was analysed separately and defined as the bronchial portion (BP), and the following fluid recovered as the bronchoalveolar portion (BAP). Before exposure, the smokers had significantly less CD3+ cells and more alveolar macrophages (AMs) in the BP and the BAP, as well as reduced AM phagocytosis in vitro compared to nonsmokers. After NO2 exposure, the smokers reacted with an increase of AMs and neutrophils in BAP. Nonsmokers reacted with an increase of neutrophils in BP, an increase of lymphocytes in BAP, and a tendency to reduced AM phagocytosis. In summary, young smokers and nonsmokers differed to some extent in their reactions to NO2 exposure. This is probably due to the pre-existing airway inflammation and compensatory mechanisms to oxidant stress in the smokers.
Fibroblast expression of collagen integrin receptors α1β1 and α2β1 is not changed in systemic scleroderma
Authors: None Herzhoff, None Sollberg, None Huerkamp, None Krieg, None Eckes
Journal: British Journal of Dermatology (1999)

The skin of patients with systemic scleroderma (SSc) is characterized by excessive extracellular matrix deposition in the dermis. As collagens represent the major structural component, we used fluorescence‐activated cell sorter analysis to study the levels of collagen receptors expressed at the surface of fibroblasts derived from involved skin areas. In contrast to previous reports, no differences in the expression of α1, α2 or β1 integrin subunits, which constitute the major collagen receptors on fibroblasts, were detected on SSc fibroblasts as compared with normal control fibroblasts. Variation of cell culture conditions, e.g. passage number (from 2 to 10), seeding density, cell cycle or serum concentration, did not change this result. These observations indicate that any abnormal response of SSc fibroblasts to their matrix environment is not controlled at the level of receptor expression.
The activating receptor NKp46 is essential for the development of type 1 diabetes
Authors: Chamutal Gur, Angel Porgador, Moran Elboim, Roi Gazit, Saar Mizrahi, Noam Stern-Ginossar, Hagit Achdout, Hormas Ghadially, Yuval Dor, Tomer Nir, Victoria Doviner, Oren Hershkovitz, Michal Mendelson, Yaakov Naparstek, Ofer Mandelboim
Journal: Nature Immunology (2009)
Antitumour necrosis factor-α therapy modulates angiopoietin-2 serum levels in non-diabetic ankylosing spondylitis patients
Authors: Fernanda Genre, José A Miranda-Filloy, Raquel López-Mejias, Beatriz Carnero-López, Rodrigo Ochoa, Javier Rueda, Carlos González-Juanatey, Ricardo Blanco, Javier Llorca, Miguel A González-Gay
Journal: Annals of the Rheumatic Diseases (2013)

Human Performance is an integrated risk management approach to improving systems, that includes human factors and systems safety, that leads to higher reliability and enhanced operational resilience. A clear picture of what Human Performance looks like in biopharma is available from the BioPhorum Operations Group (BPOG), where members of the Human Performance workstream have defined a blue-sky for the industry. This blue-sky document is both a guide and an assessment tool that will help to identify the steps to effective human performance integration with operations. The effort to improve reliable operations within biopharma using elements of human performance borrowed from other industries has experienced uneven results and slow progress across the last seven years and has been bogged down for multiple significant reasons. These include a mental model that persists within the industry where workers are assumed to be the problem that needs fixing, the mistaken belief that Lean practices (intended to improve productivity &amp; efficiency) is a cure-all and nearly equivalent to human performance, neglecting the need to fundamentally rethink why and how investigations are performed, and truly underestimating the time, effort, strength of sponsor support needed to change how work is designed, executed, and then later learned from.
Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
Authors: Oriol Morales-Ibanez, Silvia Affò, Daniel Rodrigo-Torres, Delia Blaya, Cristina Millán, Mar Coll, Luis Perea, Gemma Odena, Thomas Knorpp, Markus F Templin, Montserrat Moreno, José Altamirano, Rosa Miquel, Vicente Arroyo, Pere Ginès, Juan Caballería, Pau Sancho-Bru, Ramon Bataller
Journal: Gut (2015)

Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets.Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches.Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling.p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.
Transcription factors and asthma
Authors: PJ Barnes, IM Adcock
Journal: European Respiratory Journal (1998)

Asthma is characterized by the expression of multiple genes for inflammatory proteins, such as cytokines, enzymes, receptors and adhesion molecules. This is orchestrated by transcription factors, which are proteins that bind to the promoter regions of these genes and may be activated by inflammatory stimuli, such as cytokines. Several transcription factors are involved in asthmatic inflammation, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), nuclear factor of activated T-cells (NF-AT), cyclic AMP response element binding protein (CREB) and signal transduction-activated transcription factors (STAT). These transcription factors lead to coordinated expression of multiple inflammatory genes. There is increasing evidence that synergistic interaction of these transcription factors (e.g. NF-kappaB and AP-1) results in the optimal expression of particular genes, resulting in the specific inflammatory pattern seen in asthmatic airways. Transcription factors are a target for antiasthma therapy. Corticosteroids activate glucocorticoid receptors, which themselves are transcription factors, and interact with other transcription factors to inhibit their actions. The interaction between transcription factors may be important in amplifying and inhibiting the inflammatory process. Many transcription factors interact with a large co-activator molecule CREB-binding protein (CBP) that coordinates the activation of several transcription factors and controls transcription through the regulation of deoxyribonucleic acid coiling around histone residues in the chromatin structure. Understanding transcription factors in asthma has given new insights into the complex chronic inflammatory process, the mechanism of action of corticosteroids, and may lead to new approaches to therapy in the future.
Low-Stage Ovarian Clear Cell Carcinoma: Population-Based Outcomes in British Columbia, Canada, With Evidence for a Survival Benefit As a Result of Irradiation
Authors: Paul J. Hoskins, Nhu Le, Blake Gilks, Anna Tinker, Jennifer Santos, Frances Wong, Kenneth D. Swenerton
Journal: Journal of Clinical Oncology (2012)

To evaluate the population-based outcomes of stage I and II ovarian clear cell carcinoma (OCCC) in a North American population treated with carboplatin/paclitaxel and abdominopelvic irradiation.Retrospective analysis was performed of 241 patients referred in the carboplatin/paclitaxel era. Irradiation was to be used with a few defined exceptions. However, because of differing beliefs as to its effectiveness, its use was consistently avoided by specific oncologists, allowing the opportunity to study its possible effect on disease-free survival (DFS) in these concurrent cohorts.Five- and 10-year DFS rates were 84% and 70% for stage IA/B; 67% and 57% for stage IC; and 49% and 44% for stage II, respectively. Five- and 10-year DFS rates for those with stage IC disease based purely on rupture were similar to rates for patients with stage IA/B, at 92% and 71%, respectively. The remaining patients with stage IC had 48% 5- and 10-year DFS. Multivariate analysis using a decision tree identified positive cytology as the most important factor (72% relapse rate if positive and 27% if negative or unknown). If, in addition, the capsule surface was involved, then the relapse rate was 93%. Irradiation had no discernible survival benefit for patients with stage IA and IC (rupture alone), whereas for the remainder of patients with stage IC and stage II, it improved DFS by 20% at 5 years (relative risk, 0.5); the benefit was most evident in the cytologically negative/unknown group.DFS is similar in this North American population with early OCCC to the DFS reported in Asia. A potential benefit from irradiation was evident in a subset.
Organ donation from intensive care units in England.
Authors: S. M. Gore, C. J. Hinds, A. J. Rutherford
Journal: BMJ (1989)

OBJECTIVE--To audit all deaths in intensive care units (excepting coronary care only and neonatal intensive care units) in England to assess potential for organ procurement. DESIGN--An audit in which 14 regional health authorities and London special health authorities each designated a regional liaison officer to identify intensive care units and liaise with Department of Health and the Medical Research Council9s biostatistics unit in distribution, return, and checking of audit forms. Audit took place from 1 January to 31 March 1989 and will continue to 31 December 1990. SETTING--278 Intensive care units in England. PARTICIPANTS--Colleagues in intensive care units (doctors, nurses, coordinators, and others), who completed serially numbered audit forms for all patients who died in intensive care. RESULTS--The estimated number of deaths in intensive care units was 3085, and validated audit forms were received for 2853 deaths (92%). Brain stem death was a possible diagnosis in only 407 (14%) patients (about 1700 cases a year) and was confirmed in 282 (10%) patients (an estimated 1200 cases a year). Half the patients (95% confidence interval 45% to 57%) in whom brain stem death was confirmed became actual donors of solid organs. Tests for brain stem death were not performed in 106 (26%) of 407 patients with brain stem death as a possible diagnosis, and general medical contraindication to organ donation was recorded for 48 (17%) of 282 patients who fulfilled brain stem death criteria before cessation of heart beat. The criteria were fulfilled before cessation of heart beat and in the absence of any general medical contraindication to organ donation in 234 patients, 8% of those dying in intensive care (an estimated 1000 cases a year). Consent for organ donation was given in 152 (70%) of 218 cases (64% to 76%) when the possibility of organ donation was suggested to relatives. In only 14 out of 232 families (6%; 3% to 9%) was there no discussion of organ donation with relatives. Corneal suitability was recorded as "not known" in a high proportion (1271; 45%) of all deaths and intensive care units reported only 123 corneal donors (4% of all audited deaths). CONCLUSION--When brain stem death is a possible diagnosis tests should always be carried out for confirmation. Early referral to the transplant team or coordinator should occur in all cases of brain stem death to check contraindications to organ donation. There should be increased use of asystolic kidney donation, and patients should be routinely assessed for suitability for corneal donation. Finally, more publicity and education are necessary to promote consent.
Resistance to the Tubulin-Binding Agents in Renal Cell Carcinoma: No Mutations in the Class I <i>β-Tubulin</i> Gene but Changes in Tubulin Isotype Protein Expression
Authors: Roisean E. Ferguson, Claire Taylor, Anthea Stanley, Elizabeth Butler, Adrian Joyce, Patricia Harnden, Poulam M. Patel, Peter J. Selby, Rosamonde E. Banks
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The primary purpose of this study was to determine whether mutations of the class I β-tubulin gene may be implicated in the inherent resistance to tubulin-binding agents (TBA) in renal cancer, with a small number of samples and cell lines also being examined for class I and III β-tubulin isotype protein expression. Experimental Design: DNA was extracted from 90 renal tumors and the class I β-tubulin gene analyzed for mutations. For each sample, eight PCRs were used to cover the complete coding sequence with intronic primers ensuring highly homologous pseudogenes were not coamplified. Additionally, expression levels of class I and III β-tubulin isotypes in 17 matched normal and malignant renal samples and a panel of renal cell carcinoma cell lines with differing intrinsic resistance to the TBAs was examined by Western blotting. Results: Four polymorphic sequence changes of the class I β-tubulin gene were identified with no mutations. Class I protein expression levels were higher in tumor tissue versus normal tissue, whereas class III expression showed no consistent change. In renal cancer cell lines, a significant correlation between class III isotype expression and vinblastine sensitivity was observed. Conclusions: These results do not support a role for mutations in the class I β-tubulin gene in the intrinsic resistance of renal cancer to TBAs. Class III isotype expression may be implicated in resistance in vitro but in vivo, changes in class I isotype expression in renal cell carcinoma tissue may support a role in resistance to the TBAs and warrants further investigation.