tbuckley/cabot-search huggingface dataset:
Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells
Authors: Richard Marcotte, Kevin R. Brown, Fernando Suarez, Azin Sayad, Konstantina Karamboulas, Paul M. Krzyzanowski, Fabrice Sircoulomb, Mauricio Medrano, Yaroslav Fedyshyn, Judice L.Y. Koh, Dewald van Dyk, Bohdana Fedyshyn, Marianna Luhova, Glauber C. Brito, Franco J. Vizeacoumar, Frederick S. Vizeacoumar, Alessandro Datti, Dahlia Kasimer, Alla Buzina, Patricia Mero, Christine Misquitta, Josee Normand, Maliha Haider, Troy Ketela, Jeffrey L. Wrana, Robert Rottapel, Benjamin G. Neel, Jason Moffat
Journal: Cancer Discovery (2011)

Genomic analyses are yielding a host of new information on the multiple genetic abnormalities associated with specific types of cancer. A comprehensive description of cancer-associated genetic abnormalities can improve our ability to classify tumors into clinically relevant subgroups and, on occasion, identify mutant genes that drive the cancer phenotype ("drivers"). More often, though, the functional significance of cancer-associated mutations is difficult to discern. Genome-wide pooled short hairpin RNA (shRNA) screens enable global identification of the genes essential for cancer cell survival and proliferation, providing a "functional genomic" map of human cancer to complement genomic studies. Using a lentiviral shRNA library targeting ~16,000 genes and a newly developed, dynamic scoring approach, we identified essential gene profiles in 72 breast, pancreatic, and ovarian cancer cell lines. Integrating our results with current and future genomic data should facilitate the systematic identification of drivers, unanticipated synthetic lethal relationships, and functional vulnerabilities of these tumor types.This study presents a resource of genome-scale, pooled shRNA screens for 72 breast, pancreatic, and ovarian cancer cell lines that will serve as a functional complement to genomics data, facilitate construction of essential gene profiles, help uncover synthetic lethal relationships, and identify uncharacterized genetic vulnerabilities in these tumor types.This study presents a resource of genome-scale, pooled shRNA screens for 72 breast, pancreatic, and ovarian cancer cell lines that will serve as a functional complement to genomics data, facilitate construction of essential gene profiles, help uncover synthetic lethal relationships, and identify uncharacterized genetic vulnerabilities in these tumor types.
Leri’s pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing<i>GDF6</i>and<i>SDC2</i>and provides insight into systemic sclerosis pathogenesis
Authors: Siddharth Banka, Stuart A Cain, Sabrya Carim, Sarah B Daly, Jill E Urquhart, Günhan Erdem, Jade Harris, Michelle Bottomley, Dian Donnai, Bronwyn Kerr, Helen Kingston, Andreas Superti-Furga, Sheila Unger, Holly Ennis, Jane Worthington, Ariane L Herrick, Catherine L R Merry, Wyatt W Yue, Cay M Kielty, William G Newman
Journal: Annals of the Rheumatic Diseases (2014)

Objectives Leri’s pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. Methods and results Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2 , within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p&lt;1×10 −5 ). Conclusions Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing ‘TGF-β-pathies’ group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill–Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.
Type VIII Collagen Modulates TGF-β1-induced Proliferation of Mesangial Cells
Authors: Ivonne Loeffler, Ulrike Hopfer, Dirk Koczan, Gunter Wolf
Journal: Journal of the American Society of Nephrology (2011)

Mesangial cells in diabetic mice and human kidneys with diabetic nephropathy exhibit increased type VIII collagen, a nonfibrillar protein that exists as a heterodimer composed of α1(VIII) and α2(VIII), encoded by Col8a1 and Col8a2, respectively. Because TGF-β1 promotes the development of diabetic glomerulosclerosis, we studied whether type VIII collagen modulates the effects of TGF-β1 in mesangial cells. We obtained primary cultures of mesangial cells from wild-type, doubly heterozygous (Col8a1(+/-)/Col8a2(+/-)), and double-knockout (Col8a1(-/-)/Col8a2(-/-)) mice. TGF-β1 bound normally to double-knockout mesangial cells. In wild-type mesangial cells, TGF-β1 inhibited proliferation, but in double-knockout cells, it stimulated proliferation, promoted cell cycle progression, and reduced apoptosis; we could reverse this effect by reconstituting α1(VIII). Furthermore, in wild-type cells, TGF-β1 mainly stimulated the Smad pathways, whereas in double-knockout cells, it activated the MAPK and PI3K/Akt pathways and induced expression of fibroblast growth factor 21 (FGF21). Inhibiting FGF21 expression by either interfering with activation of the MAPK and PI3K/Akt pathways or by FGF21 siRNA attenuated the TGF-β1-induced proliferation of double-knockout mesangial cells. In vivo, diabetic double-knockout mice had significantly higher expression of renal FGF21 mRNA and protein compared with diabetic wild-type mice. Immunohistochemistry revealed strong expression of FGF21 in both glomerular (mesangial) and tubular cells of diabetic mice. Taken together, these data suggest that type VIII collagen significantly modulates the effect of TGF-β1 on mesangial cells and may therefore play a role in the pathogenesis of diabetic nephropathy.
Adult Mortality in a Randomized Trial of Mass Azithromycin for Trachoma
Authors: Jeremy D. Keenan, Paul M. Emerson, Bruce D. Gaynor, Travis C. Porco, Thomas M. Lietman
Journal: JAMA Internal Medicine (2013)

Annual mass azithromycin treatments are provided to entire communities to clear the ocular strains of Chlamydia trachomatis that cause blinding trachoma.Mass treatments reduce the community burden of ocular chlamydia and have proven efficacious in communityrandomized trials. 1 Since 1999, more than 150 million doses of azithromycin have been distributed for trachoma worldwide. 2Mass azithromycin distributions are directed at clearing ocular chlamydia but may have other effects.For example, in the Trachoma Amelioration in Northern Amhara (TANA) trial, we found that mass azithromycin distributions reduced childhood mortality. 3In contrast, a recent observational study suggested that azithromycin use may cause sudden death in adults. 4This finding could have major implications for trachoma elimination efforts.In our previous report, an intention-to-treat analysis found no evidence of increased mortality among individuals older than 9 years. 3However, in light of the recent observational study, we thought it worthwhile to reassess our data to determine the mortality rates and causes of death in an older subgroup of individuals and to compare mortality in individuals who received azithromycin with that in those who did not. Methods
Problematic severe asthma in children, not one problem but many: a GA2LEN initiative
Authors: G. Hedlin, A. Bush, K. Lødrup Carlsen, G. Wennergren, F.M. De Benedictis, E. Melén, J. Paton, N. Wilson, K.-H. Carlsen
Journal: European Respiratory Journal (2010)

Although most children with asthma are easy to treat with low doses of safe medications, many remain symptomatic despite every therapeutic effort. The nomenclature regarding this group is confusing, and studies are difficult to compare due to the proliferation of terms describing poorly defined clinical entities. In this review of severe asthma in children, the term problematic severe asthma is used to describe children with any combination of chronic symptoms, acute severe exacerbations and persistent airflow limitation despite the prescription of multiple therapies. The approach to problematic severe asthma may vary with the age of the child, but, in general, three steps need to be taken in order to separate difficult-to-treat from severe therapy-resistant asthma. First, confirmation that the problem is really due to asthma requires a complete diagnostic re-evaluation. Secondly, the paediatrician needs to systematically exclude comorbidity, as well as personal or family psychosocial disorders. The third step is to re-evaluate medication adherence, inhaler technique and the child’s environment. There is a clear need for a common international approach, since there is currently no uniform agreement regarding how best to approach children with problematic severe asthma. An essential first step is proper attention to basic care.
Phase II Trial of Combination Therapy With Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone in Patients With Newly Diagnosed Myeloma
Authors: Andrzej J. Jakubowiak, Tara Kendall, Ammar Al-Zoubi, Yasser Khaled, Shin Mineishi, Asra Ahmed, Erica Campagnaro, Christine Brozo, Thomas Braun, Moshe Talpaz, Mark S. Kaminski
Journal: Journal of Clinical Oncology (2009)

Purpose This single-center, open-label, phase II trial evaluated the bortezomib, pegylated liposomal doxorubicin (PLD), and dexamethasone combination regimen (VDD) as initial treatment for patients with newly diagnosed multiple myeloma (MM). Patients and Methods Enrolled patients (N = 40) received up to six 3-week cycles of treatment with bortezomib 1.3 mg/m 2 intravenously (IV) on days 1, 4, 8, and 11; PLD 30 mg/m 2 IV on day 4; and dexamethasone 20 to 40 mg daily as specified in the study design. The primary end point was the complete/near-complete response (CR/nCR) rate after six cycles. Secondary end points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The impact of VDD on stem-cell mobilization and collection also was evaluated. Results After six cycles, the ORR was 85.0% (CR/nCR, 37.5%; very good partial response [VGPR] or better, 57.5%). Patients who underwent stem-cell transplantation (SCT) after VDD (n = 30) experienced increased rates of VGPR or better (53.3% to 76.6% after SCT). Overall, 1-year PFS and OS rates were 92.5% and 97.5%, respectively. Those who achieved VGPR or better after treatment with VDD showed a significantly greater 1-year PFS versus those who achieved less than VGPR (100% v 82%, respectively; P = .03). Similar results were observed in patients who underwent SCT. Grades 3 or 4 hematologic toxicities occurred in ≤ 10% of patients; grade 2 painful neuropathy occurred in 7.5%; and grade 3 palmar-plantar erythrodysesthesia occurred in 2.5%. Conclusion VDD is highly effective for initial treatment of MM followed by SCT in appropriate patients, and it has a reasonable safety profile. Achievement of VGPR or better with this initial therapy predicted longer PFS, regardless of the consolidation therapy given.
SMIM1 underlies the Vel blood group and influences red blood cell traits
Authors: Ana Cvejic, Lonneke Haer-Wigman, Jonathan C Stephens, Myrto Kostadima, Peter A Smethurst, Mattia Frontini, Emile van den Akker, Paul Bertone, Ewa Bielczyk-Maczyńska, Samantha Farrow, Rudolf S N Fehrmann, Alan Gray, Masja de Haas, Vincent G Haver, Gregory Jordan, Juha Karjalainen, Hindrik H D Kerstens, Graham Kiddle, Heather Lloyd-Jones, Malcolm Needs, Joyce Poole, Aicha Ait Soussan, Augusto Rendon, Klaus Rieneck, Jennifer G Sambrook, Hein Schepers, Herman H W Silljé, Botond Sipos, Dorine Swinkels, Asif U Tamuri, Niek Verweij, Nicholas A Watkins, Harm-Jan Westra, Derek Stemple, Lude Franke, Nicole Soranzo, Hendrik G Stunnenberg, Nick Goldman, Pim van der Harst, C Ellen van der Schoot, Willem H Ouwehand, Cornelis A Albers
Journal: Nature Genetics (2013)
Survival and Years of Life Lost in Different Age Cohorts of Patients With Multiple Myeloma
Authors: Heinz Ludwig, Vanessa Bolejack, John Crowley, Joan Bladé, Jesus San Miguel, Robert A. Kyle, S. Vincent Rajkumar, Kazuyuki Shimizu, Ingemar Turesson, Jan Westin, Pieter Sonneveld, Michele Cavo, Mario Boccadoro, Antonio Palumbo, Patrizia Tosi, Jean-Luc Harousseau, Michel Attal, Bart Barlogie, A. Keith Stewart, Brian Durie
Journal: Journal of Clinical Oncology (2010)

To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma.Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation.Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients > or = age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P < .001 for age 50 to 59 v age 40 to 49, P < .001 for age 60 to 69 v age 50 to 59, P < .001 for age 70 to 79 v age 60 to 69, and P = .009 for age > or = 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients > or = age 80 years.Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age > or = 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger than 40 years old but decreases to less than 5 years in patients age 80 years or older.
Apoptosis in Toremifene-Induced Growth Inhibition of Human Breast Cancer Cells In Vivo and In Vitro
Authors: A. M. Warri, R. L. Huovinen, A. M. Laine, P. M. Martikainen, P. L. Harkonen
Journal: JNCI Journal of the National Cancer Institute (1993)

Antiestrogens inhibit the stimulative effects of estrogens on breast cancer growth, but the mechanism(s) by which they trigger tumor regression are not completely understood. Growth retardation and tumor regression can be achieved by enhanced cell death and/or arrested cell proliferation. Our aim was to investigate the effect of a new antiestrogen, toremifene, on human breast cancer cells grown either in culture or as tumors in nude mice. The growth and morphology of in vitro cultured cells of the human breast cancer cell line MCF-7 were monitored by time-lapse video. MCF-7 cells and ZR-75-1 human breast cancer cells were grown as tumors in nude mice and subsequently examined by electron microscopy. The integrity of DNA isolated from these cells was determined by standard gel electrophoretic techniques. Northern blot hybridization analysis was used to determine the steady-state levels of the mRNAs for testosterone-repressed prostatic message-2 (TRPM-2), tumor growth factor beta-1 (TGFβ1), and pS2 (a small, cysteine-rich protein of unknown function). Time-lapse video microscopy of the cell cultures indicated that treatment with 7.5 μM toremifene for 3 days caused approximately 60% of the cells to exhibit morphologic characteristics typical of cells undergoing programmed death, or apoptosis. The number of mitoses gradually decreased to zero over a 3-to 4-day period. Estrogen withdrawal for the same length of time resulted in an approximately equal number of apoptoses and mitoses. These changes were not associated with the pattern of DNA fragmentation, detectable as ladders in agarose gels, that is characteristic of the DNA of cells undergoing apoptosis. Elevated levels of TRPM-2 and TGFβ1 mRNAs were observed in in vitro or in vivo grown tumor cells treated with 5-10 μM toremifene. Elevated levels of TRPM-2, but not TGFβ1, mRNA were observed in the tumor cells after estrogen withdrawal. The steady-state level of pS2 mRNA in the tumor cells dropped in response to either toremifene treatment or estrogen withdrawal. Toremifene causes growth inhibition of estrogen-sensitive breast cancer cells by inducing some cells to undergo apoptosis and by inhibiting other cells from entering mitosis. The higher than normal amounts of TRPM-2 and TGFβ1 protein that would likely result from the elevated levels of TRPM-2 and TGFβ1 mRNAs measured in these cells after toremifene treatment may have an important role in the growth inhibition process. Apoptosis as an active, targeted process provides a potential new therapeutic approach for treating breast cancer. [J Natl Cancer Inst 85: 1412–1418, 1993]
Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-β Signaling Pathway
Authors: Aaron B. Baker, David S. Ettenson, Michael Jonas, Matthew A. Nugent, Renato V. Iozzo, Elazer R. Edelman
Journal: Circulation Research (2008)

Mechanical forces are potent modulators of the growth and hypertrophy of vascular cells. We examined the molecular mechanisms through which mechanical force and hypertension modulate endothelial cell regulation of vascular homeostasis. Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells. Mechanical strain stimulated the production of perlecan and heparan sulfate glycosaminoglycans by endothelial cells. By inhibiting the expression of perlecan with an antisense vector we demonstrated that perlecan was essential to the strain-mediated effects on endothelial cell growth control. Mechanical regulation of perlecan expression in endothelial cells was governed by a mechanotransduction pathway requiring autocrine transforming growth factor beta (TGF-beta) signaling and intracellular signaling through the ERK pathway. Immunohistochemical staining of the aortae of spontaneously hypertensive rats demonstrated strong correlations between endothelial TGF-beta, phosphorylated signaling intermediates, and arterial thickening. Further, studies on ex vivo arteries exposed to varying levels of pressure demonstrated that ERK and TGF-beta signaling were required for pressure-induced upregulation of endothelial HSPG. Our findings suggest a novel feedback control mechanism in which net arterial remodeling to hemodynamic forces is controlled by a dynamic interplay between growth stimulatory signals from VSMCs and growth inhibitory signals from endothelial cells.
Evidence based prevention of hamstring injuries in sport
Authors: J Petersen, P Hölmich
Journal: British Journal of Sports Medicine (2005)

A common soft tissue injury in sports involving sprinting and jumping is the hamstring strain. A major problem with hamstring strains is the high incidence of reinjury. Muscle injuries can be classified as direct or indirect and are typically grouped into three categories according to severity. A number of potential risk factors have been proposed for hamstring strains. Only a few are evidence based and some are mainly based on theoretical assumptions. There is a lack of clinical research on the effectiveness of rehabilitation programmes for hamstring strains. Although the initial treatment of rest, ice, compression, and elevation is accepted for muscle strains, no consensus exists for their rehabilitation. Not much evidence based research has been carried out on prevention of hamstring strain. To our knowledge only two prospective studies have so far been published. As the injuries are common in football and other sports involving sprinting and jumping, there is a need for further research preferably in the form of randomised controlled trials.
CD23 Deficient Mice Develop Allergic Airway Hyperresponsiveness Following Sensitization with Ovalbumin
Authors: ANGELA HACZKU, KATSUYUKI TAKEDA, ECKARD HAMELMANN, AKIHIRO OSHIBA, JOAN LOADER, ANTHONY JOETHAM, CHARLES IRVIN, HITOSHI KIKUTANI, ERWIN W. GELFAND
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The low affinity receptor for IgE (CD23) is reported to regulate immune and inflammatory events and as a result, it may have a role in the development of allergic airway inflammation and hyperresponsiveness (AHR). To test this hypothesis CD23-deficient mice were studied following different modes of allergic sensitization. Mice were actively sensitized either intraperitoneally with ovalbumin (OA)/alum or via the airways (10 days exposure to OA aerosol with no adjuvant). Passive sensitization was performed by intravenous injections of OA-specific IgE. Airway responsiveness, serum IgE and IgG levels were assessed together with airway inflammation. Passive sensitization followed by airway challenges resulted in increased OA-specific IgG and IgE in the serum of wild-type mice only, while both the CD23+ / + and CD23− / − groups developed tracheal smooth muscle hyperresponsiveness to electrical field stimulation, indicating that IgE/CD23-mediated immune functions may not be necessary for the development of allergic changes. Active sensitization of both CD23− / − and CD23+ / + mice resulted in increased serum levels of OA-specific IgE and IgG, airway eosinophilia and significant AHR when compared with nonsensitized mice. The genetic deficiency of CD23− / − mice not only failed to prevent but was associated with a significant increase of these responses. These results indicate that CD23 may not be essential for the development of allergen-induced AHR and further, that its presence may have some inhibitory effects on the allergic response.
Pediatric giant cell glioblastoma: New insights into a rare tumor entity
Authors: Michael Karremann, Sandra Butenhoff, Ulrike Rausche, Torsten Pietsch, Johannes E. A. Wolff, Christof M. Kramm
Journal: Neuro-Oncology (2008)

Little is known about giant cell glioblastoma (GCG) in pediatric patients. The present study identified 18 pediatric patients with centrally reviewed GCG from the HIT-GBM database of the Gesellschaft für Paediatrische Onkologie und Haematologie in Germany, Austria, and Switzerland. Clinical and epidemiological data were compared with those of 178 pediatric patients with centrally reviewed glioblastoma multiforme (GBM) from the same database. In this unique series, median age, male preference, and median clinical history did not differ significantly between pediatric GCG and GBM patients. GCG showed a stronger predilection for cerebral hemispheres than did GBM, which may only partly explain the higher percentage of gross total tumor resections in GCG patients. Most surprising, the widely distributed hypothesis that GCG may imply a better prognosis than GBM could not be substantiated for our pediatric series. Future studies with larger patient numbers and molecular pathological analyses are still needed to corroborate the present findings and further elucidate the biology of GCG in children.