tbuckley/cabot-search huggingface dataset:
The Evolutionary History of YAP and the Hippo/YAP Pathway
Authors: D. Hilman, U. Gat
Journal: Molecular Biology and Evolution (2011)

The Hippo/YAP pathway plays an important role in animal organ size control, which it exerts by regulating tissue proliferation and apoptosis rates as a response to developmental cues, cell contact, and density. With the ever increasing advance in genome sequencing and analysis tools, our understanding of the animal world and its evolution has greatly increased in the recent years. We used bioinformatic tools to study the evolution of the Hippo/YAP pathway focusing on the transcriptional coactivator YAP, which is a pivotal effector of the pathway. The aim was to establish the origin and mode of development of YAP and its pathway in the animal world. Some pathway members can be already identified in single-celled eukaryotes like the yeast that have preceded multicellular animals. Interestingly, we can find most of the components that are present in human in the sea-anemone Nematostella, which belongs to a very basal group of metazoans, the cnidarians. All the major domains of YAP have been conserved between cnidarians and mammals, and YAP can be identified even in the more basal placozoan clade. We show a very high degree of conservation in regions such as the WW and the TEAD-binding domains, TEAD being the major DNA-binding partner of YAP. Remarkably, we found that the location of an intron in the WW1 genomic region has been invariant along an evolutionary span of over 700 My. We have followed the evolutionary changes in YAP and in other main components of the pathway from the first metazoans such as sponges, described the phylogenetic relationships between the YAP genes and indicated where YAP and other components have been secondarily lost. Evidence is provided that YAP and its binding partner TEAD demonstrate strong coevolution. This gives further support for the importance of the TEAD–YAP association. Beyond contributing to an understanding of the evolutionary history of this pathway, we have provided insights into the “birth” of this pathway, its functions and its mode of operation in animals with different body plans, development, and life styles.
Campath-1H Treatment of T-Cell Prolymphocytic Leukemia in Patients for Whom at Least One Prior Chemotherapy Regimen Has Failed
Authors: M. J. Keating, B. Cazin, S. Coutré, R. Birhiray, T. Kovacsovics, W. Langer, B. Leber, T. Maughan, K. Rai, G. Tjønnfjord, M. Bekradda, M. Itzhaki, P. Hérait
Journal: Journal of Clinical Oncology (2002)

PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program. PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks. RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H–related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred. CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.
Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy
Authors: R Schulz
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Reduced endothelium dependent vasodilation has been reported in patients with obstructive sleep apnoea (OSA) but direct measurements of the most potent naturally occurring vasodilator, nitric oxide (NO) or its derivatives (nitrate and nitrite, NO<sub>x</sub>), have not yet been performed in these patients. <h3>METHODS</h3> In 21 patients with OSA of mean (SE) age 54 (2) years, body mass index (BMI) 30.9 (1.1) kg/m<sup>2</sup>, and apnoea-hypopnoea index (AHI) 37 (4)/h, NO<sub>x</sub> levels were measured in peripheral venous blood samples by chemiluminescence. Blood samples were obtained before and after two nights of continuous positive airway pressure (CPAP) and after 5.5 (1.5) months of follow up. Thirteen age matched, healthy volunteers and 18 patients without OSA but with a similar spectrum of comorbidity served as controls (control groups 1 and 2). <h3>RESULTS</h3> Before CPAP NO<sub>x</sub> levels were 21.7 (1.5) μM in patients with OSA compared with 42.6 (2.2) μM and 36.7 (1.7) μM in control groups 1 and 2, respectively (p&lt;0.01 for each comparison). NO<sub>x</sub>concentrations increased to 32.1 (2.7) μM after two nights of CPAP and remained constant at 32.9 (2.3) μM at follow up (p&lt;0.01 compared with levels before CPAP). <h3>CONCLUSIONS</h3> Plasma NO<sub>x</sub> levels are reduced in OSA and can be increased by short and long term CPAP therapy. Although the precise mechanism underlying this observation remains to be clarified, it may have important implications for the development of cardiovascular disease in patients with OSA and for the life saving effect of CPAP.
Epidemiology and pathogenesis of cryptorchidism
Authors: H.E. Virtanen, J. Toppari
Journal: Human Reproduction Update (2007)

Prospective clinical studies have shown that the prevalence of cryptorchidism among boys with birth weight ≥2500 g has increased in UK from 2.7 to 4.1% between the 1950s and the 1980s and in Denmark from 1.8 to 8.4% between the 1950s and the 1990s. In similar studies performed in different countries during the last two decades the figures have varied from 2.1 to 8.4%. Due to spontaneous descent of the testes lower figures, i.e. between 0.9 and 1.8% have been described at 3 months. Acquired cryptorchidism contributes to the increase in the rate of cryptorchidism in school-aged children. Testicular descent occurs in two phases. During the first phase, before midgestation, testis remains anchored to the inguinal area by insulin like hormone 3 (INSL3)-driven development of the gubernaculum. The second inguinoscrotal phase is dependent on testicular androgens and it is usually completed by the time of birth. Mutations of specific genes have rarely been reported in cryptorchidism. However, several risk factors for cryptorchidism, such as preterm birth and low birth weight, have been described. Environmental factors may also have a role in the etiology of cryptorchidism. Future studies on the gene–environment interaction will give new insights to the pathogenesis of cryptorchidism.
Mutation of TDP1, encoding a topoisomerase I–dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy
Authors: Hiroshi Takashima, Cornelius F. Boerkoel, Joy John, Gulam Mustafa Saifi, Mustafa A.M. Salih, Dawna Armstrong, Yuxin Mao, Florante A. Quiocho, Benjamin B. Roa, Masanori Nakagawa, David W. Stockton, James R. Lupski
Journal: Nature Genetics (2002)
Acute Kidney Injury, Mortality, Length of Stay, and Costs in Hospitalized Patients
Authors: Glenn M. Chertow, Elisabeth Burdick, Melissa Honour, Joseph V. Bonventre, David W. Bates
Journal: Journal of the American Society of Nephrology (2005)

The marginal effects of acute kidney injury on in-hospital mortality, length of stay (LOS), and costs have not been well described. A consecutive sample of 19,982 adults who were admitted to an urban academic medical center, including 9210 who had two or more serum creatinine (SCr) determinations, was evaluated. The presence and degree of acute kidney injury were assessed using absolute and relative increases from baseline to peak SCr concentration during hospitalization. Large increases in SCr concentration were relatively rare (e.g., >or=2.0 mg/dl in 105 [1%] patients), whereas more modest increases in SCr were common (e.g., >or=0.5 mg/dl in 1237 [13%] patients). Modest changes in SCr were significantly associated with mortality, LOS, and costs, even after adjustment for age, gender, admission International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis, severity of illness (diagnosis-related group weight), and chronic kidney disease. For example, an increase in SCr >or=0.5 mg/dl was associated with a 6.5-fold (95% confidence interval 5.0 to 8.5) increase in the odds of death, a 3.5-d increase in LOS, and nearly 7500 dollars in excess hospital costs. Acute kidney injury is associated with significantly increased mortality, LOS, and costs across a broad spectrum of conditions. Moreover, outcomes are related directly to the severity of acute kidney injury, whether characterized by nominal or percentage changes in serum creatinine.
Type 2 Diabetes Can Be Prevented With Early Pharmacological Intervention
Authors: Ralph A. DeFronzo, Muhammad Abdul-Ghani
Journal: Diabetes Care (2011)

In the U.S., ∼21 × 106 individuals have type 2 diabetes, and twice as many have impaired glucose tolerance (IGT). Approximately 40–50% of individuals with IGT will progress to type 2 diabetes over their lifetime. Therefore, treatment of high-risk individuals with IGT to prevent type 2 diabetes has important medical, economic, social, and human implications. Weight loss, although effective in reducing the conversion of IGT to type 2 diabetes, is difficult to achieve and maintain. Moreover, 40–50% of IGT subjects progress to type 2 diabetes despite successful weight reduction. In contrast, pharmacological treatment of IGT with oral antidiabetic agents that improve insulin sensitivity and preserve β-cell function—the characteristic pathophysiological abnormalities present in IGT and type 2 diabetes—uniformly have been shown to prevent progression of IGT to type 2 diabetes. The most consistent results have been observed with the thiazolidinediones (Troglitazone in the Prevention of Diabetes [TRIPOD], Pioglitazone in the Prevention of Diabetes [PIPOD], Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM], and Actos Now for the Prevention of Diabetes [ACT NOW]), with a 50–70% reduction in IGT conversion to diabetes. Metformin in the U.S. Diabetes Prevention Program (DPP) reduced the development of type 2 diabetes by 31% and has been recommended by the American Diabetes Association (ADA) for treating high-risk individuals with IGT. The glucagon-like peptide-1 analogs, which augment insulin secretion, preserve β-cell function, and promote weight loss, also would be expected to be efficacious in preventing the progression of IGT to type 2 diabetes. Because individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70–80% of their β-cell function, and have an ∼10% incidence of diabetic retinopathy, pharmacological intervention, in combination with diet plus exercise, should be instituted.
Home secretary accused of bullying drugs adviser over comments about ecstasy
Authors: Z. Kmietowicz
Journal: BMJ (2009)

Champions of evidence based medicine have defended the UK government’s drugs adviser who was criticised this week by the home secretary for saying that the risk associated with taking the recreational drug ecstasy was no worse than riding a horse.

Ben Goldacre, a doctor and author of Bad Science , said that it was “completely ridiculous” that David Nutt was forced to apologise for his comments, which he made in an article in the Journal of Psychopharmacology and were widely reported in the British press at the weekend (2009;23:3-5, doi:10.1177/0269881108099672).

In the article, which was written before Professor Nutt took his post as chairman of the Council on the Misuse of Drugs, he argued that “equine addiction syndrome” results in 100 deaths a year compared with 30 …
Suicide From the Golden Gate Bridge
Authors: Mel Blaustein, Anne Fleming
Journal: American Journal of Psychiatry (2009)

The Golden Gate Bridge is the number one suicide site in the world. In this clinical case conference, the authors begin by presenting vignettes to capture the diversity of bridge suicide. They then examine the demographic characteristics of those who commit suicide from the bridge as well as the fatal attraction of the Golden Gate Bridge. Interviews with jump survivors and potential jumpers are presented, and the authors examine the evidence for the efficacy of suicide barriers.
Prospective, Randomized, Multicenter Evaluation of a Polyethylene Terephthalate Micronet Mesh–Covered Stent (MGuard) in ST-Segment Elevation Myocardial Infarction
Authors: Gregg W. Stone, Alexandre Abizaid, Sigmund Silber, Jose M. Dizon, Béla Merkely, Ricardo A. Costa, Ran Kornowski, Andrea Abizaid, Roman Wojdyła, Akiko Maehara, Ovidiu Dressler, Sorin J. Brener, Eli Bar, Dariusz Dudek
Journal: Journal of the American College of Cardiology (2012)
Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure
Authors: Prakash K. Rao, Yumiko Toyama, H. Rosaria Chiang, Sumeet Gupta, Michael Bauer, Rostislav Medvid, Ferenc Reinhardt, Ronglih Liao, Monty Krieger, Rudolf Jaenisch, Harvey F. Lodish, Robert Blelloch
Journal: Circulation Research (2009)

Rationale: Heart failure is a deadly and devastating disease that places immense costs on an aging society. To develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. Objective: microRNAs are important regulators of gene expression, and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. Methods and Results: First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Second, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8 , a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality. Conclusions: These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs may ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8 .
Sulphapyridine in the Treatment of Acute Urethritis
Authors: N. S. Taylor
Journal: BMJ (1940)

MEDICAL JOURNAI,half an hour and "the colours came."About ten minutes later there were three bad pains and a baby boy of 8' lb. was born.The afterbirth came in ten minutes.There was no great bleeding and there were no after-pains."Everything was cleared up in one and a half hours and I was back to sleep again."In September, 1939, she looked very well.There has been
Effect of needle size on immunogenicity and reactogenicity of vaccines in infants: randomised controlled trial
Authors: Linda Diggle, Jonathan J Deeks, Andrew J Pollard
Journal: BMJ (2006)

<h3>Background</h3> Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease which causes painful discharging nodules and skin tunnels. HS has associations with several systemic diseases, including cardiovascular (CV) disease and anxiety-depression. High levels of chronic morbidity suggest an important role for Primary Care. However, little evidence exists regarding current management of HS and its co-morbidities in UK General Practice. <h3>Aim</h3> To describe current practice amongst UK GPs in treating and referring people with HS <h3>Design &amp; setting</h3> Web-based survey circulated to UK Primary Care Dermatology Society members and GPs in Forth Valley, Scotland. <h3>Method</h3> Survey responses were analysed with descriptive statistics. <h3>Results</h3> 134 UK GPs completed the survey. 71% (n=94) saw at least one patient with HS in the previous month. 94% (n=125) reported confidence in diagnosis, and 87% (n=120) in initial treatment of HS. Most GPs initiated topical treatments and extended courses of oral antibiotic for HS, and many advised regarding adverse lifestyle factors. A minority provided analgesia, or screening for CV disease risk factors and anxiety-depression. Most GPs referred to Dermatology if Secondary Care input was required, with few referrals to specialised multi-disciplinary services. <h3>Conclusion</h3> GPs regularly diagnose and manage uncomplicated HS, but screening for important co-morbidities associated with HS is not common practice.
Exposure to allergen and diesel exhaust particles potentiates secondary allergen-specific memory responses, promoting asthma susceptibility
Authors: Eric B. Brandt, Jocelyn M. Biagini Myers, Thomas H. Acciani, Patrick H. Ryan, Umasundari Sivaprasad, Brandy Ruff, Grace K. LeMasters, David I. Bernstein, James E. Lockey, Timothy D. LeCras, Gurjit K. Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2015)
Hypoxia-Induced Endothelial Proliferation Requires Both mTORC1 and mTORC2
Authors: Weimin Li, Marco Petrimpol, Klaus D. Molle, Michael N. Hall, Edouard J. Battegay, Rok Humar
Journal: Circulation Research (2006)

A central regulator of cell growth that has been implicated in responses to stress such as hypoxia is mTOR ( m ammalian T arget O f R apamycin). We have shown previously that mTOR is required for angiogenesis in vitro and endothelial cell proliferation in response to hypoxia. Here we have investigated mTOR-associated signaling components under hypoxia and their effects on cell proliferation in rat aortic endothelial cells (RAECs). Hypoxia (1% O 2 ) rapidly (&gt;30 minutes) and in a concentration-dependent manner promoted rapamycin-sensitive and sustained phosphorylation of mTOR-Ser2448 followed by nuclear translocation in RAECs. Similarly, hypoxia induced phosphorylation of the mTORC2 substrate Akt-Ser473 (3 to 6 hours at 1% O 2 ) and a brief phosphorylation peak of the mTORC1 substrate S6 kinase–Thr389 (10 to 60 minutes). Phosphorylation of Akt was inhibited by mTOR knockdown and partially with rapamycin. mTOR knockdown, rapamycin, or Akt inhibition specifically and significantly inhibited proliferation of serum-starved RAECs under hypoxia ( P &lt;0.05; n≥4). Similarly, hypoxia induced Akt-dependent and rapamycin-sensitive proliferation in mouse embryonic fibroblasts. This response was partially blunted by hypoxia-inducible factor-1α knockdown and not affected by TSC2 knockout. Finally, mTORC2 inhibition by rictor silencing, especially ( P &lt;0.001; n=7), and mTORC1 inhibition by raptor silencing, partially ( P &lt;0.05; n=7), inhibited hypoxia-induced RAEC proliferation. Thus, mTOR mediates an early response to hypoxia via mTORC1 followed by mTORC2, promoting endothelial proliferation mainly via Akt signaling. mTORC1 and especially mTORC2 might therefore play important roles in diseases associated with hypoxia and altered angiogenesis.
Longitudinal observations of serum IgE and skin prick test response.
Authors: M P Oryszczyn, I Annesi, F Neukirch, M F Doré, F Kauffmann
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The objective of the study was to assess skin prick test and IgE changes in a working population surveyed 5 yr apart and to determine whether age and smoking habits modify these changes. SPTs were performed on 223 subjects by the same method and common allergens (a mixture of grass pollens and a mixture of 95% house dust and 5% house dust mite). IgE measurements were done in duplicate by the same technique at each survey. A SPT-positive response at the first survey was highly predictive of a positive value at the second survey. The prevalence of positive SPT significantly increased in 5 yr (from 17.5 to 24.7%). A strong correlation was observed between IgE levels 5 yr apart (r = 0.92), and the IgE level appeared very stable. The initial IgE level was significantly greater among the converters than in consistently negative subjects (92.3 versus 30.1 IU/ml). Conversely, the initial IgE level was lower for the reverters than in consistently positive subjects (36.8 versus 97.0 IU/ml). In SPT negatives, non- and exsmokers had a greater decrease in IgE than current smokers (p = 0.06). IgE level appears to be a good predictor of SPT changes for both conversion and reversion. The IgE level appears very stable in midadulthood, which suggests that the adult environment may play a small effect in IgE level.
EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors
Authors: A.G. Pallis, A. Ring, C. Fortpied, B. Penninckx, M.C. Van Nes, U. Wedding, G. vonMinckwitz, C.D. Johnson, L. Wyld, A. Timmer-Bonte, F. Bonnetain, L. Repetto, M. Aapro, A. Luciani, H. Wildiers
Journal: Annals of Oncology (2011)
HTLV-I AND BLOOD DONORS
Authors: W.V. Bolton, B.R. Wylie, K.G. Kenrick, G.T. Archer, C.A. Hyland, S.L. Parker, I.F. Young, R.K. Maloney, V.A. Armstrong, A.J. Keller, P.W. Robertson
Journal: The Lancet (1989)
Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial
Authors: Frédéric Peyrade, Fabrice Jardin, Catherine Thieblemont, Antoine Thyss, Jean-François Emile, Sylvie Castaigne, Bertrand Coiffier, Corinne Haioun, Serge Bologna, Olivier Fitoussi, Gérard Lepeu, Christophe Fruchart, Dominique Bordessoule, Michel Blanc, Richard Delarue, Maud Janvier, Bruno Salles, Marc André, Marion Fournier, Philippe Gaulard, Hervé Tilly
Journal: The Lancet Oncology (2011)