tbuckley/cabot-search huggingface dataset:
BMP Receptor ALK3 Controls Collecting System Development
Authors: Sunny Hartwig, Darren Bridgewater, Valeria Di Giovanni, Jason Cain, Yuji Mishina, Norman D. Rosenblum
Journal: Journal of the American Society of Nephrology (2008)

The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.
The National Emphysema Treatment Trial (NETT)
Authors: Gerard J. Criner, Francis Cordova, Alice L. Sternberg, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Substantial information regarding the role of lung volume reduction surgery (LVRS) in severe emphysema emanates from the National Emphysema Treatment Trial (NETT). The NETT was not a crossover trial and therefore was able to examine the effects of optimal medical management and LVRS on short- and long-term survival,as well as lung function, exercise performance, and quality of life.The NETT generated multiple insights into the preoperative, perioperative,and postoperative management of patients undergoing thoracotomy; described pain control techniques that were safe and effective; and emphasized the need to address nonpulmonary issues to optimize surgical outcomes. After the NETT, newer investigation has focused on bronchoscopic endobronchial interventions and other techniques less invasive than LVRS to achieve lung reduction.In this review, we summarize what we currently know about the role of LVRS in the treatment of severe emphysema as a result of insights gained from the NETT and provide a brief review of the newer techniques of lung volume reduction.
Consultant--By any Other Name
Authors: I. M. Thompson
Journal: BMJ (1970)

MDICcALJOURNAL acetate appears to be the only available oral contraceptive which does not produce rises in blood clotting factors and increased plate- let aggregation.'2Abnormal levels of clotting factors and platelet aggregation arising from the taking of combined pre- parations do in fact return to normal when chlormadinone acetate is substituted.The harmful element in all the other oral contraceptives appears to be oestrogen, and we found no difference in clotting response between the high and low dose oestrogen combinations.Inman and Vessey4 showed a mortality of 3-4 women in the 35 to 44 year and 1-3 per 100,000 in the 20 to 34 year age groups resulted from conventional oestrogen- progestogen contraception.To this must be added the much greater numbers of non-fatal thromboembolisms.Though chlormadinone acetate in some respects may not be ideal, it does appear to represent a considerable advance.The cor- rect procedure, surely, for the manufacturers should have been to report the experimental findings to the Committee on Safety of Drugs.Doctors could then have been made aware of a possible hazard and the ultimate decision on the advisability of withdrawal could then have been left in the hands of Professor Scowen's committee.By wishing to be seen to do "the right thing" the manufacturers may, from the clinical standpoint, be making a tragic mistake, as it must of necessity be a considerable time before other progestogen pre- parations are developed for clinical use.-I
Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
Authors: I-Wen Teng, Pei-Chi Hou, Kuan-Der Lee, Pei-Yi Chu, Kun-Tu Yeh, Victor X. Jin, Min-Jen Tseng, Shaw-Jenq Tsai, Yu-Sun Chang, Chi-Sheng Wu, H. Sunny Sun, Kuen-daw Tsai, Long-Bin Jeng, Kenneth P. Nephew, Tim H.-M. Huang, Shu-Huei Hsiao, Yu-Wei Leu
Journal: Cancer Research (2011)

Abstract Although DNA hypermethylation within promoter CpG islands is highly correlated with tumorigenesis, it has not been established whether DNA hypermethylation within a specific tumor suppressor gene (TSG) is sufficient to fully transform a somatic stem cell. In this study, we addressed this question using a novel targeted DNA methylation technique to methylate the promoters of HIC1 and RassF1A, two well-established TSGs, along with a two-component reporter system to visualize successful targeting of human bone marrow–derived mesenchymal stem cells (MSC) as a model cell system. MSCs harboring targeted promoter methylations of HIC1/RassF1A displayed several features of cancer stem/initiating cells including loss of anchorage dependence, increased colony formation capability, drug resistance, and pluripotency. Notably, inoculation of immunodeficient mice with low numbers of targeted MSC resulted in tumor formation, and subsequent serial xenotransplantation and immunohistochemistry confirmed the presence of stem cell markers and MSC lineage in tumor xenografts. Consistent with the expected mechanism of TSG hypermethylation, treatment of the targeted MSC with a DNA methyltransferase inhibitor reversed their tumorigenic phenotype. To our knowledge, this is the first direct demonstration that aberrant TSG hypermethylation is sufficient to transform a somatic stem cell into a fully malignant cell with cancer stem/initiating properties. Cancer Res; 71(13); 4653–63. ©2011 AACR.
The Case for Biennial Retinopathy Screening in Children and Adolescents
Authors: Ann Maguire, Albert Chan, Janine Cusumano, Stephen Hing, Maria Craig, Martin Silink, Neville Howard, Kim Donaghue
Journal: Diabetes Care (2005)

Current guidelines recommend annual retinopathy screening 2 years after onset (for pubertal-onset type 1 diabetes) and after 5 years (or age 11, whichever is earlier) for prepubertal onset. Our aim was to describe the natural history of retinopathy and to explore optimal retinal screening intervals for children and adolescents (aged <20 years) screened according to these guidelines.More than 1,000 children and adolescents, followed longitudinally, were screened for retinopathy using seven-field stereoscopic fundus photography through dilated pupils. Of these, 668 had baseline and follow-up retinal screening. Using generalized estimating equations, we compared the risk of retinopathy with baselines at yearly intervals, in older and younger groups, in higher risk groups (diabetes duration >10 years or HbA(1c) >10% at any screening), and after stratification </=10 and <10 years in duration.After 1 year, retinopathy did not increase significantly in the older group (n = 618, median HbA(1c) 8.7%, range 8.0-9.5), younger group (n = 50, median HbA(1c) 8.5%, range 8.0-9.2), or the higher-risk groups. Retinopathy increased significantly after 2 years in the older group (P = 0.003) but not until 6 years in the younger group (P = 0.01). In the group with HbA(1c) >10% recorded at any visit, retinopathy increased significantly after 2 years (P = 0.001) but not until 3 years in the group whose HbA(1c) was always </=10% (P = 0.003). After the second eye assessment, retinopathy did not increase significantly until 3 and 6 years later in the older and younger groups, respectively (P = 0.028 and 0.014).These results suggest that adolescents (in reasonable metabolic control) could safely be screened every 2 years rather than the currently recommended 1-year interval. In younger children, the next screening interval could be >2 years later. Individuals with especially poor control, duration >10 years, or significant retinopathy should be screened more frequently.
Getting Past Denial — The High Cost of Health Care in the United States
Authors: Jason M. Sutherland, Elliott S. Fisher, Jonathan S. Skinner
Journal: New England Journal of Medicine (2009)

What seemed to be a golden opportunity to achieve badly needed health care reform now appears to be threatened. Many Americans believe that we simply cannot afford to cover the uninsured, since doing so would require taxes to be raised beyond the level the public can sustain. Others believe that we can slow spending growth only by rationing needed care. Neither option is attractive. Evidence regarding regional variations in spending and growth, however, points to a more hopeful alternative: we should be able to reorganize and improve care to eliminate wasteful and unnecessary services.1 But not everyone is convinced. Some . . .
Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis
Authors: Jackie L Nam, Sofia Ramiro, Cecile Gaujoux-Viala, Kaoru Takase, Mario Leon-Garcia, Paul Emery, Laure Gossec, Robert Landewe, Josef S Smolen, Maya H Buch
Journal: Annals of the Rheumatic Diseases (2014)

Objectives To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism(EULAR) Task Force treatment recommendations. Methods Medline, Embase and Cochrane databases were searched for articles published between January 2009 and February 2013 on infliximab, etanercept, adalimumab, certolizumab-pegol, golimumab, anakinra, abatacept, rituximab, tocilizumab and biosimilar DMARDs (bsDMARDs) in phase 3 development. Abstracts from 2011 to 2012 American College of Rheumatology (ACR) and 2011–2013 EULAR conferences were obtained. Results Fifty-one full papers, and 57 abstracts were identified. The randomised controlled trials (RCT) confirmed the efficacy of bDMARD+conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone (level 1B evidence). There was some additional evidence for the use of bDMARD monotherapy, however bDMARD and MTX combination therapy for all bDMARD classes was more efficacious (1B). Clinical and radiographic responses were high with treat-to-target strategies. Earlier improvement in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, mainly due to initial treatment effects. Although patients may achieve bDMARD- and drug-free remission, maintenance of clinical responses was higher with bDMARD continuation (1B), but bDMARD dose reduction could be applied (1B). There was still no RCT data for bDMARD switching. Conclusions The systematic literature review confirms efficacy of biological DMARDs in RA. It addresses different treatment strategies with the potential for reduction in therapy, particularly with early disease control, and highlights emerging therapies.
Effects of psychosocial stimulation and dietary supplementation in early childhood on psychosocial functioning in late adolescence: follow-up of randomised controlled trial
Authors: Susan P Walker, Susan M Chang, Christine A Powell, Emily Simonoff, Sally M Grantham-McGregor
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To determine whether dietary supplementation or psychosocial stimulation given to growth retarded (stunted) children age 9-24 months has long term benefits for their psychosocial functioning in late adolescence. <b>Design</b> Sixteen year follow-up study of a randomised controlled trial. <b>Setting</b> Poor neighbourhoods in Kingston, Jamaica. <b>Participants</b> Of 129 stunted children identified at age 9-24 months, 103 adolescents aged 17-18 were followed up. <b>Intervention</b> Supplementation with 1 kg milk based formula each week or psychosocial stimulation (weekly play sessions with mother and child), or both, for two years. <b>Main outcome measures</b> Anxiety, depression, self esteem, and antisocial behaviour assessed by questionnaires administered by interviewers; attention deficit, hyperactivity, and oppositional behaviour assessed by interviews with parents. <b>Results</b> Primary analysis indicated that participants who received stimulation had significantly different overall scores from those who did not (F = 2.047, P = 0.049). Supplementation had no significant effect (F = 1.505, P = 0.17). Participants who received stimulation reported less anxiety (mean difference - 2.81, 95% confidence interval - 5.02 to - 0.61), less depression (- 0.43, - 0.78 to - 0.07), and higher self esteem (1.55, 0.08 to 3.02) and parents reported fewer attention problems (- 3.34, - 6.48 to - 0.19). These differences are equivalent to effect sizes of 0.40-0.49 standard deviations. <b>Conclusions</b> Stimulation in early childhood has sustained benefits to stunted children9s emotional outcomes and attention.
Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks
Authors: Jordan J. Feld, Christophe Moreno, Roger Trinh, Edward Tam, Stefan Bourgeois, Yves Horsmans, Magdy Elkhashab, David E. Bernstein, Ziad Younes, Robert W. Reindollar, Lois Larsen, Bo Fu, Kevin Howieson, Akshanth R. Polepally, Andreas Pangerl, Nancy S. Shulman, Fred Poordad
Journal: Journal of Hepatology (2015)

Graphical abstractAbstractBackground & AimsPatients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis.MethodsTreatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ⩾10g/dl, albumin ⩾2.8g/dl, platelet count ⩾25×109/L, creatinine clearance ⩾30ml/min, and Child-Pugh score ⩽6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug.ResultsSixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90×109/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0–100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant.ConclusionsThe HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population.
Psychosocial and Neurocognitive Outcomes in Adult Survivors of Adolescent and Early Young Adult Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Pinki K. Prasad, Kristina K. Hardy, Nan Zhang, Kim Edelstein, Deokumar Srivastava, Lonnie Zeltzer, Marilyn Stovall, Nita L. Seibel, Wendy Leisenring, Gregory T. Armstrong, Leslie L. Robison, Kevin Krull
Journal: Journal of Clinical Oncology (2015)

To characterize psychological and neurocognitive function in long-term cancer survivors diagnosed during adolescence and early young adulthood (AeYA).Six thousand one hundred ninety-two survivors and 390 siblings in the Childhood Cancer Survivor Study completed the Brief Symptom Inventory-18 and a Neurocognitive Questionnaire. Treatment and demographic predictors were examined, and associations with social attainment (employment, education, and living independently) were evaluated. Logistic regression models were used to compute odds ratios (ORs) and corresponding 95% CIs.Among survivors, 2,589 were diagnosed when AeYA (11 to 21 years old). Adjusted for current age and sex, these survivors, compared with siblings, self-reported higher rates of depression (11.7% v 8.0%, respectively; OR, 1.55; 95% CI, 1.04 to 2.30) and anxiety (7.4% v 4.4%, respectively; OR, 2.00; 95% CI, 1.17 to 3.43) and more problems with task efficiency (17.2% v 10.8%, respectively; OR, 1.72; 95% CI, 1.21 to 2.43), emotional regulation (19.1% v 14.1%, respectively; OR, 1.74; 95% CI, 1.26 to 2.40), and memory (25.9% v 19.0%, respectively; OR, 1.44; 95% CI, 1.09 to 1.89). Few differences were noted between survivors diagnosed with leukemia or CNS tumor before 11 years old versus during later adolescence, although those diagnosed with lymphoma or sarcoma during AeYA were at reduced risk for self-reported psychosocial and neurocognitive problems. Unemployment was associated with self-reports of impaired task efficiency (OR, 2.93; 95% CI, 2.28 to 3.77), somatization (OR, 2.29; 95% CI, 1.77 to 2.98), and depression (OR, 1.94; 95% CI, 1.43 to 2.63).We demonstrated that risk for poor functional outcome is not limited to survivors' diagnoses in early childhood. AeYA is a critical period of development, and cancer during this period can impact neurocognitive and emotional function and disrupt vocational attainment.
Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer
Authors: Alan L. Ho, Ravinder K. Grewal, Rebecca Leboeuf, Eric J. Sherman, David G. Pfister, Desiree Deandreis, Keith S. Pentlow, Pat B. Zanzonico, Sofia Haque, Somali Gavane, Ronald A. Ghossein, Julio C. Ricarte-Filho, José M. Domínguez, Ronglai Shen, R. Michael Tuttle, Steve M. Larson, James A. Fagin
Journal: New England Journal of Medicine (2013)

Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium–iodide symporter and uptake of iodine. Their effects in humans are not known.
A microRNA links prolactin to peripartum cardiomyopathy
Authors: Ying Yang, Jessica E. Rodriguez, Richard N. Kitsis
Journal: Journal of Clinical Investigation (2013)

For decades, peripartum cardiomyopathy has remained an enigma. Despite extensive research, our understanding of how a previously healthy woman can develop lethal heart failure in the context of pregnancy remains vague. Recent work suggests that inadequacy of the cardiac microvasculature may be the primary abnormality and has implicated an antiangiogenic fragment of the nursing hormone prolactin as playing an important role. In this issue of the JCI, Halkein et al. explore signaling downstream of this prolactin fragment and demonstrate that miR-146a is a critical mediator of the antiangiogenic effects in endothelial cells. In addition, the study uncovers unexpected exosomal transfer of this microRNA to cardiomyocytes that may affect myocardial metabolism.
MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion
Authors: Qian-Qian Zhang, Hui Xu, Mian-Bo Huang, Li-Ming Ma, Qiao-Juan Huang, Qing Yao, Hui Zhou, Liang-Hu Qu
Journal: Neuro-Oncology (2012)

Accumulating evidence has implicated the deregluation of miRNAs in tumorigenesis. Previous studies have reported that microRNA-195 (miR-195) is markedly down-regulated in human glioblastoma cells, compared with normal brain tissue, but the biological role of miR-195 in glioblastoma development is currently unknown. In this study, we define a tumor-suppressor role for miR-195 in human glioblastoma cells. Over-expression of miR-195 in glioblastoma cell lines robustly arrested cell cycle progression and significantly repressed cellular invasion. We identified E2F3 and CCND3 as functional downstream targets of miR-195 in glioblastoma cells. Through knockdown studies, we demonstrated that E2F3 was the dominant effector of miR-195-mediated cell cycle arrest and that CCND3 was a key mediator of miR-195-induced inhibition of glioblastoma cell invasion. Furthermore, we showed that p27(Kip1) was an important regulator downstream of CCND3 and that the accumulation of p27(Kip1) in the cytoplasm might be responsible for the miR-195-mediated cell invasion inhibition in glioblastoma cells. This work provides evidence for the initial mechanism by which miR-195 negatively regulates both the proliferation and invasion of glioblastoma cells, suggesting that the down-regulation of miR-195 might contribute to the malignant transformation of glioblastoma cells and could be a molecular signature associated with glioblastoma progression.