tbuckley/cabot-search huggingface dataset:
Tumor Genetic Screening Programs: A Call to Action
Authors: David M. Hyman, David B. Solit
Journal: Journal of Clinical Oncology (2015)

that although 39% of patients had at least one potentially actionable alteration, only 11% of these patients (4% of patients overall) were subsequentlyenrolledontoagenomicallymatchedstudy.Theactionablegenomicalterationsthatmostcommonlypromptedenrolledtoa genotype-matched trial were mutations in PIK3CA (41%), BRAF (28%), EGFR (8%), KRAS (5%), and ERBB2 (5%). Interestingly, patientswithanactionablealterationwereonlymarginallymorelikelyto enrollontoaclinicaltrial(eithermatchedorunmatched)whencompared with patients without an actionable alteration (28.4% v24.4%). This prospective tumor profiling effort was conducted at a large cancer center with an extensive clinical trial portfolio. Therefore, we are forced to consider whether the 4% enrollment rate to a genotypematched study may be the upper limit of what can expected from similarprofilingeffortsinadiversepatientpopulation.Itisimportant
Growth Hormone, Insulin-Like Growth Factors, and the Skeleton
Authors: Andrea Giustina, Gherardo Mazziotti, Ernesto Canalis
Journal: Endocrine Reviews (2008)

GH and IGF-I are important regulators of bone homeostasis and are central to the achievement of normal longitudinal bone growth and bone mass. Although GH may act directly on skeletal cells, most of its effects are mediated by IGF-I, which is present in the systemic circulation and is synthesized by peripheral tissues. The availability of IGF-I is regulated by IGF binding proteins. IGF-I enhances the differentiated function of the osteoblast and bone formation. Adult GH deficiency causes low bone turnover osteoporosis with high risk of vertebral and nonvertebral fractures, and the low bone mass can be partially reversed by GH replacement. Acromegaly is characterized by high bone turnover, which can lead to bone loss and vertebral fractures, particularly in patients with coexistent hypogonadism. GH and IGF-I secretion are decreased in aging individuals, and abnormalities in the GH/IGF-I axis play a role in the pathogenesis of the osteoporosis of anorexia nervosa and after glucocorticoid exposure.
Pivotal Role of Lnk Adaptor Protein in Endothelial Progenitor Cell Biology for Vascular Regeneration
Authors: Sang-Mo Kwon, Takahiro Suzuki, Atsuhiko Kawamoto, Masaaki Ii, Masamichi Eguchi, Hiroshi Akimaru, Mika Wada, Tomoyuki Matsumoto, Haruchika Masuda, Yoshihiro Nakagawa, Hiromi Nishimura, Kenji Kawai, Satoshi Takaki, Takayuki Asahara
Journal: Circulation Research (2009)

Despite the fact that endothelial progenitor cells (EPCs) are important for postnatal neovascularization, their origins, differentiation, and modulators are not clear. Here, we demonstrate that Lnk, a negative regulator of hematopoietic stem cell proliferation, controls endothelial commitment of c-kit(+)/Sca-1(+)/Lineage(-) (KSL) subpopulations of bone marrow cells. The results of EPC colony-forming assays reveal that small (primitive) EPC colony formation by CD34(-) KSLs and large (definitive) EPC colony formation by CD34((dim)) KSLs are more robust in lnk(-/-) mice. In hindlimb ischemia, perfusion recovery is augmented in lnk(-/-) mice through enhanced proliferation and mobilization of EPCs via c-Kit/stem cell factor. We found that Lnk-deficient EPCs are more potent actors than resident cells in hindlimb perfusion recovery and ischemic neovascularization, mainly via the activity of bone marrow-EPCs. Similarly, lnk(-/-) mice show augmented retinal neovascularization and astrocyte network maturation without an increase in indicators of pathogenic angiogenesis in an in vivo model of retinopathy. Taken together, our results provide strong evidence that Lnk regulates bone marrow-EPC kinetics in vascular regeneration. Selective targeting of Lnk may be a safe and effective strategy to augment therapeutic neovascularization by EPC transplantation.
Adi Nadimpalli, MD, on Doing Field Work With Doctors Without Borders
Authors: Laura Buchholz
Journal: JAMA (2015)

In this Medical News &amp; Perspectives interview, Adi Nadimpalli, MD, Doctors Without Borders/Médecins Sans Frontières (MSF) Head of Mission in Nepal, talks about the logistics and priorities of working in the field to meet the medical needs of populations in crisis.
Cardiovascular Thrombotic Events in Controlled, Clinical Trials of Rofecoxib
Authors: Marvin A. Konstam, Matthew R. Weir, Alise Reicin, Deborah Shapiro, Rhoda S. Sperling, Eliav Barr, Barry J. Gertz
Journal: Circulation (2001)

Background In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs. Methods and Results CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists’ Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing &gt;14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen. Conclusions This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.
Cardiomyocyte-Specific Knockout and Agonist of Peroxisome Proliferator–Activated Receptor-γ Both Induce Cardiac Hypertrophy in Mice
Authors: Sheng Zhong Duan, Christine Y. Ivashchenko, Mark W. Russell, David S. Milstone, Richard M. Mortensen
Journal: Circulation Research (2005)

Peroxisome proliferator-activated receptor (PPAR)-gamma is required for adipogenesis but is also found in the cardiovascular system, where it has been proposed to oppose inflammatory pathways and act as a growth suppressor. PPAR-gamma agonists, thiazolidinediones (TZDs), inhibit cardiomyocyte growth in vitro and in pressure overload models. Paradoxically, TZDs also induce cardiac hypertrophy in animal models. To directly determine the role of cardiomyocyte PPAR-gamma, we have developed a cardiomyocyte-specific PPAR-gamma-knockout (CM-PGKO) mouse model. CM-PGKO mice developed cardiac hypertrophy with preserved systolic cardiac function. Treatment with a TZD, rosiglitazone, induced cardiac hypertrophy in both littermate control mice and CM-PGKO mice and activated distinctly different hypertrophic pathways from CM-PGKO. CM-PGKO mice were found to have increased expression of cardiac embryonic genes (atrial natriuretic peptide and beta-myosin heavy chain) and elevated nuclear factor kappaB activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-gamma, whereas rosiglitazone induced phosphorylation of extracellular signal-related kinase 1/2 in the heart dependent of PPAR-gamma. Phosphorylation of c-Jun N-terminal kinases was not affected by rosiglitazone or CM-PGKO. Surprisingly, despite hypertrophy, Akt phosphorylation was suppressed in CM-PGKO mouse heart. These data show that cardiomyocyte PPAR-gamma suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor kappaB activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR-gamma in cardiomyocytes and through different mechanisms from CM-PGKO.
Do Researchers Have an Obligation to Actively Look for Genetic Incidental Findings?
Authors: Catherine Gliwa, Benjamin E. Berkman
Journal: The American Journal of Bioethics (2013)

The rapid growth of next-generation genetic sequencing has prompted debate about the responsibilities of researchers toward genetic incidental findings. Assuming there is a duty to disclose significant incidental findings, might there be an obligation for researchers to actively look for these findings? We present an ethical framework for analyzing whether there is a positive duty to look for genetic incidental findings. Using the ancillary care framework as a guide, we identify three main criteria that must be present to give rise to an obligation to look: high benefit to participants, lack of alternative access for participants, and reasonable burden on researchers. Our analysis indicates that there is no obligation to look for incidental findings today, but during the ongoing translation of genomic analysis from research to clinical care, this obligation may arise.
New Strategies in Pancreatic Cancer: Emerging Epidemiologic and Therapeutic Concepts
Authors: Donghui Li, James L. Abbruzzese
Journal: Clinical Cancer Research (2010)

Pancreatic cancer (PC) is a highly lethal disease with complex etiology involving both environmental and genetic factors. Although cigarette smoking is known to explain 25% of cases, data from recent studies suggest that obesity and long-term type II diabetes are two major modifiable risk factors for PC. Furthermore, obesity and diabetes seem to affect the clinical outcome of patients with PC. Understanding the mechanistic effects of obesity and diabetes on the pancreas may identify new strategies for prevention or therapy. Experimental and epidemiologic evidence suggests that the antidiabetic drug metformin has protective antitumor activity in PC. In addition to insulin resistance and inflammation as mechanisms of carcinogenesis, obesity and diabetes are linked to impairments in endothelial function and coagulation status, which increase the risks of thrombosis and angiogenesis and, in turn, the risk of PC development and progression. The associations of the ABO blood group gene and NR5A2 gene variants with PC discovered by recent genome-wide association studies may link insulin resistance, inflammation, and thrombosis to pancreatic carcinogenesis. These exciting findings open new avenues for understanding the etiology of PC and provide opportunities for developing novel strategies for prevention and treatment of this disease.
Total Plasma Homocysteine and Arteriosclerotic Outcomes in Type 2 Diabetes with Nephropathy
Authors: Allon N. Friedman, Lawrence G. Hunsicker, Jacob Selhub, Andrew G. Bostom
Journal: Journal of the American Society of Nephrology (2005)

Total serum homocysteine (tHcy) has been shown to predict de novo and recurrent cardiovascular events in many studies. However, results in diabetic populations with minimal nephropathy are mixed. The independent relationship between tHcy and arteriosclerotic outcomes and congestive heart failure (CHF) events in a population with high cardiovascular risk and diabetic nephropathy was examined. A total of 1575 individuals were enrolled in the international Irbesartan Diabetic Nephropathy Trial (IDNT) and followed for 2.6 yr. All participants had baseline diabetic nephropathy, overt proteinuria, and hypertension and were recruited between 1996 and 1999. A total of 492 total arteriosclerotic outcomes (primary outcome) and 317 CHF events (secondary outcome) were tallied. Established cardiovascular risk factors were highly prevalent, as were high tHcy levels (quintiles [microM]: first 4.5 to 11; second >11 to 13; third >13 to 15; fourth >15 to 19; fifth >19). No association between tHcy and arteriosclerotic outcomes was observed in a univariate model or after adjustment for study randomization and established cardiovascular risk factors. The strongest outcome predictor was the presence of baseline cardiovascular disease, followed by an inverse relationship to diastolic BP. The significant univariate association between tHcy and CHF events disappeared when serum creatinine alone was added to the model. These findings question the utility of tHcy in predicting de novo or recurrent cardiovascular events in individuals with diabetic nephropathy. Further studies are needed to confirm whether these negative results apply to other populations with heavy cardiovascular risk burdens. Previous positive findings can potentially be explained through tHcy's role as a sensitive surrogate marker for kidney disease, itself a recognized cardiovascular risk factor.
Effect of the Direct Renin Inhibitor Aliskiren, the Angiotensin Receptor Blocker Losartan, or Both on Left Ventricular Mass in Patients With Hypertension and Left Ventricular Hypertrophy
Authors: Scott D. Solomon, Evan Appelbaum, Warren J. Manning, Anil Verma, Tommy Berglund, Valentina Lukashevich, Cheraz Cherif Papst, Beverly A. Smith, Björn Dahlöf
Journal: Circulation (2009)

Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients.We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m(2) to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5+/-14.9/3.8+/-10.1 mm Hg in the aliskiren group; 5.5+/-15.6/3.7+/-10.7 mm Hg in the losartan group; 6.6+/-16.6/4.6+/-10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m(2) reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and tolerability were similar across all treatment groups.Aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy.
Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse
Authors: Dontscho Kerjaschki, Zsuzsanna Bago-Horvath, Margaretha Rudas, Veronika Sexl, Christine Schneckenleithner, Susanne Wolbank, Gregor Bartel, Sigurd Krieger, Romana Kalt, Brigitte Hantusch, Thomas Keller, Katalin Nagy-Bojarszky, Nicole Huttary, Ingrid Raab, Karin Lackner, Katharina Krautgasser, Helga Schachner, Klaus Kaserer, Sandra Rezar, Sybille Madlener, Caroline Vonach, Agnes Davidovits, Hitonari Nosaka, Monika Hämmerle, Katharina Viola, Helmut Dolznig, Martin Schreiber, Alexander Nader, Wolfgang Mikulits, Michael Gnant, Satoshi Hirakawa, Michael Detmar, Kari Alitalo, Sebastian Nijman, Felix Offner, Thorsten J. Maier, Dieter Steinhilber, Georg Krupitza
Journal: Journal of Clinical Investigation (2011)

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.
Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high‐risk myelodysplastic syndrome
Authors: Mazyar Shadman, Raya Mawad, Carol Dean, Tara L. Chen, Kathleen Shannon‐Dorcy, Vicky Sandhu, Paul C. Hendrie, Bart L. Scott, Rol B. Walter, Pamela S. Becker, John M. Pagel, Elihu H. Estey
Journal: American Journal of Hematology (2015)

Previous studies suggest that idarubicin/cytarabine(ara-C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly-diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment-related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1-8), cytarabine (1.5 g/m(2) /day; days 4-7), and idarubicin (12 mg/m(2) /day, days 4-6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were "good CR" rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true "good CR rate" was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty-four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved "good CR". 4 of 12 (33%) patients with "good CR" relapsed at median of 16 weeks (10.5-19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7-64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3-4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset.
Use of rituximab in two unusual antibody-mediated autoimmune disorders
Authors: M. Adler
Journal: Journal of the Royal Society of Medicine (2005)

How might tuberculosis chemotherapy induce hyperglycaemia?In patients taking rifampicin for tuberculosis Japanese investigators obtained normal results for intravenous glucose tolerance but hyperglycaemia after oral glucose. 10No such effect was seen with other agents including isoniazid, ethambutol and streptomycin.These workers suggested that rifampicin either augments intestinal absorption of glucose or reduces insulin sensitivity.
Inhaled antibiotics for stable non-cystic fibrosis bronchiectasis: a systematic review
Authors: Alessandra Monteiro Brodt, Elizabeth Stovold, Linjie Zhang
Journal: European Respiratory Journal (2014)

We conducted a meta-analysis of randomised trials to evaluate the efficacy and safety of inhaled antibiotics in patients with stable non-cystic fibrosis (CF) bronchiectasis. We searched the Cochrane Airways Group Register of Trials from inception until March 2014. 12 trials with 1264 adult patients were included, of which five were unpublished studies. Eight trials on 590 patients contributed data to the meta-analysis. Amikacin, aztreonam, ciprofloxacin, gentamicin, colistin or tobramycin were used for 4 weeks to 12 months. Inhaled antibiotics were more effective than placebo or symptomatic treatment in reducing sputum bacterial load (five trials; weighted mean difference −2.65 log 10 CFU·g −1 , 95% CI -4.38– -0.92 log 10 CFU·g −1 ), eradicating the bacteria from sputum (six trials; risk ratio 4.2, 95% CI 1.66–10.64) and reducing the risk of acute exacerbations (five trials; risk ratio 0.72, 95% CI 0.55–0.94). Bronchospasm occurred in 10% of patients treated with inhaled antibiotics compared with 2.3% in the control group (seven trials; risk ratio 2.96, 95% CI 1.30–6.73), but the two groups had the same withdrawal rate due to adverse events (12.2%). Inhaled antibiotics may provide an effective suppressive antibiotic therapy with an acceptable safety profile in adult patients with stable non-CF bronchiectasis and chronic bronchial infection.
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Authors: Shannon L. Maude, Noelle Frey, Pamela A. Shaw, Richard Aplenc, David M. Barrett, Nancy J. Bunin, Anne Chew, Vanessa E. Gonzalez, Zhaohui Zheng, Simon F. Lacey, Yolanda D. Mahnke, Jan J. Melenhorst, Susan R. Rheingold, Angela Shen, David T. Teachey, Bruce L. Levine, Carl H. June, David L. Porter, Stephan A. Grupp
Journal: New England Journal of Medicine (2014)

Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor–modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.