tbuckley/cabot-search huggingface dataset:
miR-21 promotes fibrosis in an acute cardiac allograft transplantation model
Authors: Shashi Kumar Gupta, Ryo Itagaki, Xiang Zheng, Sandor Batkai, Sabrina Thum, Fareed Ahmad, Lucas N. Van Aelst, Amit Sharma, Maria-Teresa Piccoli, Florian Weinberger, Jan Fiedler, Michael Heuser, Stephane Heymans, Christine S. Falk, Reinhold Förster, Sonja Schrepfer, Thomas Thum
Journal: Cardiovascular Research (2016)

Cardiac transplantation is the only curative therapy for end-stage heart failure. Fibrosis is one of the major causes for impaired function of cardiac allografts. MicroRNAs, a class of small non-coding RNAs, play a critical role in the development of cardiovascular disease, but the role of microRNAs in cardiac allograft failure is not well understood. To uncover a role of microRNAs during cardiac graft fibrosis, we generated global microRNA profiles in allogeneic (BALB/c in C57BL/6N) and isogeneic (C57BL/6N in C57BL/6N) murine hearts after transplantation. miR-21 together with cardiac fibrosis was increased in cardiac allografts compared with isografts. Likewise, patients with cardiac rejection after heart transplantation showed increased cardiac miR-21 levels. miR-21 was induced upon treatment with IL-6 in a monocyte cell line. Overexpression of miR-21 in this monocyte cell line activated a fibrotic gene programme and promoted monocyte-to-fibrocyte transition together with activation of chemokine (C-C) motif ligand 2 (monocyte chemoattractant protein 1) via the phosphatase and tensin homologue/activator protein 1 regulatory axis. In vivo, both genetic and pharmacological inhibition of miR-21 successfully reduced fibrosis and fibrocyte accumulation in cardiac allografts. Thus, inhibition of miR-21 is a novel strategy to target fibrosis development in cardiac allografts.
Abstract 15832: Complete Heart Block After Transcatheter Aortic Valve Implantation: A Meta-Analysis
Authors: Arun Kanmanthareddy, Avanija Buddam, Suresh Sharma, Rizwan Afzal, Venkata S Koripalli, Nivedita Adabala, Max Martin, Gabriel Ries, Sudharani Bommana, Donita Atkins, Madhu Reddy, Dhanunjaya Lakkireddy
Journal: Circulation (2014)

Introduction:  Both transcatheter aortic valve implantation (TAVI) surgical aortic valve replacement (SAVR) are associated with risk of complete heart block requiring a pacemaker. Pooled meta-analysis was performed to evaluate the relative risk of developing complete heart block with the above procedures.   Methods:  All electronic databases were queried and studies reporting outcomes of heart block in patients undergoing TAVI and SAVR were included. Exclusion criteria applied was: studies lacking SAVR as controls, studies comparing trans-apical versus trans-femoral TAVI procedures and studies not reporting on the outcome of heart block or pacemaker implantation. Meta-analysis was done using Mantel-Haenszel random effects model.   Results:  A total of 21 studies with a total of 5061 patients were included in the study. TAVI was done in 2692 patients. The risk of AV heart block necessitating pacemaker implantation was very high in the patients undergoing TAVI compared to SAVR (OR 3.5, 95% CI 2.4 - 5.1). Majority of the pacemaker implantations were done immediately after the TAVI procedure. Trans-femoral TAVI’s were associated with higher risk (OR 8.6, 95% CI 3.1 - 28.3) of developing permanent heart block compared to transapical route (OR 2.4, 95% CI, 1.3 - 4.3). CoreValve use was associated with a higher risk of developing permanent heart block (OR 2.4, 95% CI 1.6 - 3.6) than Edward Sapiens Valve (OR 1.9, 95% CI 1.2 - 2.8) compared to SAVR.   Conclusion:  TAVI increases the risk of permanent heart block by 3.5 times and this risk is higher when CoreValve is used and when performed by the transfemoral route. The predictors of development of heart block with TAVI procedure needs further investigation.
Widespread Impact of Chromosomal Inversions on Gene Expression Uncovers Robustness via Phenotypic Buffering
Authors: Samina Naseeb, Zorana Carter, David Minnis, Ian Donaldson, Leo Zeef, Daniela Delneri
Journal: Molecular Biology and Evolution (2016)

The nonrandom gene organization in eukaryotes plays a significant role in genome evolution and function. Chromosomal structural changes impact meiotic fitness and, in several organisms, are associated with speciation and rapid adaptation to different environments. Small sized chromosomal inversions, encompassing few genes, are pervasive in Saccharomyces "sensu stricto" species, while larger inversions are less common in yeasts compared with higher eukaryotes. To explore the effect of gene order on phenotype, reproductive isolation, and gene expression, we engineered 16 Saccharomyces cerevisiae strains carrying all possible paracentric and pericentric inversions between Ty1 elements, a natural substrate for rearrangements. We found that 4 inversions were lethal, while the other 12 did not show any fitness advantage or disadvantage in rich and minimal media. At meiosis, only a weak negative correlation with fitness was seen with the size of the inverted region. However, significantly lower fertility was seen in heterozygote invertant strains carrying recombination hotspots within the breakpoints. Altered transcription was observed throughout the genome rather than being overrepresented within the inversions. In spite of the large difference in gene expression in the inverted strains, mitotic fitness was not impaired in the majority of the 94 conditions tested, indicating that the robustness of the expression network buffers the deleterious effects of structural changes in several environments. Overall, our results support the notion that transcriptional changes may compensate for Ty-mediated rearrangements resulting in the maintenance of a constant phenotype, and suggest that large inversions in yeast are unlikely to be a selectable trait during vegetative growth.
Levels of Cyclic Nucleotides in Autotransplanted 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene-Induced Rat Mammary Tumors During Their Growth and Regression&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Lee, Chung
Journal: JNCI Journal of the National Cancer Institute (1980)

Previous studies indicated that autotransplanted 7, 12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors were hormone-dependent and, if derived from a single primary tumor, many of their metabolic parameters varied little. Therefore, these tumors transplanted in multiple sites provided an opportunity for serial sampling of individual tumors for repeated biochemical evaluations. In the present study, primary mammary tumors induced by DMBA in female noninbred Sprague-Dawley rats were autotransplanted at six sites. When these grafts grew to an average size of 6 cm, the hosts were ovariectomized. Eighteen days later when all tumors were apparently regressing, a silastic tubing 2 cm long containing crystalline estradiol was implanted sc into each host for 14 days. Individual tumors were serially removed from each host before ovariectomy, after ovariectomy, and after estrogen replacement. Levels of cyclic AMP (cAMP) and cyclic GMP (cGMP) in these tumors were measured by radioimmunoassay. Results indicated that tumor regression was associated with an elevation of cAMP levels and that tumor growth was accompanied by a decline in cAMP. The level of cGMP did not correlate with either tumor growth or regression. Therefore, the concept that cAMP is a biologic regulator for tissue proliferation and regression may be applied to the present model of autotransplanted, DMBA-induced rat mammary tumors.
Nutritional Variation Influence on Simian Virus 40-Transformed Human Amnion Cell Strains&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Jorgen Fogh, Edwin V. Gaffney
Journal: JNCI Journal of the National Cancer Institute (1970)

Variation in culture medium and serum affected strains of human amnion cells transformed by simian virus 40 (SV40). McCoy's medium and medium 512, supplemented with either agamma calf serum or fetal bovine serum, were compared. The growth potential, expressed by transfer dilutions or culture longevity before “crisis,” was greater in McCoy's medium than in medium 512, and for each medium increased in the presence of agamma calf serum. Change of medium or serum type during subcultivation did not affect the growth potential. The morphology was epithelium-like in McCoy's medium, fibroblastic in medium 512; however, this could be reversed by change of medium. Chromosome analysis revealed only a few differences related to medium or serum. For 3 of the medium-serum combinations, the SV40 production pattern was triphasic; in medium 512 with fetal bovine serum the level of virus titers was more constant during subcultivation. The earlier appearance and the higher proportion of tumor to viral antigen-containing cells during the period of transformation are correlated with the earlier appearance of transformed foci and the increased growth potential of the transformed cells in McCoy's medium. It is concluded, therefore, that many characteristics of an SV40-transformed amnion cell strain are influenced by the cultural conditions at the time of transformation.
Histological grading in lung cancer: one system for all or separate systems for each histological type?
Authors: William D. Travis, Elisabeth Brambilla, Kim R. Geisinger
Journal: European Respiratory Journal (2016)

The grading of cancer is a histological method intended to help predict prognosis based on specific morphological features. It typically is based on architectural or cytological features (nuclear grade or number of mitoses), or in some cases, a combination of both. Grading is usually broken down into a spectrum from well differentiated (grade 1) to the most poorly differentiated (grade 3 or 4). The number of grades ranges from two to five [1–3]. The highest grade tumours (grade 3 or 4) lack any specific differentiation. The morphological criteria for grading usually differ from that used in histological classification, but in some systems, histological classification is a major component of grade. Two recent studies show the importance of tumour budding and nest size in grading of lung squamous cell carcinoma <http://ow.ly/WTaQ2>
Abstract 10881: Impact of Successive Glycated Hemoglobin Level on Cardiovascular Events in Patients With Type 2 Diabetes
Authors: Takeshi Morimoto, Hisao Ogawa, Mio Sakuma, Sadanori Okada, Hirofumi Soejima, Makiko Ohtorii, Masafumi Nakayama, Shiro Uemura, Masao Kanauchi, Naofumi Doi, Hideaki Jinnouchi, Seigo Sugiyama, Masako Waki, Takahiro Kawano, Yoshihiko Saito
Journal: Circulation (2013)

Objectives: Appropriate glycemic control for preventing cardiovascular events in patients with diabetes is still under investigation. We investigated whether appropriate threshold of glycated hemog...
Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma.
Authors: J L Grem, N McAtee, R F Murphy, J M Hamilton, F Balis, S Steinberg, S G Arbuck, A Setser, E Jordan, A Chen
Journal: Journal of Clinical Oncology (1994)

PURPOSE To determine the toxicities and potential for dose escalation of intravenous (IV) bolus fluorouracil (5-FU) given with 500 mg/m2/d leucovorin (LCV) and granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS Thirty-seven patients received escalating doses of 5-FU/LCV on days 1 to 5 with subcutaneous GM-CSF either 5 or 10 micrograms/kg/d starting on day 6 or 3 micrograms/kg/d starting on day 1. 5-FU was escalated from 370 mg/m2/d by 15% increments between patient cohorts and within patients according to tolerance. RESULTS With GM-CSF starting on day 6, dose-limiting toxicity occurred during cycle no. 1 in all three patients entered at 5-FU 490 mg/m2/d. However, individual patients tolerated 5-FU doses up to 644 mg/m2/d. When all cycles were analyzed, grade 3 to 4 mucositis and grade 4 granulocytopenia complicated &lt; or = 15% and &lt; or = 6% of cycles with 5-FU doses &lt; or = 560 mg/m2/d (115 cycles). With GM-CSF starting on day 1, dose-limiting granulocytopenia occurred during cycle no. 1 in five of 10 patients entered at 5-FU 490 mg/m2/d. Although the granulocyte nadirs were significantly lower at each 5-FU dose level with the concurrent GM-CSF schedule (eg, 490 mg/m2/d: median, 879/microL v3,286/microL; two-tailed P [P2] &lt; .001), dose-limiting granulocytopenia complicated &lt; or = 16% of cycles with 5-FU &lt; or = 560 mg/m2/d (99 cycles); &gt; or = grade 3 mucositis occurred in &lt; or = 20% of cycles. Grade 3 to 4 diarrhea was unusual with either GM-CSF schedule. Most patients treated with GM-CSF &gt; or = 5 micrograms/kg/d required dose reductions for constitutional toxicity; 3.0 to 3.8 micrograms/kg/d was better tolerated. Venous thrombosis occurred in 17% of patients (concurrent v sequential GM-CSF, 29% v 5%; P2 = .08). The median delivered 5-FU dose-intensity for GM-CSF starting either on day 6 or on day 1 was 615 and 647 mg/m2/wk (P2 = .41), respectively. Pharmacologic exposure to 5-FU increased with higher doses of 5-FU, and concurrent GM-CSF administration did not affect 5-FU clearance. CONCLUSION A starting dose of 425 mg/m2/d of 5-FU with LCV on days 1 to 5 could be safely combined with GM-CSF starting either on day 1 or day 6, with further 5-FU dose escalation according to individual tolerance.
Epidemiology of Cancer of the Renal Pelvis and Ureter2
Authors: Rolf Schmauz, Philip Cole
Journal: JNCI Journal of the National Cancer Institute (1974)

forty-three persons with cancer of the renal pelvis or ureter were compared with 509 persons with cancer of the bladder and with controls. Controls were drawn from the population in which the cases occurred. Data were gathered by at-home interviews. Cancers of all 3 sites occur predominantly in men and in old age. Some environmental exposures associated with bladder cancer, i.e., cigarette smoking, coffee drinking, and work with leather, are also related to cancer of the renal pelvis and ureter. However, it appears that only high levels of exposure are associated with increased risk of cancer of the renal pelvis and the ureter. Nonetheless, if causal, these associations would account for most cancers at these sites. The rapid transit of carcinogens through the renal pelvis and ureter may explain the association of cancer at these sites with only high-level exposures.
Abstract 17716: Pre-Procedural Beta Blockade is Associated with Reduced Inpatient Mortality Following Primary PCI: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)
Authors: Javier Valle, Min Zhang, Thomas A Lalonde, Herbert D Aronow, Mauro Moscucci, Hitinder S Gurm
Journal: Circulation (2012)

Introduction:  Early use of beta-adrenergic blockade in acute myocardial infarction (AMI) remains the subject of controversy, with some studies showing benefit and others demonstrating harm. There is a paucity of data on the clinical impact of pre-PCI BB use in patients undergoing primary PCI for ST-elevation myocardial infarction (STEMI).   Methods:  We assessed the association between pre-PCI BB and in-hospital outcome among consecutive patients undergoing primary PCI for STEMI from 2008 to 2009 who were enrolled in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Pre-PCI BB use was defined as any BB given prior to presentation to the cath lab (home, ED, ACS protocol, IV or PO). Inverse propensity score weighting was used to account for the non-randomized use of pre-PCI BBs.   Results:  Our study cohort comprised of 7,667 patients undergoing primary PCI for STEMI during the study period, with 4,769 (62.2%) receiving pre-PCI BB. Patients receiving pre-PCI BB were older and had higher rates of diabetes, HTN, and prior MI, PCI or CABG. In propensity-matched, risk-adjusted models pre-PCI BB use was associated with lower rates of intraprocedural VT/VF requiring therapy (OR 0.58, CI 0.44-0.76, p   Conclusions:  We found that pre-PCI BB use was associated with less intraprocedural VT/VF and lower in-hospital mortality without any increase in the incidence of cardiogenic shock. Our study may suggest a beneficial role for pre-PCI BB in STEMI.
New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape
Authors: Ami B. Patel, Nadeem A. Vellore, Michael W. Deininger
Journal: Clinical Cancer Research (2016)

The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Although these clonal disorders share certain clinical and genetic features, MF in particular is distinct for its complex mutational landscape, severe disease phenotype, and poor prognosis. The genetic complexity inherent to MF has made this disease extremely challenging to treat. Pharmacologic JAK inhibition has proven to be a transformative therapy in MPNs, alleviating symptom burden and improving survival, but has been hampered by off-target toxicities and, as monotherapy, has shown limited effects on mutant allele burden. In this review, we discuss the genetic heterogeneity contributing to the pathogenesis of MPNs, focusing on novel driver and epigenetic mutations and how they relate to combination therapeutic strategies. We discuss results from ongoing studies of new JAK inhibitors and report on new drugs and drug combinations that have demonstrated success in early preclinical and clinical trials, including type II JAK inhibitors, antifibrotic agents, and telomerase inhibitors.
KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung
Authors: David H. Hwang, Lynette M. Sholl, Vanesa Rojas-Rudilla, Dimity L. Hall, Priyanka Shivdasani, Elizabeth P. Garcia, Laura E. MacConaill, Marina Vivero, Jason L. Hornick, Frank C. Kuo, Neal I. Lindeman, Fei Dong
Journal: Journal of Thoracic Oncology (2016)
Polymerase chain reaction detection of melanoma cells in the circulation: relation to clinical stage, surgical treatment, and recurrence from melanoma.
Authors: B J Curry, K Myers, P Hersey
Journal: Journal of Clinical Oncology (1998)

PURPOSE The detection of melanoma cells in the circulation by polymerase chain reaction (PCR) assays has been shown by several investigators to correlate with the stage of the disease and possibly with prognosis. PATIENTS AND METHODS We performed prospective studies on 276 patients with primary melanoma and regional lymph node (LN) metastases to assess the predictive value of PCR detection of tyrosinase and melanoma antigen recognized by T cells-1 (MART-1) in the blood for recurrence of melanoma. RESULTS PCR tests for gp 100, Muc-18, and p97 reacted with RNA in blood from healthy subjects and were considered unsuitable for patient monitoring. The tests were most frequently positive in the first 3 months after surgery. There were 47 recurrences in 123 patients who had been followed up for 18 months. Assays within 3 months of surgery predicted recurrence from melanoma in 66% of the latter (tests for tyrosinase alone detected 51% and MART-1 alone 21% of the patients). Hence, 34% of recurrences were not predicted by tests in the early postoperative period. This did not appear to be because of marker-negative melanoma because summation of tests over the first year identified 89% of those with recurrent disease. CONCLUSION Positive tests were recorded in 35% of patients who remained disease free, but it is too early to assess whether these represent false-positive results. The false-negative results raise the question of whether the assays will provide a reliable basis for selection of patients for adjuvant therapy.
<b>Overspending driven by oversized single dose vials of cancer drugs</b>
Authors: Peter B Bach, Rena M Conti, Raymond J Muller, Geoffrey C Schnorr, Leonard B Saltz
Journal: BMJ (2016)

<b>Peter B Bach and colleagues</b> call for an end to contradictory regulatory standards in the US that allow drug manufacturers to boost profits by producing single dose vials containing quantities that increase leftover drug
Bronchiolitis and Pulse Oximetry
Authors: Lalit Bajaj, Joseph J. Zorc
Journal: JAMA Pediatrics (2016)

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Screening primary sclerosing cholangitis and biliary dysplasia with endoscopic retrograde cholangiography and brush cytology: risk factors for biliary neoplasia
Authors: Sonja Boyd, Andrea Tenca, Kalle Jokelainen, Harri Mustonen, Leena Krogerus, Johanna Arola, Martti Färkkilä
Journal: Endoscopy (2016)

Primary sclerosing cholangitis (PSC) is associated with increased risk of biliary dysplasia and cholangiocarcinoma (CCA). The aim of this study was to evaluate the role of early endoscopic retrograde cholangiography (ERC) with systematic brush cytology to identify risk factors associated with biliary neoplasia.Patients who were referred for their first ERC for suspicion of PSC between January 2006 and October 2011 were included in the study. Brush cytology specimens were scored as benign, suspicious, or malignant. End points were CCA, biliary dysplasia, benign histology, or benign disease course for ≥ 2 years.PSC was diagnosed in 261 patients (125 men, 136 women), most of whom were asymptomatic (n = 211). Cholangiographic changes were mild in 57.1 %. Men presented with advanced disease more often than women. Brush cytology was benign in 243, suspicious in 16, and malignant in 2 patients. Follow-up completed in 249 patients indicated a benign disease course in 232 patients. Seven patients were diagnosed with CCA and eight had biliary dysplasia in the explanted liver. Thus, 15 patients had biliary neoplasia, and suspicious or malignant brush cytology had been detected in 8 of them at initial brushing. Advanced extrahepatic cholangiographic changes with elevated aminotransferases at diagnosis seemed to be associated with increased risk of biliary neoplasia.Even in mostly asymptomatic patients with PSC, 42.9 % had advanced disease and 6.9 % presented with suspicious or malignant brush cytology at first ERC. Advanced extrahepatic ERC changes with elevated aminotransferases at diagnosis might be risk factors for biliary neoplasia.