tbuckley/cabot-search huggingface dataset:
Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the Pathophysiology of Obesity-Associated Cardiovascular Disease
Authors: Robert H. Eckel, Winifred W. Barouch, Abby G. Ershow
Journal: Circulation (2002)

T he ongoing obesity epidemic and its impending cardio- vascular consequences represent a serious public health problem with worrisome implications for medical treatment.The urgency of providing new research directions recently led the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to convene a Working Group on the Pathophysiology of Obesity-Associated Cardiovascular Disease.Gathered at this meeting were researchers with substantial experience and expertise in either obesity-related sciences, including epidemiology, endocrinology, and metabolism, or cardiovascular sciences, including cardiology, neurobiology, hematology, renal function, and pediatrics.This report is the culmination of the blending of ideas during the 2-day meeting.The resulting research recommendations include the development of new models and synergistic approaches to basic studies of obesity-associated cardiovascular diseases.
Role of angiotensin-converting enzyme in Bacille Calmette-Guérin-induced granulomatous inflammation. Increased angiotensin-converting enzyme levels in lung lavage and suppression of inflammation with captopril.
Authors: D J Schrier, L M Ripani, A L Katzenstein, V L Moore
Journal: Journal of Clinical Investigation (1982)

Lung lavage levels of angiotensin-converting enzyme (ACE)-like activity were increased in C57BL/6 mice with Bacille Calmette-Guérin (BCG)-induced chronic granulomatous pulmonary inflammation and splenomegaly. Contrariwise, ACE activity was not increased in lung lavage fluids of CBA mice that developed only minimal pulmonary inflammation in response to BCG. ACE-like activity correlated with the intensity of inflammation and Captopril, a specific competitive inhibitor of ACE activity, markedly suppressed the induction and maintenance of the BCG-induced inflammatory response in both lungs and spleen. It was necessary, however, to provide sustained treatment with large doses of Captopril in order to reduce the inflammatory response. After a single intraperitoneal injection of Captopril, ACE levels in lung lavage of BCG-injected mice were reduced but returned to preinjection levels or greater within 24 h. The highest dose of Captopril was more effective in reducing the lung fluid level of ACE in BCG-inflamed lungs. This suggests that sustained daily injections of Captopril were necessary to maintain reduced ACE levels. In vitro studies indicated that high concentrations of Captopril did not affect macrophage mobility or chemotactic activity for macrophages. Thus, ACE may act as a molecular mediator of BCG-induced granulomatous inflammation in the lung.
Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease
Authors: Danilo Fliser, Barbara Kollerits, Ulrich Neyer, Donna P. Ankerst, Karl Lhotta, Arno Lingenhel, Eberhard Ritz, Florian Kronenberg
Journal: Journal of the American Society of Nephrology (2007)

It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated.
Cutis marmorata telangiectatica congenita: report of 18 cases
Authors: M.J.P. Gerritsen, P.M. Steijlen, H.G. Brunner, P. Rieu
Journal: British Journal of Dermatology (2000)

We report 18 patients with cutis marmorata telangiectatica congenita (CMTC) who visited the University Hospital Nijmegen between 1982 and 1999. In 11 patients (61%), associated abnormalities of varying severity were observed. Three of these patients had a previously described distinct syndrome comprising CMTC, a naevus flammeus at the upper lip/philtrum, macrocephaly and syndactyly, among other abnormalities. Findings in the other eight patients with associated abnormalities included hydrocephalus, hyperplasia/hypoplasia (body asymmetry), anal atresia, hearing loss, cardiovascular abnormalities, strabismus hypothyroidism, haemangioma, naevus anaemicus, café‐au‐lait spot, lipoma and an elevation of the right diaphragm. All cases were sporadic.
Dual mTORC1/2 and HER2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-HER2 Therapy
Authors: Celina García-García, Yasir H. Ibrahim, Violeta Serra, Maria Teresa Calvo, Marta Guzmán, Judit Grueso, Claudia Aura, José Pérez, Katti Jessen, Yi Liu, Christian Rommel, Josep Tabernero, José Baselga, Maurizio Scaltriti
Journal: Clinical Cancer Research (2012)

The PI3K/Akt/mTOR pathway is an attractive target in HER2-positive breast cancer that is refractory to anti-HER2 therapy. The hypothesis is that the suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance.We analyzed in vitro cell viability and induction of apoptosis in five different cell lines resistant to trastuzumab and lapatinib. Inhibition of HER2/HER3 phosphorylation, PI3K/Akt/mTOR, and extracellular signal-regulated kinase (ERK) signaling pathways was evaluated by Western blotting. Tumor growth inhibition after treatment with lapatinib, INK-128, or the combination of both agents was evaluated in three different animal models: two cell-based xenograft models refractory to both trastuzumab and lapatinib and a xenograft derived from a patient who relapsed on trastuzumab-based therapy.The addition of lapatinib to INK-128 prevented both HER2 and HER3 phosphorylation induced by INK-128, resulting in inhibition of both PI3K/Akt/mTOR and ERK pathways. This dual blockade produced synergistic induction of cell death in five different HER2-positive cell lines resistant to trastuzumab and lapatinib. In vivo, both cell line-based and patient-derived xenografts showed exquisite sensitivity to the antitumor activity of the combination of lapatinib and INK-128, which resulted in durable tumor shrinkage and exhibited no signs of toxicity in these models.The simultaneous blockade of both PI3K/Akt/mTOR and ERK pathways obtained by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer models refractory to anti-HER2 therapy.
10-year long-term survival of a metastatic<i>EGFR</i>-mutated nonsmall cell lung cancer patient
Authors: Emmanuelle Kempf, David Planchard, Thierry Le Chevalier, Jean-Charles Soria
Journal: European Respiratory Journal (2015)

10 years ago, the US Food and Drug Administration approved erlotinib in the second and third line settings for unselected advanced nonsmall cell lung cancer (NSCLC) patients. Activating EGFR mutations were discovered by analysing patient subgroups who responded to oral, first-generation, single-target reversible EGFR tyrosine kinase inhibitor (TKI). Nine randomised phase III chemotherapy-controlled trials in EGFR -mutant NSCLC naive patients showed the superiority of gefitinib, erlotinib and afatinib, respectively, in terms of response rate and progression-free survival. Response rate is in the range of 70% and progression-free survival about 1 year. Exon 19 in-frame deletions represent about 45% of overall EGFR mutations and half of the sensitising ones [1]. New generation targeted therapies are currently under clinical development. However, treatment sequence is still debated after a first line of EGFR TKI regimen in these molecularly selected patients. We herein report a case of a metastatic EGFR -mutated lung adenocarcinoma patient who achieved a prolonged survival of 10 years through multiple surgical and medical treatments (fig. 1) TKI should be used sequentially with chemotherapy and local procedures to prolong life in EGFR -mutated lung cancer <http://ow.ly/KRWP4>
PharmGKB Submission Update: VIII. PBAT Submission of Genetic Variation in <i>VKORC1</i> to the PharmGKB Network
Authors: Brian F. Gage, Charles S. Eby
Journal: Pharmacological Reviews (2006)

Category: genotype Project: Pharmacogenetics, Biomarkers, and Antithrombotic Therapy [Table 1][1] provides the HUGO Gene Nomenclature Committee (HGNC) symbol, PharmGKB submission URL, submission date, and release date. [Table 2][2] provides the HGNC symbol, HGNC name, synonym, GenBank accession
Met Kinase Inhibitor E7050 Reverses Three Different Mechanisms of Hepatocyte Growth Factor–Induced Tyrosine Kinase Inhibitor Resistance in <i>EGFR</i> Mutant Lung Cancer
Authors: Wei Wang, Qi Li, Shinji Takeuchi, Tadaaki Yamada, Hitomi Koizumi, Takahiro Nakamura, Kunio Matsumoto, Naofumi Mukaida, Yasuhiko Nishioka, Saburo Sone, Takayuki Nakagawa, Toshimitsu Uenaka, Seiji Yano
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI–resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. Experimental Design: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed. Results: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. Conclusions: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs. Clin Cancer Res; 18(6); 1663–71. ©2012 AACR.
Cost-Effectiveness of Pooled Nucleic Acid Amplification Testing for Acute HIV Infection after Third-Generation HIV Antibody Screening and Rapid Testing in the United States: A Comparison of Three Public Health Settings
Authors: Angela B. Hutchinson, Pragna Patel, Stephanie L. Sansom, Paul G. Farnham, Timothy J. Sullivan, Berry Bennett, Peter R. Kerndt, Robert K. Bolan, James D. Heffelfinger, Vimalanand S. Prabhu, Bernard M. Branson
Journal: PLoS Medicine (2010)

Angela Hutchinson and colleagues conducted a cost-effectiveness analysis of pooled nucleic acid amplification testing following HIV testing and show that it is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.
HER-2 Testing and Trastuzumab Therapy for Metastatic Breast Cancer: A Cost-Effectiveness Analysis
Authors: Elena B. Elkin, Milton C. Weinstein, Eric P. Winer, Karen M. Kuntz, Stuart J. Schnitt, Jane C. Weeks
Journal: Journal of Clinical Oncology (2004)

Trastuzumab therapy has been shown to benefit metastatic breast cancer patients whose tumors exhibit HER-2 protein overexpression or gene amplification. Several tests of varying accuracy and cost are available to identify candidates for trastuzumab. We estimated the cost-effectiveness of alternative HER-2 testing and trastuzumab treatment strategies.We performed a decision analysis using a state-transition model to simulate clinical practice in a hypothetical cohort of 65-year-old metastatic breast cancer patients. Outcomes were quality-adjusted life-years (QALYs), lifetime cost, and incremental cost-effectiveness ratio (ICER). Interventions included testing with the HercepTest (DAKO, Carpinteria, CA) immunohistochemical assay alone, fluorescence in situ hybridization (FISH) alone, and both tests, followed by trastuzumab and chemotherapy for patients with positive test results and chemotherapy alone for patients with negative test results.In the base case, initial HercepTest with FISH confirmation of all positive results had an ICER of $125,000 per QALY gained. The incremental cost-effectiveness of initial FISH was $145,000 per QALY gained. Other strategies yielded the same or poorer effectiveness at a higher cost, or lower effectiveness at a lower cost, but with a less favorable ICER. These findings persisted under a range of assumptions, and only changes in test characteristics substantially altered results.It is more cost-effective to use FISH alone or as confirmation of all positive HercepTest results, rather than using FISH to confirm only weakly positive results or using HercepTest alone. When multiple tests are available to identify treatment candidates, test characteristics may have a substantial impact on the aggregate costs and effectiveness of treatment.
Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome
Authors: C. J. J. Boogerd, D. Dooijes, A. Ilgun, I. B. Mathijssen, R. Hordijk, I. M. B. H. van de Laar, P. Rump, H. E. Veenstra-Knol, A. F. M. Moorman, P. Barnett, A. V. Postma
Journal: Cardiovascular Research (2010)

Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome, the majority of which lead to premature stops. In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations.Functional characterization of mutant proteins shows a dramatic loss of DNA-binding capacity, as well as diminished binding to known cardiac interaction partners NKX2-5 and GATA4. The disturbance of these interactions leads to a loss of function, as measured by the reduced activation of Nppa and FGF10 in rat heart derived cells, although with variable severity. Two out of the five mutations are peculiar: one, p.H220del, is associated with additional extra-cardiac defects, perhaps by interfering with other T-box dependant pathways, and another, p.I106V, leads to limb defects only, which is supported by its normal interaction with cardiac-specific interaction partners.Overall, our data are consistent with the hypothesis that these novel missense mutations in TBX5 lead to functional haploinsufficiency and result in a reduced transcriptional activation of target genes, which is likely central to the pathogenesis of HOS.
Impairment of T Cell Development in <i>δ</i> <i>EF1</i> Mutant Mice
Authors: Yujiro Higashi, Hiroki Moribe, Tsuyoshi Takagi, Ryohei Sekido, Kiyoshi Kawakami, Hitoshi Kikutani, Hisato Kondoh
Journal: The Journal of Experimental Medicine (1997)

Using the method of gene targeting in mouse embryonic stem cells, regulatory function of δEF1, a zinc finger and homeodomain-containing transcription factor, was investigated in vivo by generating the δEF1 mutant mice. The mutated allele of δEF1 produced a truncated form of the δEF1 protein lacking a zinc finger cluster proximal to COOH terminus. The homozygous δEF1 mutant mice had poorly developed thymi with no distinction of cortex and medulla. Analysis of the mutant thymocyte showed reduction of the total cell number by two orders of magnitude accompanying the impaired thymocyte development. The early stage intrathymic c-kit+ T precursor cells were largely depleted. The following thymocyte development also seemed to be affected as assessed by the distorted composition of CD4- or CD8-expressing cells. The mutant thymocyte showed elevated α4 integrin expression, which might be related to the T cell defect in the mutant mice. In the peripheral lymph node tissue of the mutant mice, the CD4−CD8+ single positive cells were significantly reduced relative to CD4+CD8− single positive cells. In contrast to T cells, other hematopoietic lineages appeared to be normal. The data indicated that δEF1 is involved in regulation of T cell development at multiple stages.
The Kiwi way: lessons from New Zealand
Authors: J. Ovretveit
Journal: BMJ (1996)

New Zealand is proud of being the first country to create a universal social security system and free health care in the late 1930s. This reflects the strong socialist tradition of the country, which has been sustained by a scarcity of labour for most of its history. It was the socialist party that introduced deregulation and market reforms in the 1980s. Nationalised industries were privatised, but the health service was untouched until a conservative government introduced market type reforms in 1993. Reforms are modelled on the British system, with a purchaser and provider split, competition for income through contracts, but without primary care purchasing. The area health boards have been abolished and four purchasing regional health authorities set up with populations of around 800000 each. The changes generated much controversy, although it is arguable that the reforms only made more visible the many problems of the health care system that are similar to those faced by Britain.

Two unpopular changes were abolishing political boards at area and hospital level and introducing charges for each day of stay in hospital. After a few months the hospital charges were dropped but there is still concern about the lack of local representation and accountability, especially in relation to the large purchasing organisations, which are viewed as remote from the people they are supposed to serve. Partly to make up for lack of local representation, purchasers and other public health …
A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.
Authors: Y Pei, N He, K Wang, M Kasenda, A D Paterson, G Chan, Y Liang, J Roscoe, J Brissenden, D Hefferton, P Parfrey, S Somlo, P St George-Hyslop
Journal: Journal of the American Society of Nephrology (1998)

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Linkage studies have shown that the majority (approximately 85%) of cases are due to mutations in PKD1 on chromosome 16p, while mutations in PKD2 on chromosome 4q account for most of the remaining cases. Locus heterogeneity in ADPKD is known to contribute to differences in disease severity, with PKD1-linked families having earlier onset of end-stage renal disease (ESRD) than PKD2-linked families (mean age at ESRD: 56 versus 70, respectively). In this study, 11 Canadian families with ADPKD were screened for PKD2 mutations. In four families, linkage to PKD2 was previously documented. In the remaining seven smaller families, one or more affected members had late-onset ESRD at age 70 or older. Using single-stranded conformational polymorphism analysis, one affected member from each family was screened for mutations in all 15 exons of PKD2, which were PCR-amplified from genomic templates. A spectrum of mutations was found in approximately 73% (8 of 11) of the families screened, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In three unrelated families, insertion or deletion of an adenosine in a polyadenosine tract (i.e., (A)8 at nt 2152-2159) was found on exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from "slipped strand mispairing." All mutations, scattered between exons 1 and 11, are predicted to result in a truncated polycystin 2 that lacks both the calcium-binding EF-hand domain and the two cytoplasmic domains required for the interaction of polycystin 2 with polycystin 1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. Thus, these findings are consistent with other recently published reports and suggest that most PKD2 mutations are inactivating.
Morphological Methods for Evaluation of Pulmonary Toxicity in Animals
Authors: D L Dungworth, L W Schwartz, W S Tyler, R F Phalen
Journal: The Annual Review of Pharmacology and Toxicology (1976)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Stress Reactions of Children and Adolescents in War and Siege Conditions
Authors: Syed Arshad Husain, Jyotsna Nair, William Holcomb, John C. Reid, Victor Vargas, Satish S. Nair
Journal: American Journal of Psychiatry (1998)

Objective:This was a study of posttraumatic stress symptoms in children and adolescents during siege conditions in Sarajevo.Method:Seven hundred ninety-one students aged 7–15 years were surveyed to assess symptoms of posttraumatic stress and level of deprivation.Results:Girls reported more stress than boys. Loss of family members and deprivation of basic needs were associated with more symptoms. Conclusions:Personal experiences of siege are related to increased stress. Am J Psychiatry 1998; 155: 1718-1719