tbuckley/cabot-search huggingface dataset:
Relation of Drinking Alcohol to Atherosclerotic Risk in Type 2 Diabetes
Authors: Ichiro Wakabayashi, Rie Kobaba-Wakabayashi, Hiroshi Masuda
Journal: Diabetes Care (2002)

The effects of drinking alcohol on atherosclerotic risks were investigated in 194 type 2 diabetic patients to determine whether drinking alcohol influences risk of atherosclerosis in diabetic subjects.The subjects were divided by the degree of their average weekly alcohol consumption into three groups: nondrinkers, light drinkers (ethanol consumption <210 g/week), and heavy drinkers (ethanol consumption > or = 210 g/week). The degree of atherosclerotic progression was evaluated using aortic pulse wave velocity (a-PWV), and possible atherosclerotic risks were evaluated using known atherosclerotic risk factors.a-PWV was significantly lower in light drinkers than in nondrinkers and heavy drinkers, but there was no significant difference in a-PWV between nondrinkers and heavy drinkers. Systolic blood pressure, HDL cholesterol, and triglyceride levels were significantly higher in heavy drinkers than in nondrinkers and light drinkers, whereas there was no significant difference in these levels between nondrinkers and light drinkers. The mean levels of BMI and blood HbA(1c), uric acid, and fibrinogen were not different between the three groups. There were significant positive correlations of a-PWV with age and systolic blood pressure and weak but significant negative correlations of a-PWV with alcohol consumption and HDL cholesterol level.Light drinking, but not heavy drinking, has preventive effects on atherosclerosis in type 2 diabetic subjects. The known beneficial effects of drinking alcohol on blood lipids and fibrinogen may not be involved in the preventive effect of light drinking on atherosclerosis in diabetic subjects.
Development of Resistance Models to Tyrosine Kinase Inhibitors (TKIS) in Patient-Derived Xenograft Models (PDXS) of Lung Adenocarcinoma with Epidermal Growth Factor Receptor (EGFR) Mutations
Authors: E.L. Stewart, S. Sakashita, T. Wang, N.-A. Pham, M. Li, G. Liu, M.S. Tsao
Journal: Annals of Oncology (2015)
New Strategies in Head and Neck Cancer: Understanding Resistance to Epidermal Growth Factor Receptor Inhibitors
Authors: Lucy F. Chen, Ezra E.W. Cohen, Jennifer R. Grandis
Journal: Clinical Cancer Research (2010)

Abstract The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma of the head and neck (HNSCC). However, despite high expression of EGFR in these cancers, EGFR inhibitor monotherapy has only had modest activity. Potential mechanisms of resistance to EGFR-targeted therapies involve EGFR and Ras mutations, epithelial-mesenchymal transition, and activation of alternative and downstream pathways. Strategies to optimize EGFR-targeted therapy in head and neck cancer involve not only the selection for patients most likely to benefit but also the use of combination therapies to target the network of pathways involved in tumor growth, invasion, angiogenesis, and metastasis. Clin Cancer Res; 16(9); 2489–95. ©2010 AACR.
Impaired voluntary drive to breathe: a possible link between depression and unexplained ventilatory failure in asthmatic patients.
Authors: G M Allen, I Hickie, S C Gandevia, D K McKenzie
Journal: Thorax (1994)

BACKGROUND--Although psychological distress predicts mortality in asthma, an underlying physiological link has not been shown. This study examined relations between impaired voluntary drive to breathe and measures of mood states. METHODS--The level of maximal voluntary activation of the diaphragm and elbow flexors was measured in a previous study using a sensitive modification of the twitch interpolation technique in 11 asthmatic and 10 control subjects. In this study psychological distress was assessed using the Profile of Mood States questionnaire and measures of distress were compared with the muscle voluntary activation results. RESULTS--For the asthmatic subjects, depressed mood increased the risk of impaired maximal voluntary activation of the diaphragm by 3.5 times (95% CI 1.09 to 11.3). No such association was observed in control subjects. CONCLUSIONS--These results suggest that depressed mood may predispose an asthmatic patient to impaired voluntary activation of the diaphragm. Such individuals would be at increased risk of rapidly developing ventilatory failure if faced with severe airway narrowing.
Cytogenetic Findings in Persons Living Near the Love Canal
Authors: Clark W. Heath
Journal: JAMA (1984)

Cytogenetic analyses were performed on peripheral blood from 46 present or past residents of the area surrounding Love Canal, a former dump site for chemical wastes in Niagara Falls, NY. Participants included 17 persons in whom cytogenetic analyses had been performed in 1980 and 29 persons who had been living in 1978 in seven homes that directly adjoined the canal and in which environmental tests showed elevated levels of chemicals spreading from the canal. Frequencies of chromosomal aberrations and of sister chromatid exchange (SCE) did not differ significantly from control levels. For all participants, cigarette smoking was associated with an increase in sister chromatid exchange frequency.
Abstract 1776: Lymphomas associated with aberrant DNA rearrangements are suppressed by Mre11 mutation.
Authors: Cheryl J. Smith, Jeffrey Xie, David O. Ferguson, JoAnn M. Sekiguchi
Journal: Cancer Research (2013)

Abstract Many translocations associated with spontaneous human lymphoid malignancies are mediated by short regions of sequence homology (microhomology) at the breakpoints. The hallmark features of this error prone pathway are deletions of flanking sequence and short homologies of 1-25 bases at the junctions that serve to align the DNA ends prior to joining. In addition to its importance in the etiology of human cancers, microhomology-mediated joining or alternative NHEJ (aNHEJ) also appears to play a significant role in therapy-induced oncogenic translocations. Studies have provided compelling evidence that the DNA end-binding complex composed of Mre11 (nuclease), Rad50 (tetherer) and Nbs1 (signaler)–MRN–functions in the context of the aNHEJ pathway. In addition, in vivo and cell based studies have identified that deficiencies in components of the MRN complex reduce aNHEJ activity. However, it is not known whether the MRN complex participates in the generation of aNHEJ catalyzed translocations that can predispose to cancer. Therefore, our studies seek to better understand the contribution of Mre11/MRN to the aNHEJ pathway and thus, in generation of translocations. We have obtained mice harboring an Mre11 conditionally targeted null allele as well as an Mre11 knock-in mutation that abrogates nuclease activity. We have included mutant mice in this study that succumb to early onset Pro-B lymphomas associated with clonal translocations containing microhomologies of 2-8 nucleotides. Thus, the spontaneously arising tumors in this mutant background represent a valuable in vivo system to assess the involvement of Mre11/MRN in aNHEJ mediated translocations. We have determined that Mre11/MRN inactivation in the B-cell lineage suppresses Pro-B lymphoma in this mutant background. In future experiments we are investigating the impact of Mre11/MRN inactivation on various cancer phenotypes. Together, these studies will provide insights into the mechanisms underlying human lymphoma and may ultimately provide insights into targets for improved treatment of lymphoid malignancies. Citation Format: Cheryl J. Smith, Jeffrey Xie, David O. Ferguson, JoAnn M. Sekiguchi. Lymphomas associated with aberrant DNA rearrangements are suppressed by Mre11 mutation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1776. doi:10.1158/1538-7445.AM2013-1776
Macrophages are a significant source of type 1 cytokines during mycobacterial infection
Authors: Jun Wang, Julia Wakeham, Robin Harkness, Zhou Xing
Journal: Journal of Clinical Investigation (1999)

T-helper 1 (Th1) cells are believed to be the major producer of the type 1 cytokine interferon-γ (IFN-γ) in cell-mediated immunity against intracellular infection. We have investigated the ability of macrophages to release type 1 cytokines and their regulatory mechanisms using both in vivo and in vitro models of pulmonary mycobacterial infection. During pulmonary infection by live Mycobacterium bovis bacilli Calmette-Guérin (BCG) in wild-type mice, lung macrophages released interleukin-12 (IL-12), IFN-γ, and tumor necrosis factor-α (TNF-α), and expressed surface activation markers. However, macrophages in infected IL-12–/– mice released TNF-α but not IFN-γ and lacked surface activation makers. In freshly isolated lung macrophages from naive IL-2–/– mice, mycobacteria alone released TNF-α but not IFN-γ, whereas exogenously added IL-12 alone released a minimum of IFN-γ. However, these macrophages released large quantities of IFN-γ upon stimulation with both mycobacteria and IL-12. In contrast, mycobacteria and exogenous IFN-γ released only a minimum of endogenous IFN-γ. Endogenous IL-18 (IFN-γ–inducing factor) played little role in IFN-γ responses by macrophages stimulated by mycobacteria and IL-12. Our data reveal that macrophages are a significant source of type 1 cytokines during mycobacterial infection and that both IL-12 and intracellular pathogens are required for the release of IFN-γ but not TNF-α. These findings suggest that macrophages regulate cell-mediated immunity by releasing not only IL-12 and TNF-α but also IFN-γ and that full activation of IFN-γ response in macrophages is tightly regulated.
Long-Term Event-Free Survival After Intensive Chemotherapy for Ewing’s Family of Tumors in Children and Young Adults
Authors: E. Anders Kolb, Brian H. Kushner, Richard Gorlick, Caroline Laverdiere, John H. Healey, Michael P. LaQuaglia, Andrew G. Huvos, Jing Qin, Ha Thanh Vu, Leonard Wexler, Suzanne Wolden, Paul A. Meyers
Journal: Journal of Clinical Oncology (2003)

To improve the long-term event-free survival of patients with Ewing's family of tumors (EFTs) using high-dose, short-term chemotherapy.P6 was a prospective study of previously untreated patients with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d.Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy.Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.
Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles
Authors: Nur Duale, Birgitte Lindeman, Mitsuko Komada, Ann-Karin Olsen, Ashild Andreassen, Erik J Soderlund, Gunnar Brunborg
Journal: Molecular Cancer (2007)

Abstract Background Testicular germ cell tumors (TGCTs) respond well to cisplatin-based chemotherapy and show a low incidence of acquired resistance compared to most somatic tumors. The reasons for these specific characteristics are not known in detail but seem to be multifactorial. We have studied gene expression profiles of testicular and colon cancer derived cell lines treated with cisplatin. The main goal of this study was to identify novel gene expression profiles with their functional categories and the biochemical pathways that are associated with TGCT cells' response to cisplatin. Results Genes that were differentially expressed between the TGCT cell lines vs the (somatic) HCT116 cell line, after cisplatin treatment, were identified using the significance analysis of microarrays (SAM) method. The response of TGCT cells was strikingly different from that of HCT116, and we identified 1794 genes that were differentially expressed. Functional classification of these genes showed that they participate in a variety of different and widely distributed functional categories and biochemical pathways. Database mining showed significant association of genes (n = 41) induced by cisplatin in our study, and genes previously reported to by expressed in differentiated TGCT cells. We identified 37 p53-responsive genes that were altered after cisplatin exposure. We also identified 40 target genes for two microRNAs, hsa-mir-372 and 373 that may interfere with p53 signaling in TGCTs. The tumor suppressor genes NEO1 and LATS2 , and the estrogen receptor gene ESR1 , all have binding sites for p53 and hsa-mir-372/373. NEO1 and LATS2 were down-regulated in TGCT cells following cisplatin exposure, while ESR1 was up-regulated in TGCT cells. Cisplatin-induced genes associated with terminal growth arrest through senescence were identified, indicating associations which were not previously described for TGCT cells. Conclusion By linking our gene expression data to publicly available databases and literature, we provide a global pattern of cisplatin induced cellular response that is specific for testicular cancer cell lines. We have identified cisplatin-responsive functional classes and pathways, such as the angiogenesis, Wnt, integrin, and cadherin signaling pathways. The identification of differentially expressed genes in this study may contribute to a better understanding of the unusual sensitivity of TGCT to some DNA-damaging agents.
Drug Detailing in Academic Medical Centers: Regulating for the Right Reasons, with the Right Evidence, at the Right Time
Authors: Michael A. Steinman, Dean Schillinger
Journal: The American Journal of Bioethics (2010)

In this month's issue of AJOB, Huddle recapitulates several arguments against prohibiting drug detailing in academic medical centers. Briefly stated, Huddle argues that empiric data on the effects of detailing are not definitive, and that restricting interaction with sales representatives does not rise to the level of an “unqualified ethical imperative.” As a result, Huddle argues that professional ethics do not mandate an opposition to detailing, and that policy responses should be “prudential.” In recommending a blanket prohibition on detailing and framing the issue as one of professional ethics, Huddles believes the AAMC overstepped its bounds.

While Huddle outlines the reasoning for each of these arguments in more detail than is often articulated, the conclusions of each of these arguments are nonetheless incorrect.
The role of complement in the adherence of microbubbles to dysfunctional arterial endothelium and atherosclerotic plaque
Authors: D ANDERSON, J TSUTSUI, F XIE, S RADIO, T PORTER
Journal: Cardiovascular Research (2006)

To determine whether serum complement C3 mediates adherence of albumin-encapsulated microbubbles to vascular endothelium in the development of atherosclerotic plaques.Adherence of microbubbles to aortic endothelium was examined with scanning electron microscopy following intravenous injection of 20% intralipid in wild-type mice, genetic complement-deficient mice (C3-/-), and in pharmacologic C3-depleted wild-type mice. In a second experimental model, atherosclerostic plaque was induced in apolipoprotein E-deficient mice (apoE-/-), and adherence of microbubbles to atherosclerotic plaques was evaluated using fluorescent microscopy of fluorescein isothiocynate-conjugated microbubbles. Finally, imaging of aortas was performed in eight rats (four JCR:LA-cp atherosclerosis-prone rats on high cholesterol diets; four controls) following intravenous albumin microbubble injections (PESDA) to determine whether microbubble adherence to the endothelium could be detected with low mechanical index pulse sequence schemes.Scanning electron microscopy confirmed the adherence of microbubbles to the endothelial cells of the aorta in wild-type mice following induction of hypertriglyceridemia but not in C3-depleted mice. Microbubble adherence to the endothelial surface of atherosclerotic plaque was confirmed in all apoE-/- mice (median 172 microbubbles/field; compared to a median of 3 microbubbles/field in cobra venom factor-treated apoE-/- mice; p < 0.001). Low mechanical index ultrasound imaging detected microbubble adherence in all JCR atherosclerosis prone rats even in the absence of vasomotor or phenotypical evidence of endothelial dysfunction. The numbers of adherent microbubbles correlated with serum triglyceride levels, and were seen in conjunction with increased endothelial nitric oxide synthase activity.Complement C3 binds to albumin-encapsulated microbubbles and mediates microbubble adherence to vascular endothelium both early and late in the atherosclerotic process.
Chronic painless pancreatitis
Authors: S. J. M. Goulston, N. D. Gallagher
Journal: Gut (1962)

This paper describes four patients whose chief symptoms were steatorrhoea and loss of weight. Despite the absence of a history of abdominal pain investigations showed that these patients had chronic pancreatitis, which responded to medical treatment. The pathological findings in two of these cases and in six which came to necropsy are reported.
Dysfunctional uterine bleeding
Authors: Joan Pitkin
Journal: BMJ (2007)

#### Practical tips

Dysfunctional uterine bleeding is defined as abnormal uterine bleeding in the absence of organic disease. It usually presents as menorrhagia without an underlying cause, and it affects women's health both medically and socially. Among women aged 30-49 years, one in 20 consults her general practitioner each year with menorrhagia; making dysfunctional uterine bleeding one of the most often encountered gynaecological problems. About 30% of all women report having had menorrhagia, and it accounts for two thirds of all hysterectomies and most endoscopic endometrial destructive surgery.

Excessive menstrual bleeding has several adverse effects, including anaemia and iron deficiency, reduced quality of life, and increased healthcare costs because it is a major indication for referral to gynaecological outpatient clinics. Each year around £7m (€10m; $14m) is spent in the United Kingdom on prescriptions in primary care to treat menorrhagia.

Menorrhagia …
Radiographic assessment of the knee joint in osteoarthritis.
Authors: C Cooper, J Cushnaghan, J R Kirwan, P A Dieppe, J Rogers, T McAlindon, F McCrae
Journal: Annals of the Rheumatic Diseases (1992)

The development of radiographic systems for the grading of osteoarthritis requires knowledge of the reproducibility of their individual component features. This paper reports the reproducibility, both within and between observers, for five commonly used radiographic features of osteoarthritis in the tibiofemoral and patellofemoral compartments of the knee joint. The results suggest that assessments of joint space narrowing, osteophyte, and bony contour in the tibiofemoral compartments are more reproducible than those of sclerosis and cyst. Patellofemoral assessments, with the exception of osteophyte, are considerably less reproducible between observers than tibiofemoral assessments.
Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy
Authors: Chantal A Mutsaers, Douglas J Lamont, Gillian Hunter, Thomas M Wishart, Thomas H Gillingwater
Journal: Genome Medicine (2013)

Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations in the survival motor neuron 1 (SMN1) gene. Recent breakthroughs in preclinical research have highlighted several potential novel therapies for SMA, increasing the need for robust and sensitive clinical trial platforms for evaluating their effectiveness in human patient cohorts. Given that most clinical trials for SMA are likely to involve young children, there is a need for validated molecular biomarkers to assist with monitoring disease progression and establishing the effectiveness of therapies being tested. Proteomics technologies have recently been highlighted as a potentially powerful tool for such biomarker discovery.We utilized label-free proteomics to identify individual proteins in pathologically-affected skeletal muscle from SMA mice that report directly on disease status. Quantitative fluorescent western blotting was then used to assess whether protein biomarkers were robustly changed in muscle, skin and blood from another mouse model of SMA, as well as in a small cohort of human SMA patient muscle biopsies.By comparing the protein composition of skeletal muscle in SMA mice at a pre-symptomatic time-point with the muscle proteome at a late-symptomatic time-point we identified increased expression of both Calreticulin and GRP75/Mortalin as robust indicators of disease progression in SMA mice. We report that these protein biomarkers were consistently modified in different mouse models of SMA, as well as across multiple skeletal muscles, and were also measurable in skin biopsies. Furthermore, Calreticulin and GRP75/Mortalin were measurable in muscle biopsy samples from human SMA patients.We conclude that label-free proteomics technology provides a powerful platform for biomarker identification in SMA, revealing Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers capable of reporting on disease progression in samples of muscle and skin.
Rat aortic smooth muscle cells in culture express kallikrein, kininogen, and bradykininase activity.
Authors: N B Oza, J H Schwartz, H D Goud, N G Levinsky
Journal: Journal of Clinical Investigation (1990)

We have studied rat vascular smooth muscle (VSM) cells in culture for the presence of key elements of the glandular kallikrein-kinin system. Direct radioimmunoassay (RIA) using antiserum against rat urinary kallikrein detected a glandular kallikrein-like enzyme (GKLE) in VSM cells and in media. VSM homogenates and culture media had kininogenase activity, generating kinins from dog kininogen. About half of the GKLE was enzymatically inactive which could be activated with trypsin. Kininogenase activity was inhibited completely by aprotinin but only 20% by soybean trypsin inhibitor (SBTI). Trypsin liberated kinins from homogenates and media, demonstrating that VSM cells contain kininogen. Homogenates and media rapidly degrade bradykinin. GKLE, kininogen, and bradykininase activity were all present in VSM cells grown in defined media that contain no serum, thus eliminating any contamination or artefacts from fetal calf serum in standard culture media. Blood vessels of the rat have been reported to contain GKLE. Our observations indicate that GKLE is synthesized by VSM cells, not deposited from plasma. Furthermore, VSM cells synthesize kininogen and bradykininase(s), the other key elements of the glandular kallikrein-kinin system. Thus it is possible that the system functions as an autocoid mechanism that regulates local vascular tone.