tbuckley/cabot-search huggingface dataset:
Insulin-like growth factor receptor 1(IGFIR) is overexpressed in a subset of triple negative breast cancers
Authors: Jessica Kline, Inna Chervoneva, Boris Freydin, Charalambos solomides, Agnieszka K. Witkiewicz, Carl Martin, Stephen Peiper
Journal: Clinical Cancer Research (2010)

Abstract Insulin-like growth factor receptor 1 (IGF-1R) has a key regulatory role in malignancy and is the target of several drugs currently tested in clinical trials. Few studies have shown that IGF-IR expression is associated with estrogen receptor positive breast cancer. However, there are no systematic studies of IGF1R expression in triple negative breast carcinoma (TNBC). The aim of this study was to evaluate IGF1R protein expression and gene amplification in TNBC. Material and Methods: Ninety-seven TNBC (73 from Caucasian and 24 from African American women) were stained with anti-IGF1R antibody (clone G11, Ventana Medical Systems, Tucson, AZ, USA). IGF1R protein expression was scored according to standardized criteria originally developed for HER 2. Chromogenic in situ hybridization for IGF1R gene was performed on 35 cases using experimental Ventana probe. The tumor was interpreted as positive for gene amplification when the ration of IGF1R gene signal to chromosome 15 signal was ≥ 2.2. For statistical analysis, the IGF1R scores (0, 1, 2, 3) were dichotomized as low (0-2) vs. high (3). Association between IGF1R protein expression and clinicopathologic variables (lymph node metastases, grade, race, age) was analyzed using Fisher's exact test. The association between tumor size and IGF1R expression was analyzed using the Wilcoxon two-sample test. The overall survival was analyzed using LogRank test and Cox proportional hazard model. Results: A significant association was observed between IGF1R protein expression and IGF1R gene amplification (p&amp;lt;0.001). Respectively, the agreement between IGF1R 3+ protein expression and gene amplification was high (kappa=0.84, 95% CI: 0.62, 1.0; p&amp;lt;0.001). Low (0-2+) IGF1R expression was associated with lymph node metastases (p=0.033) while cases with high (3+) expression had borderline significantly (p=0.080) smaller tumor size. There was no statistically significant association between IGF1R expression and grade or race. In younger patients (&amp;lt;55 years), high IGF1R score was associated with longer survival (HR=0.13; 95% CI: 0.02- 1.00; p=0.050), while in older patients, no significant survival differences were observed between patients with low and high IGF1R scores. Conclusion: This study suggests that IGF1R is overexpressed and amplified in a subset of TNBC and may be a potential therapeutic target.
From Allergen Genes to Allergy Vaccines
Authors: Rudolf Valenta, Fatima Ferreira, Margarete Focke-Tejkl, Birgit Linhart, Verena Niederberger, Ines Swoboda, Susanne Vrtala
Journal: Annual Review of Immunology (2010)

IgE-mediated allergy is a hypersensitivity disease affecting more than 25% of the population. The structures of the most common allergens have been revealed through molecular cloning technology in the past two decades. On the basis of this knowledge of the sequences and three-dimensional structures of culprit allergens, investigators can now analyze the immune recognition of allergens and the mechanisms of allergic inflammation in allergic patients. Allergy vaccines have been constructed that are able to selectively target the aberrant immune responses in allergic patients via different pathways of the immune system. Here we review various types of allergy vaccines that have been developed based on allergen structures, results from their clinical application in allergic patients, and future strategies for allergen-specific immunotherapy and allergy prophylaxis.
Arterial blood gases during exercise in chronic obstructive pulmonary disease with and without pulmonary hypertension
Authors: Ingunn Skjorten, Janne Mykland Hilde, Morten Nissen Melsom, Viggo Hansteen, Kjetil Steine, Sjur Humerfelt
Journal: European Respiratory Journal (2011)

Aim: To evaluate blood gas responses during cardiopulmonary exercise test (CPET) when patients with chronic obstructive pulmonary disease (COPD) were categorized by GOLD stages and the presence of pulmonary hypertension (PH).

Methods: Right heart catheterization (RHC) and CPET to exhaustion with serial blood gas measurements were performed in 98 COPD patients in GOLD stages II-IV without left heart disease. Mean age±SD was 64±7 yrs and 50% were men. PH was defined as mean pulmonary artery pressure (mPAP) at rest ≥ 25mmHg.

Results: See table. PH was observed in 5, 28 and 52% in GOLD stages II, III and IV, respectively. At rest and at peak exercise PaO2 decreased whereas PaCO2 increased with advancing GOLD stages. At rest, only stage IV had lower (p<0.05) PaO2 in patients with PH than in those without. At peak exercise, both stages III and IV had lower (p<0.05) PaO2 in patients with PH than in those without. For PaCO2 no significant differences were observed within each GOLD stage.

View this table:

Table 1





Conclusion: PH was a common finding in advanced COPD. Arterial PaO2 at rest and at peak exercise was inversely related to GOLD stages. Presence of PH within each stage was associated with lower PaO2. Since RHC is not available to all COPD patients, CPET is useful in selecting candidates. Low resting PaO2 and excessive decline in PaO2 during exercise justify referral to further PH investigation.
Ultrahigh-Speed, Swept-Source Optical Coherence Tomography Angiography in Nonexudative Age-Related Macular Degeneration with Geographic Atrophy
Authors: WooJhon Choi, Eric M. Moult, Nadia K. Waheed, Mehreen Adhi, ByungKun Lee, Chen D. Lu, Talisa E. de Carlo, Vijaysekhar Jayaraman, Philip J. Rosenfeld, Jay S. Duker, James G. Fujimoto
Journal: Ophthalmology (2015)
Development of Resistance to Targeted Therapies Transforms the Clinically Associated Molecular Profile Subtype of Breast Tumor Xenografts
Authors: Chad J. Creighton, Suleiman Massarweh, Shixia Huang, Anna Tsimelzon, Susan G. Hilsenbeck, C. Kent Osborne, Jiang Shou, Luca Malorni, Rachel Schiff
Journal: Cancer Research (2008)

The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER-/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change.
Use of complementary therapies by patients attending musculoskeletal clinics
Authors: A Chandola, Y Young, J McAlister, J S Axford
Journal: Journal of the Royal Society of Medicine (1999)

Patients with musculoskeletal disorders commonly seek treatment outside orthodox medicine (complementary therapy). In patients attending hospital clinics we investigated the prevalence of such behaviour and the reasons for it. Patients attending rheumatology and orthopaedic clinics who agreed to participate were interviewed on the same day by means of a structured questionnaire in three sections: the first section about demographic characteristics; the second about the nature and duration of the complaint, the length of any treatment and whether the patient was satisfied with conventional treatment; and the third about the use of complementary medicine, the types of therapy that had been considered and the reasoning behind these decisions. The data were examined by univariate and bivariate analysis as well as logistic regression multivariate analysis. 166 patients were interviewed (99% response rate) and the predominant diagnosis was rheumatoid arthritis (22.3%). 109 patients (63%) were satisfied with conventional medical treatment; 63 (38%) had considered the use of complementary therapies, and 47 (28%) had tried such a therapy. 26 of the 47 who had used complementary therapy said they had gained some benefit. Acupuncture, homoeopathy, osteopathy and herbal medicine were the most popular types of treatment to be considered. Patients of female gender (P = 0.009) and patients who had expressed dissatisfaction with current therapies (P = 0.01) were most likely to have considered complementary medicine. These results indicate substantial use of complementary therapy in patients attending musculoskeletal disease clinics. The reasons for dissatisfaction with orthodox treatment deserve further investigation, as does the effectiveness of complementary treatments, which must be demonstrated before they are integrated with orthodox medical practice.
Impact of bile acids on the growth of human cholangiocarcinoma via FXR
Authors: Jiaqi Dai, Hongxia Wang, Yihui Shi, Ying Dong, Yinxin Zhang, Jian Wang
Journal: Journal of Hematology & Oncology (2011)

Abstract Background The objective of the study was to investigate the effect of different types of bile acids on proliferation of cholangiocarcinoma and the potential molecular mechanisms. Methods PCR assay and Western blot were performed to detect the expression of farnesoid × receptor (FXR) in mRNA and protein level. Immunohistochemical analysis was carried out to monitor the expression of FXR in cholangiocarcinoma tissues from 26 patients and 10 normal controls. The effects on in vivo tumor growth were also studied in nude mouse model. Results Free bile acids induced an increased expression of FXR; on the contrary, the conjugated bile acids decreased the expression of FXR. The FXR effect has been illustrated with the use of the FXR agonist GW4064 and the FXR antagonist GS. More specifically, when the use of free bile acids combined with FXR agonist GW4064, the tumor cell inhibitory effect was even more pronounced. But adding FXR antagonist GS into the treatment attenuated the tumor inhibitory effect caused by free bile acids. Combined treatment of GS and CDCA could reverse the regulating effect of CDCA on the expression of FXR. Administration of CDCA and GW 4064 resulted in a significant inhibition of tumor growth. The inhibitory effect in combination group (CDCA plus GW 4064) was even more pronounced. Again, the conjugated bile acid-GDCA promoted the growth of tumor. We also found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth. And the characteristic and difference of FXR expressions were in agreement with previous experimental results in mouse cholangiocarcinoma tissues. There was also significant difference in FXR expression between normal and tumor tissues from patients with cholangiocarcinoma. Conclusions The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma. FXR, a member of the nuclear receptor superfamily, may mediate the effects induced by the bile acids.
Role of Soluble Epoxide Hydrolase in Postischemic Recovery of Heart Contractile Function
Authors: John M. Seubert, Christopher J. Sinal, Joan Graves, Laura M. DeGraff, J. Alyce Bradbury, Craig R. Lee, Kerry Goralski, Michelle A. Carey, Ayala Luria, John W. Newman, Bruce D. Hammock, John R. Falck, Holly Roberts, Howard A. Rockman, Elizabeth Murphy, Darryl C. Zeldin
Journal: Circulation Research (2006)

Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase ( Ephx2 , sEH). To examine the functional role of sEH in the heart, mice with targeted disruption of the Ephx2 gene were studied. Hearts from sEH null mice have undetectable levels of sEH mRNA and protein and cannot convert EETs to DHETs. sEH null mice have normal heart anatomy and basal contractile function, but have higher fatty acid epoxide:diol ratios in plasma and cardiomyocyte cell culture media compared with wild type (WT). sEH null hearts have improved recovery of left ventricular developed pressure (LVDP) and less infarction compared with WT hearts after 20 minutes ischemia. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10 to 100 nmol/L) before ischemia abolishes this cardioprotective phenotype. Inhibitor studies demonstrate that perfusion with phosphatidylinositol-3 kinase (PI3K) inhibitors wortmannin (200 nmol/L) or LY294002 (5 μmol/L), the ATP-sensitive K + channel (K ATP ) inhibitor glibenclamide (1 μmol/L), the mitochondrial K ATP (mitoK ATP ) inhibitor 5-hydroxydecanoate (100 to 200 μmol/L), or the Ca 2+ -sensitive K + channel (K Ca ) inhibitor paxilline (10 μmol/L) abolishes the cardioprotection in sEH null hearts. Consistent with increased activation of the PI3K cascade, sEH null mice exhibit increased cardiac expression of glycogen synthase kinase-3β (GSK-3β) phospho-protein after ischemia. Together, these data suggest that targeted disruption of sEH increases the availability of cardioprotective EETs that work by activating PI3K signaling pathways and K + channels.
Estrogen-Progestin Replacement Therapy and Endometrial Cancer
Authors: M. C. Pike, R. K. Peters, W. Cozen, N. M. Probst-Hensch, P. C. Wan, T. M. Mack, J. C. Felix
Journal: JNCI Journal of the National Cancer Institute (1997)

It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per "month" in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy.We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer.A population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors.The adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects).The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.
Incretin Effects on β-Cell Function, Replication, and Mass
Authors: Alan J. Garber
Journal: Diabetes Care (2011)

There is a progressive deterioration in β-cell function in patients with type 2 diabetes. At diagnosis, islet function may be reduced by up to 50% compared with healthy control subjects, and there is also likely to be a reduction in β-cell mass of up to 60%. The reduction in β-cell mass is due to accelerated apoptosis. Currently, few pharmacological therapies address this reduction in β-cell mass and function. This means that patients are generally subjected to an increasing polypharmacy to control their diabetes, with most eventually being treated by insulin. Incretin hormones, which are released from the gastrointestinal tract after a meal, enhance glucose-dependent insulin secretion from the pancreas, aiding the overall regulation of glucose homeostasis in healthy subjects. In addition, these hormones, especially glucagon-like peptide (GLP)-1, have a number of protective effects on the β-cells, including a reduction in apoptosis and enhancement of β-cell proliferation and neogenesis. These benefits are lost to a significant extent in patients with diabetes. The recently developed diabetes therapies, GLP-1 receptor agonists, such as exenatide and liraglutide, appear to have beneficial effects on β-cell function and hence offer promise for durable glycemic control as well as potentially reducing the micro- and macrovascular complications associated with type 2 diabetes.

The clinical course of type 2 diabetes is characterized by a progressive decline in β-cell mass and function. Although the elevated levels of fasting glucose and impairment of insulin action in peripheral tissues may predate the diagnosis of type 2 diabetes, chronic hyperglycemia only results after a prolonged period of β-cell degeneration, a process that may begin as much as 12 years before diagnosis, involving a progressive reduction in functionality and mass (1,2). In the UK Prospective Diabetes Study, it was estimated that, at diagnosis, type 2 diabetic patients may have already lost up …
Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension.
Authors: G Lembo, R Napoli, B Capaldo, V Rendina, G Iaccarino, M Volpe, B Trimarco, L Saccà
Journal: Journal of Clinical Investigation (1992)

The reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/kg per min) while maintaining euglycemia. Hyperinsulinemia (50-60 microU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28 +/- 45 ng.liter-1.min-1 in hypertensives and 0.80 +/- 0.27 ng.liter-1 in normals; P less than 0.01). Forearm glucose uptake rose to 5.1 +/- .7 mg.liter-1.min-1 in response to insulin in hypertensives and to 7.9 +/- 1.3 mg.liter-1.min-1 in normotensives (P less than 0.05). To clarify whether insulin action was due to a direct effect on muscle NE metabolism, in another set of experiments insulin was infused locally into the brachial artery to expose only the forearm tissues to the same insulin levels as in the systemic studies. During local hyperinsulinemia, forearm NE release remained virtually unchanged both in hypertensive and in normal subjects. Furthermore, forearm glucose disposal was activated to a similar extent in both groups (5.0 +/- 0.6 and 5.2 +/- 1.1 mg.liter-1.min-1 in hypertensives and in normals, respectively). These data demonstrate that: (a) insulin evokes an abnormal muscle sympathetic overactivity in essential hypertension which is mediated by mechanisms involving the central nervous system; and (b) insulin resistance associated with hypertension is demonstrable in the skeletal muscle tissue only with systemic insulin administration which produces muscle sympathetic overactivity. The data fit the hypothesis that the sympathetic system mediates the pathophysiologic link between hyperinsulinemia and essential hypertension.
Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients
Authors: C Charlier, C Henegar, O Launay, C Pagnoux, A Berezné, B Bienvenu, P Cohen, L Mouthon, L Guillevin
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To characterise major infectious complications and analyse potential risk factors in patients with Wegener granulomatosis (WG). Methods: Data from 113 patients with WG (69 male) followed at least once between January 1984 and March 2006 in our internal medicine department, were analysed retrospectively. Results: A total of 35 patients (mean (SD) age at WG diagnosis: 50.2 (13.05) years) developed 53 major infections. Infections were: bronchopneumonias (n = 19), herpes zoster recurrences (n = 9), cellulitis (n = 4), prostatitis (n = 4), spondylodiscitis and septic arthritis (n = 3), digestive tract infections (n = 2), Enterococcus faecalis or Staphylococcus aureus septicaemia (n = 2), viral hepatitis B reactivations (n = 2), post transfusion HIV infection with fatal cerebral toxoplasmosis, oesophageal candidiasis, disseminated herpes simplex and cytomegalovirus infection, cytomegalovirus retinitis, herpetic keratitis, herpetic stomatitis, Serratia sp. node suppuration and fever resolving under broad spectrum antibiotics (n = 1 each). Half of the major infectious episodes occurred within 3 years after WG diagnosis. Eight (7%) patients died, with two (2%) infection-related deaths. Patients diagnosed with WG before 1996 had a significantly higher rate of infection than those diagnosed later (48% vs 24%, p = 0.02). Cyclophosphamide and corticosteroids were independently associated with significantly higher risk of major infection (p&lt;0.05 and &lt;0.001, respectively). All patients treated since 1993 received antipneumocystosis prophylaxis. Conclusion: Cyclophosphamide and corticosteroids were associated with higher risk of infection. Despite systematic cotrimoxazole prophylaxis, major infections, mostly bronchopneumonias and herpes zoster recurrences, were still common in the course of WG.