tbuckley/cabot-search huggingface dataset:
EGFR isoforms and gene regulation in human endometrial cancer cells
Authors: Lina Albitar, Gavin Pickett, Marilee Morgan, Jason A Wilken, Nita J Maihle, Kimberly K Leslie
Journal: Molecular Cancer (2010)

Abstract Background Epidermal growth factor (EGF) and its receptor (EGFR) constitute a principal growth-promoting pathway in endometrial cancer cells. Pre-clinical studies were undertaken to compare the expression of EGFR isoforms and the downstream effects of activating or blocking EGFR function in Ishikawa H cells, derived from a moderately differentiated type I endometrioid adenocarcinoma, or in Hec50co cells, derived from a poorly differentiated type II adenocarcinoma with papillary serous sub-differentiation. Results We investigated whether EGFR mutations are present in the tyrosine kinase domain (exons 18-22) of EGFR and also whether EGFR isoforms are expressed in the Ishikawa H or Hec50co cell lines. Sequence of the EGFR tyrosine kinase domain proved to be wild type in both cell lines. While both cell lines expressed full-length EGFR (isoform A), EGFR and sEGFR (isoform D) were expressed at significantly lower levels in Hec50co cells compared to Ishikawa H cells. Analysis of gene expression following EGF vs. gefitinib treatment (a small molecule EGFR tyrosine kinase inhibitor) was performed. Early growth response 1, sphingosine kinase 2, dual specificity phosphatase 6, and glucocorticoid receptor DNA binding factor 1 are members of a cluster of genes downstream of EGFR that are differentially regulated by treatment with EGF compared to gefitinib in Ishikawa H cells, but not in Hec50co cells. Conclusions Type I Ishikawa H and type II Hec50co endometrial carcinoma cells both express EGFR and sEGFR, but differ markedly in their responsiveness to the EGFR inhibitor gefitinib. This difference is paralleled by differences in the expression of sEGFR and EGFR, as well as in their transcriptional response following treatment with either EGF or gefitinib. The small cluster of differently regulated genes reported here in these type I vs. type II endometrial cancer-derived cell lines may identify candidate biomarkers useful for predicting sensitivity to EGFR blockade.
A pharmacological review of selective oestrogen receptor modulators
Authors: S. R. Goldstein
Journal: Human Reproduction Update (2000)

Selective oestrogen receptor modulators (SERMs) are structurally diverse non-steroidal compounds that bind to oestrogen receptors and produce oestrogen agonist effects in some tissues and oestrogen antagonist effects in others. SERMs are being evaluated for a number of oestrogen-related diseases, including post-menopausal osteoporosis, hormone-dependent cancers, and cardiovascular disease. Several compounds that exhibit a SERM profile are currently available for clinical use, including clomiphene, tamoxifen, and toremifene (which are triphenylethylenes) and raloxifene (a benzothiophene). Clomiphene is used for the induction of ovulation in sub-fertile women attempting pregnancy. Tamoxifen and toremifene are both used to treat breast cancer. Tamoxifen may have beneficial effects on bone mineral density and serum lipids. The effects of toremifene on serum lipids are similar to that of tamoxifen. Both compounds have stimulatory effects on the endometrium. Raloxifene, indicated for the treatment and prevention of post-menopausal osteoporosis, has beneficial effects on bone mineral density and serum lipids, but does not increase the risk of endometrial hyperplasia or endometrial cancer. Recently, raloxifene was shown to reduce the incidence of vertebral fractures in otherwise healthy women with osteoporosis; in the same study, a reduced incidence of breast cancer was also observed. Similar to oestrogens, SERMs increase the incidence of venous thromboembolism. Several newer compounds that exhibit a SERM profile are also in clinical development, including other triphenylethylenes (droloxifene, idoxifene) and benzothiophenes (LY353381·HCl), benzopyrans (EM-800), and naphthalenes (CP-336,156).
Rosiglitazone Is Associated with Mortality in Chronic Hemodialysis Patients
Authors: Sylvia P.B. Ramirez, Justin M. Albert, Margaret J. Blayney, Francesca Tentori, David A. Goodkin, Robert A. Wolfe, Eric W. Young, George R. Bailie, Ronald L. Pisoni, Friedrich K. Port
Journal: Journal of the American Society of Nephrology (2009)

Recent studies have associated rosiglitazone, a thiazolidinedione drug, with adverse cardiovascular outcomes in the general population with diabetes. Using data from the Dialysis Outcomes and Practice Patterns Study in the United States, we examined cardiovascular hospitalization and mortality associated with prescription of rosiglitazone, compared with other oral hypoglycemic agents, among 2393 long-term hemodialysis patients who were followed for a median of 1.1 yr. We assessed mortality risk using Cox models in patient-level and dialysis facility–level analyses that used the facility proportion of patients on rosiglitazone as the predictor (instrumental variable approach) and adjusted the models for demographics, comorbid conditions, laboratory values, and achieved dialysis dosage. Compared with patients prescribed other oral hypoglycemic agents, patients prescribed rosiglitazone had significantly higher all-cause (hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.05 to 1.82) and cardiovascular (HR 1.59; 95% CI 1.14 to 2.22) mortality, and their adjusted HR for hospitalization with myocardial infarction was 3.5-fold higher (P = 0.02). We did not observe similar associations in a secondary analysis evaluating pioglitazone. By the instrumental variable approach, facilities with more than the median adjusted percentage (6.2%) of patients who had diabetes and were prescribed rosiglitazone had significantly higher all-cause mortality (HR 1.36; 95% CI 1.15 to 1.62) and cardiovascular mortality (HR 1.42; 95% CI 1.07 to 1.88) than facilities with less than the median expected percentage prescribed rosiglitazone. Our practice-based findings suggest significant associations of rosiglitazone use with higher cardiovascular and all-cause mortality among hemodialysis patients with diabetes.
The mouse antibody response to infection with Cryptococcus neoformans: VH and VL usage in polysaccharide binding antibodies.
Authors: A Casadevall, M D Scharff
Journal: The Journal of Experimental Medicine (1991)

Cryptococcus neoformans is a ubiquitous fungus that can cause serious infections in humans. The fungus has a polysaccharide (C. neoformans capsular polysaccharide; CNPS) capsule that contributes to its pathogenicity and can elicit an antibody response. Nevertheless, only 4 of 60 BALB/c mice chronically infected with C. neoformans had a detectable increase in serum anti-CNPS. The sera of three responder mice contained both IgM and IgG anti-CNPS antibody, and the titers of lambda and kappa anti-CNPS antibody were approximately equal. Eight IgM and one IgG3 monoclonal antibodies (mAbs) were generated from the spleen of one responder mouse, and one IgA was generated from the spleen of another mouse. Seven of the IgMs, the IgG3, and the IgA mAb had lambda light chains and were specific for serotype D CNPS. Molecular analysis confirmed that this was a highly restricted antibody response. All of the D-specific antibodies used VH441, JH3, and either V lambda 2/J lambda 2 or V lambda 1/J lambda 1, and all had the same heavy chain CDR3 amino acid sequence, even though there were differences in the nucleotide sequence of the N/D segment. One IgM mAb reacted with both serotype A and D CNPS, and this mAb used different VH and JH genetic elements and had kappa light chains. All the anti-CNPS mAbs used J proximal VH gene elements that have previously been shown to bind dextran and other polysaccharides. Sequence and Southern blot analysis indicate that the serotype-D CNPS-specific mAbs arose from only a few precursor B cells.
Association of Paclitaxel Pharmacokinetics with the Development of Peripheral Neuropathy in Patients with Advanced Cancer
Authors: Stephan Mielke, Alex Sparreboom, Seth M. Steinberg, Hans Gelderblom, Clemens Unger, Dirk Behringer, Klaus Mross
Journal: Clinical Cancer Research (2005)

The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 micromol/L (T >0.05) remains almost constant. As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity.Patients with advanced cancer of different origin were randomized to receive a maximum of 12 weekly-given 1- or 3-hour infusions of 100 mg/m2 paclitaxel (Taxol). Twenty-four patients were assessable for both pharmacokinetics and peripheral neuropathy development evaluated by a clinical scoring system including sensory symptoms, strength, tendon reflexes, and vibratory sense.Patients with peripheral neuropathy development (n=14) received more weeks of therapy (P=0.056) and showed significantly higher T(>0.05) (P=0.022) and overall systemic drug exposures (weeks of therapy x AUC) for total paclitaxel (P=0.002) and unbound paclitaxel (P=0.003) than those without peripheral neuropathy. In Kaplan-Meier analyses, T(>0.05) > or = 10.6 hours (P=0.023), AUC of total paclitaxel > or = 4.7 microg/mL x hour (P = 0.047), and AUC of unbound paclitaxel > or = 0.375 microg/mL x hour (P = 0.095) were identified as being potential factors for peripheral neuropathy development. In a Cox regression analysis, only T(>0.05) > or = 10.6 hours remained as an independent risk factor (relative risk, 18.43; P = 0.036) after adjusting for prior vincamycin (relative risk, 11.28; P = 0.038).From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development.
Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin
Authors: Arti Shukla, Jedd M Hillegass, Maximilian B MacPherson, Stacie L Beuschel, Pamela M Vacek, Harvey I Pass, Michele Carbone, Joseph R Testa, Brooke T Mossman
Journal: Molecular Cancer (2010)

Malignant mesotheliomas (MM) have a poor prognosis, largely because of their chemoresistance to anti-cancer drugs such as doxorubicin (Dox). Here we show using human MM lines that Dox activates extracellular signal-regulated kinases (ERK1 and 2), causally linked to increased expression of ABC transporter genes, decreased accumulation of Dox, and enhanced MM growth. Using the MEK1/2 inhibitor, U0126 and stably transfected shERK1 and shERK2 MM cell lines, we show that inhibition of both ERK1 and 2 sensitizes MM cells to Dox. U0126 significantly modulated endogenous expression of several important drug resistance (BCL2, ABCB1, ABCC3), prosurvival (BCL2), DNA repair (BRCA1, BRCA2), hormone receptor (AR, ESR2, PPARγ) and drug metabolism (CYP3A4) genes newly identified in MM cells. In comparison to shControl lines, MM cell lines stably transfected with shERK1 or shERK2 exhibited significant increases in intracellular accumulation of Dox and decreases in cell viability. Affymetrix microarray analysis on stable shERK1 and shERK2 MM lines showed more than 2-fold inhibition (p ≤ 0.05) of expression of ATP binding cassette genes (ABCG1, ABCA5, ABCA2, MDR/TAP, ABCA1, ABCA8, ABCC2) in comparison to shControl lines. Moreover, injection of human MM lines into SCID mice showed that stable shERK1 or shERK2 lines had significantly slower tumor growth rates in comparison to shControl lines after Dox treatment. These studies suggest that blocking ERK1 and 2, which play critical roles in multi-drug resistance and survival, may be beneficial in combination with chemotherapeutic drugs in the treatment of MMs and other tumors.
Endogenous Sex Hormones, Prolactin, and Mammographic Features of Breast Tissue in Premenopausal Women2
Authors: François Meyer, Jacques Brisson, Alan S. Morrison, James B. Brown
Journal: JNCI Journal of the National Cancer Institute (1986)

The relationship between levels of certain endogenous hormones and the mammographic features of breast tissue was evaluated in 110 premenopausal women who were referred to hospital-based radiology units for a routine xeromammogram. This analysis was based on specimens collected during the luteal phase of the menstrual cycle. Plasma 17 beta-estradiol, progesterone, and prolactin were measured, as well as urine estrone, estradiol, estriol, and pregnanediol. The main xeromammographic features of the breast assessed were Wolfe's parenchymal pattern and the percentages of the breast showing nodular densities and homogeneous density. In these data, endogenous hormones were not strongly associated with mammographic features of breast tissue. However, women with the N1 and P1 parenchymal patterns had somewhat higher levels of estrogens and prolactin and somewhat lower levels of progesterone than women with the P2 and DY patterns.
Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects
Authors: Pavan Reddy, Takanori Teshima, Gerhard Hildebrandt, Debra L. Williams, Chen Liu, Kenneth R. Cooke, James L.M. Ferrara
Journal: Blood (2003)
Maternal BMI Before Pregnancy, Maternal Weight Gain During Pregnancy, and Risk of Persistent Positivity for Multiple Diabetes-Associated Autoantibodies in Children With the High-Risk HLA Genotype
Authors: Trond Rasmussen, Lars C. Stene, Sven O. Samuelsen, Ondrej Cinek, Turid Wetlesen, Peter A. Torjesen, Kjersti S. Rønningen
Journal: Diabetes Care (2009)

OBJECTIVE To assess whether maternal BMI before pregnancy and weight gain during pregnancy predicted the risk of islet autoimmunity in genetically susceptible children. RESEARCH DESIGN AND METHODS Of 46,939 newborns screened for the high-risk HLA genotype DR4-DQ8/DR3-DQ2, 1,003 were positive and 885 were followed with serial blood samples tested for autoantibodies to insulin, GAD, and insulinoma-associated protein 2 (IA2). The end point was defined as repeated positivity for two or three autoantibodies or the onset of type 1 diabetes (islet autoimmunity). RESULTS Thirty-six children developed islet autoimmunity, of whom 10 developed type 1 diabetes. Both maternal BMI ≥30 kg/m2 before pregnancy and maternal weight gain ≥15 kg predicted the increased risk of islet autoimmunity (hazard ratio [HR] 2.5, P = 0.023, and HR 2.5, P = 0.015, respectively), independent of maternal diabetes. CONCLUSIONS Maternal weight may predict risk of islet autoimmunity in offspring with a high genetic susceptibility for type 1 diabetes.
Is Tropical Pancreatic Diabetes Malnutrition Related?
Authors: R Harsha Rao
Journal: Diabetes Care (1993)

Clinical syndromes of diabetes in tropical countries defy attempts to separate them into reasonably homogeneous groups that are analogous to the traditional classification into IDDM and NIDDM. Their geographical and clinical uniqueness has only been recognized relatively recently. For most of this century, diabetes in the tropics was thought to be no different from the classical form seen in more temperate climates, being found only in the well-nourished elite, but not in the malnourished masses (1). Thus, the WHO, in its first examination of the problem of diabetes from a world-wide perspective in 1965, stated emphatically that “the evidence that malnutrition protects populations from diabetes seems unassailable (2).” Notwithstanding this assertion, evidence had been accumulating for at least a decade that many diabetic individuals in the tropics had unusual features that made it impossible to pigeonhole them into either of the classic varieties of diabetes mellitus. From the earliest descriptions of the two syndromes of diabetes that have come to be recognized as being unique to the tropics (type J diabetes and TPD), the association of both syndromes with malnutrition was emphasized (3,4). Faced with the overwhelming evidence that diabetes did occur in malnourished individuals, WHO reversed its opinion in 1980, acknowledging that “in some societies … malnutrition is probably a major determinant (of diabetes) (5).”
The effect of captopril on cutaneous blood flow in patients with primary Raynaud's phenomenon
Authors: M.H.A. RUSTIN, N.E. ALMOND, J.A. BEACHAM, R.J. BROOKS, D.P. JONES, E.D. COOKE, P.M. Dowd
Journal: British Journal of Dermatology (1987)

Fifteen patients with primary Raynaud's phenomenon received captopril 25 mg or placebo, three times daily for 6 weeks, in a randomized double-blind cross-over study. Compared with placebo, captopril produced a significant improvement in cutaneous blood flow but did not alter the frequency or severity of attacks of Raynaud's phenomenon.
Noncytolytic Control of Viral Infections by the Innate and Adaptive ImmuneResponse
Authors: Luca G. Guidotti, Francis V. Chisari
Journal: Annual Review of Immunology (2001)

This review describes the contribution of noncytolytic mechanisms to the control of viral infections with a particular emphasis on the role of cytokines in these processes. It has long been known that most cell types in the body respond to an incoming viral infection by rapidly secreting antiviral cytokines such as interferon alpha/beta (IFN-α/β). After binding to specific receptors on the surface of infected cells, IFN-α/β has the potential to trigger the activation of multiple noncytolytic intracellular antiviral pathways that can target many steps in the viral life cycle, thereby limiting the amplification and spread of the virus and attenuating the infection. Clearance of established viral infections, however, requires additional functions of the immune response. The accepted dogma is that complete clearance of intracellular viruses by the immune response depends on the destruction of infected cells by the effector cells of the innate and adaptive immune system [natural killer (NK) cells and cytotoxic T cells (CTLs)]. This notion, however, has been recently challenged by experimental evidence showing that much of the antiviral potential of these cells reflects their ability to produce antiviral cytokines such as IFN-γ and tumor necrosis factor (TNF)-α at the site of the infection. Indeed, these cytokines can purge viruses from infected cells noncytopathically as long as the cell is able to activate antiviral mechanisms and the virus is sensitive to them. Importantly, the same cytokines also control viral infections indirectly, by modulating the induction, amplification, recruitment, and effector functions of the immune response and by upregulating antigen processing and display of viral epitopes at the surface of infected cells. In keeping with these concepts, it is not surprising that a number of viruses encode proteins that have the potential to inhibit the antiviral activity of cytokines.
Novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions
Authors: M. Oki, H. Saka, C. Kitagawa, S. Tanaka, T. Shimokata, K. Mori, S. Kajikawa
Journal: European Respiratory Journal (2008)

In the present study, the authors evaluated the diagnostic utility of a novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions. A total of 118 patients were included in this prospective study. Bronchoscopic examination was performed using a 5.9-mm standard bronchoscope. If no visible endobronchial lesion was found, transbronchial biopsies were performed with 1.5-mm biopsy forceps under fluoroscopic guidance and the bronchus were washed with 10–20 mL of saline solution, using a prototype 3.5-mm thin bronchoscope with a 1.7-mm working channel. Endobronchial lesion was visualised with the standard bronchoscope in 16 patients, and the other 102 patients underwent biopsies with the thin bronchoscope. The mean bronchus levels reached with the standard bronchoscope and the thin bronchoscope were 2.3 and 4.3 generations, respectively. Endobronchial abnormality was revealed with the thin bronchoscope in a further 14 patients. Diagnostic material was obtained in 50 of 68 (74%) patients with malignant disease and 18 of 30 (60%) patients with benign disease. Four patients did not return to follow-up. The diagnostic yield was 57%, even in lesions &lt;20 mm. There were no major complications. In conclusion, bronchoscopy using a 3.5-mm thin bronchoscope with a 1.7-mm working channel is useful and safe for the diagnosis of peripheral pulmonary lesions.
The Impact of Protein Intake on Renal Function Decline in Women with Normal Renal Function or Mild Renal Insufficiency
Authors: Eric L. Knight, Meir J. Stampfer, Susan E. Hankinson, Donna Spiegelman, Gary C. Curhan
Journal: Annals of Internal Medicine (2003)

Background: In individuals with moderate to severe renal insufficiency, low protein intake may slow renal function decline. However, the long-term impact of protein intake on renal function in persons with normal renal function or mild renal insufficiency is unknown. Objective: To determine whether protein intake influences the rate of renal function change in women over an 11-year period. Design: Prospective cohort study. Setting: Nurses' Health Study. Participants: 1624 women enrolled in the Nurses' Health Study who were 42 to 68 years of age in 1989 and gave blood samples in 1989 and 2000. Ninety-eight percent of women were white, and 1% were African American. Measurements: Protein intake was measured in 1990 and 1994 by using a semi-quantitative food-frequency questionnaire. Creatinine concentration was used to estimate glomerular filtration rate (GFR) and creatinine clearance. Results: In multivariate linear regression analyses, high protein intake was not significantly associated with change in estimated GFR in women with normal renal function (defined as an estimated GFR 80 mL/min per 1.73 m2). Change in estimated GFR in this subgroup over the 11-year period was 0.25 mL/min per 1.73 m2 (95% CI, 0.78 to 1.28 mL/min per 1.73 m2) per 10-g increase in protein intake; the change in estimated GFR was 1.14 mL/min per 1.73 m2 (CI, 3.63 to 5.92 mL/min per 1.73 m2) after measurement-error adjustment for protein intake. In women with mild renal insufficiency (defined as an estimated GFR > 55 mL/min per 1.73 m2 but <80 mL/min per 1.73 m2), protein intake was significantly associated with a change in estimated GFR of 1.69 mL/min per 1.73 m2 (CI, 2.93 to 0.45 mL/min per 1.73 m2) per 10-g increase in protein intake. After measurement-error adjustment, the change in estimated GFR was 7.72 mL/min per 1.73 m2 (CI, 15.52 to 0.08 mL/min per 1.73 m2) per 10-g increase in protein intake, an association of borderline statistical significance. High intake of nondairy animal protein in women with mild renal insufficiency was associated with a significantly greater change in estimated GFR (1.21 mL/min per 1.73 m2 [CI, 2.34 to 0.33 mL/min per 1.73 m2] per 10-g increase in nondairy animal protein intake). Conclusions: High protein intake was not associated with renal function decline in women with normal renal function. However, high total protein intake, particularly high intake of nondairy animal protein, may accelerate renal function decline in women with mild renal insufficiency.