tbuckley/cabot-search huggingface dataset:
A new estrogen receptor on ER-negative breast cancer?
Authors: E. Peralta, B. D. Paris, O. W. Kamel, S. Louis, G. L. Dunnington
Journal: Journal of Clinical Oncology (2007)

10604 Background: Premenopausal women and BRCA-1 mutation carriers have estrogen receptor-negative (ER-) breast cancers that paradoxically seem responsive to hormonal deprivation such as oophorectomy. GPR30 is a G protein-coupled receptor that is activated not only by estradiol but also tamoxifen and fulvestrant. The prevalence and significance of GPR30 in breast cancer are unknown. We hypothesized that GPR30 may be present in ER-negative tumors and may promote growth of ER-negative breast cancer in premenopausal patients. Methods: An immunohistochemical staining protocol for rabbit polyclonal GPR30 antibody (Novus Biological) was developed initially on the known GPR30-positive breast cancer cell line MCF-7 and the GPR30-negative breast cancer cell line MDA-MB-231 and later on a panel of human breast tumors from archived paraffin blocks. After an automated protocol was optimized, under an IRB-approved protocol all incoming breast cancer specimens were stained for GPR30 and reviewed by a pathologist blinded to the ER/PR status. Significance of associations was tested by chi square analysis. Results: Twenty-seven breast cancer tumors were studied. The mean age of the patients was 53 (range 20–87). All of 10 triple negative (ER-,PR-, HER2 neu-) and 2 ER-/Her2 neu+ tumors stained positive for GPR30. Only 4 of 11 ER+/Her2neu - tumors stained positive for GPR30 (p=0.004). The mean age of triple negative patients was 43.7 yr, while the mean age of ER+/Her2 neu- was 63.2 (p=0.02). Three out of 4 ER+/HER2 neu+ tumors stained positive for GPR30. Four patients were African Americans, 2 had triple negative tumors and 2 ER+/Her2+, all 4 were positive for GPR30. Conclusions: GPR30 appears to be frequently expressed in ER-negative breast cancer and may represent an adverse factor. ER+ tumors with good prognostic features (PR+, HER2 neu-) were mostly negative for GPR30, while high-risk tumors were positive for GRP30. Premenopausal status and African-American race are known risk factors for lower survival. In this study, the African-American patients had high-risk tumors that were also positive for GPR30. A longer- range study is needed to test the association of GPR30 expression with recurrence and death. Future studies to assess the function of GPR30 in breast cancer cells may yield prognostic and therapeutic applications. No significant financial relationships to disclose.
Multiple Hereditary Infundibulocystic Basal Cell Carcinoma Syndrome Associated With a Germline<i>SUFU</i>Mutation
Authors: Joshua M. Schulman, Dennis H. Oh, J. Zachary Sanborn, Laura Pincus, Timothy H. McCalmont, Raymond J. Cho
Journal: JAMA Dermatology (2015)

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC) is a rare genodermatosis in which numerous indolent, well-differentiated basal cell carcinomas develop primarily on the face and genitals, without other features characteristic of basal cell nevus syndrome. The cause is unknown. The purpose of the study was to identify a genetic basis for the syndrome and a mechanism by which the associated tumors develop.Whole-exome sequencing of 5 tumors and a normal buccal mucosal sample from a patient with MHIBCC was performed. A conserved splice-site mutation in 1 copy of the suppressor of fused gene (SUFU) was identified in all tumor and normal tissue samples. Additional distinct deletions of the trans SUFU allele were identified in all tumor samples, none of which were present in the normal sample.A germline SUFU mutation was present in a patient with MHIBCC, and additional acquired SUFU mutations underlie the development of infundibulocystic basal cell carcinomas. The downstream location of the SUFU gene within the sonic hedgehog pathway may explain why its loss is associated with relatively well-differentiated tumors and suggests that MHIBCC will not respond to therapeutic strategies, such as smoothened inhibitors, that target upstream components of this pathway.
AMG 102, an HGF/SF antagonist, in combination with anti-angiogenesis targeted therapies in adult patients with advanced solid tumors
Authors: P. J. Rosen, C. J. Sweeney, D. J. Park, E. Rasmussen, P. Shubhakar, C. Scripture, I. Leitch, J. Lu, D. M. Beaupre, L. K. Yee
Journal: Journal of Clinical Oncology (2008)

3570 Background: AMG 102 is a novel, fully human monoclonal antibody that selectively targets hepatocyte growth factor/scatter factor (HGF/SF), the only ligand for the c-Met receptor, potentially inhibiting tumor cell proliferation, survival, and invasion. Bevacizumab and the small-molecule tyrosine kinase inhibitor motesanib diphosphate deter tumor angiogenesis by disrupting the VEGF pathway; in combination with AMG 102, they may have synergistic antitumor effects by targeting multiple signaling pathways. Methods: In an open-label Phase 1b study, 3 cohorts of 3–6 patients with advanced solid tumors received AMG 102 (3, 10, or 20 mg/kg) + bevacizumab 10 mg/kg every 2 weeks (Q2W); 2 patients received AMG 102 3 mg/kg IV Q2W + daily oral motesanib diphosphate 75 mg. Safety, tolerability, pharmacokinetics (PK), and tumor response (RECIST) were assessed. Results: Patient enrollment was complete in April 2007 with 14 patients (7 men, mean age 67). Prior treatment included radiotherapy (50%) and ≥ 3 lines of chemotherapy (71%). No dose-limiting toxicities were seen at any dosing levels. All patients reported treatment-related adverse events (AEs), most commonly nausea and fatigue. Serious treatment-related AEs included pulmonary embolism (PE) (n = 1) and hypotension (n = 1). Another case of PE was deemed not treatment-related. The PK profile of AMG 102 in combination with anti-angiogenic agents was similar to monotherapy. A decrease in the sum of tumor diameters and a best response of stable disease were seen in 8 of 10 evaluable patients. Stable disease persisted for > 12 months in a patient with carcinoid tumor (AMG 102 3 mg/kg + motesanib diphosphate) and > 9 months in a patient with endometrial cancer (AMG 102 10 mg/kg +bevacizumab). Levels of plasma HGF increased in all patients; the magnitude of increase appeared to be dose-dependent. Conclusions: AMG 102 in combination with anti-angiogenesis agents appeared to be well tolerated with an acceptable safety profile, and may inhibit tumor progression for some patients. Phase 2 evaluations of AMG 102 at 10–20 mg/kg are underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen Inc. Amgen Inc. Amgen Inc.
Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation
Authors: Andreas M. Beyer, Julie K. Freed, Matthew J. Durand, Michael Riedel, Karima Ait-Aissa, Paula Green, Joseph C. Hockenberry, R. Garret Morgan, Anthony J. Donato, Refael Peleg, Mario Gasparri, Chris K. Rokkas, Janine H. Santos, Esther Priel, David D. Gutterman
Journal: Circulation Research (2015)

Telomerase is a nuclear regulator of telomere elongation with recent reports suggesting a role in regulation of mitochondrial reactive oxygen species. Flow-mediated dilation in patients with cardiovascular disease is dependent on the formation of reactive oxygen species.We examined the hypothesis that telomerase activity modulates microvascular flow-mediated dilation, and loss of telomerase activity contributes to the change of mediator from nitric oxide to mitochondrial hydrogen peroxide in patients with coronary artery disease (CAD).Human coronary and adipose arterioles were isolated for videomicroscopy. Flow-mediated dilation was measured in vessels pretreated with the telomerase inhibitor BIBR-1532 or vehicle. Statistical differences between groups were determined using a 2-way analysis of variance repeated measure (n≥4; P<0.05). L-NAME (N(ω)-nitro-L-arginine methyl ester; nitric oxide synthase inhibitor) abolished flow-mediated dilation in arterioles from subjects without CAD, whereas polyethylene glycol-catalase (PEG-catalase; hydrogen peroxide scavenger) had no effect. After exposure to BIBR-1532, arterioles from non-CAD subjects maintained the magnitude of dilation but changed the mediator from nitric oxide to mitochondrial hydrogen peroxide (% max diameter at 100 cm H2O: vehicle 74.6±4.1, L-NAME 37.0±2.0*, PEG-catalase 82.1±2.8; BIBR-1532 69.9±4.0, L-NAME 84.7±2.2, PEG-catalase 36.5±6.9*). Conversely, treatment of microvessels from CAD patients with the telomerase activator AGS 499 converted the PEG-catalase-inhibitable dilation to one mediated by nitric oxide (% max diameter at 100 cm H2O: adipose, AGS 499 78.5±3.9; L-NAME 10.9±17.5*; PEG-catalase 79.2±4.9). Endothelial-independent dilation was not altered with either treatment.We have identified a novel role for telomerase in re-establishing a physiological mechanism of vasodilation in arterioles from subjects with CAD. These findings suggest a new target for reducing the oxidative milieu in the microvasculature of patients with CAD.
Visualizing the Coronaries in Patients Presenting With Heart Failure of Unknown Etiology⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: João A.C. Lima, Joshua Hare
Journal: Journal of the American College of Cardiology (2007)
Effects of Postoperative Adjuvant Chemotherapy and Radiotherapy on Ovarian Function in Women Undergoing Treatment for Soft Tissue Sarcoma&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: R C Shamberger, R J Sherins, J L Ziegler, E Glatstein, S A Rosenberg
Journal: JNCI Journal of the National Cancer Institute (1981)

Ovarian function was evaluated in 11 women 16 to 43 years of age at treatment who received doxorubicin, cyclophosphamide, and high doses of methotrexate with or without radiotherapy in adjuvant therapy of soft tissue sarcoma. Five women (16-33 yr old) who received chemotherapy alone or combined with radiotherapy only at sites distant from the ovaries (chest wall, thigh, and leg) had minimal menstrual irregularities or temporary cessation of menses during therapy; cyclic menses returned promptly after therapy. Gonadotropin levels (expressed as means +/- SD [follicle-stimulating hormone (FSH), 10 +/- 5 mlU/ml; luteinizing hormone (LH), 10 +/- 4 mlU/ml] and 17 beta-estradiol (E2) levels (means +/- SD, 208 +/- 147 pg/ml) were normal. By contrast, 4 older women (ages 36-43 yr) who received similar treatment developed persistent amenorrhea with postmenopausal levels of gonadotropin (FSH, 108 +/- 29 mlU/ml; LH, 72 +/- 19 mlU/ml) and E2 (19 +/- 8 pg/ml). Two additional women (ages 21 and 39 yr) who received radiation (7,000 rad) to the pelvis plus chemotherapy developed prompt cessation of menses and became functional castrates (FSH, 77 and 80 mlU/ml; LH, 40 and 58 mlU/ml; E2, 10 and 19 pg/ml). However, this result would be expected from the radiation dose alone. The data demonstrated that ovarian dysfunction may follow the use of doxorubicin, cyclophosphamide, and high doses of methotrexate and that the injury is age related.
Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide.
Authors: E J Bow, J A Sutherland, M G Kilpatrick, G J Williams, J J Clinch, T B Shore, M Rubinger, B A Schacter
Journal: Journal of Clinical Oncology (1996)

PURPOSE The University of Manitoba Adult Acute Leukemia Study Group sought to examine the safety, efficacy, and impact on quality of life of a non-cytarabine-containing remission-induction regimen followed by intermediate-dose cytarabine (IDARA-C) postremission therapy for the management of untreated acute myeloid leukemia (AML) in patients age 60 to 80 years. PATIENTS AND METHODS Eligible patients received mitoxantrone 10 mg/m2 and etoposide 100 mg/m2 on days 1 to 5. Complete remitters received a single course of cytarabine 0.5 mg/m2 every 12 hours on days 1 to 6. Cytogenetic and immunophenotyping studies were performed at diagnosis and were examined for prognostic importance. The Functional Living Index-Cancer (FLI-C) was used in the longitudinal assessment of quality of life. RESULTS A total of 37 (55%) of 67 eligible patients achieved remission, 34 (92%) of whom did so with a single course. The induction mortality rate was 12%. The median disease-free and overall survival times were 8.4 and 9.2 months, respectively. CD34 stem-cell phenotype, poor performance status, and high cytogenetic complexity score were independent covariates of failure to achieve remission. Very complex karotype combined with CD34 stem-cell phenotype to predict induction death in 67% of cases (P = .0003). Cytotoxic therapy-related gut epithelial damage was maximal during weeks 2 and 3 of therapy. Complete remitters and partial responders exhibited significantly improved global FLI-C scores following completion of therapy. CONCLUSION Mitoxantrone plus etoposide was an effective and well-tolerated first-line induction regimen for AML in the elderly that should be studied further in comparison to the standard cytarabine/anthracycline-based therapy.
Cross-sensitization profiles of edible nuts in a birch-endemic area
Authors: R. Uotila, A. K. Kukkonen, A. S. Pelkonen, M. J. Mäkelä
Journal: Allergy (2015)

Background Sensitization to birch pollen causes cross-sensitization to nuts, but rarely leads to clinical nut allergy. The aim was to study sensitizations to nuts in individuals sensitized to birch pollen and examine cross-reactivities between birch and nut species. Methods All subjects with skin prick tests (SPTs) for birch pollen conducted during 1997–2013 in the Skin and Allergy Hospital in Helsinki (n = 114 572) and their available SPTs for nuts (n = 50 604) were included. Nut sensitizations were analyzed both with and without cosensitization to birch and stratified into age-categories. Cross-reactivities were analyzed with hierarchical clustering. One group of 1589 patients was surveyed for symptoms. Data were gathered also from Lapland to examine sensitizations in an area with less birch-pollen exposure. Results Of subjects with birch sensitization, 84% were cosensitized to hazelnut, 71% to almond, and 60% to peanut. In a subgroup without birch sensitization, young children (<5 years) were most commonly nut-sensitized (8–40%); and this prevalence decreased in adolescents and further in adults (4–12%). Cashew and pistachio (ρ = 0.66; P < 0.001) and pecan and walnut (ρ = 0.65; P < 0.001) correlated the strongest. The majority of nut-sensitized patients (71% hazelnut, 83% almond, 73% peanut) reported no or mild symptoms. Cosensitizations between nuts and birch were similar in Lapland with its lower birch-pollen exposure. Conclusion Birch-sensitized individuals are frequently cosensitized to hazelnut, almond, and peanut. Among the birch-negatives, prevalences of nut sensitizations decrease from early childhood to adolescence. Cashew and pistachio, and pecan and walnut cross-react the most.
Association of renal dysfunction with cardiac output and right atrial pressure in pulmonary arterial hypertension
Authors: Marielle van de Veerdonk, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2011)

Background:  Pulmonary arterial hypertension is disease of the pulmonary vasculature that results in right ventricular (RV) failure and death. Renal insufficiency is recently identified as a key predictor of mortality in PAH patients [1]. Renal dysfunction is associated with decreased cardiac output (CO) in patients with left heart failure. However, little is known about the mechanisms of renal dysfunction and its association with venous congestion in PAH patients with RV dysfunction.   Objectives:  To investigate the relationship between CO, right atrial pressure (RAP) and estimated glomerular filtration rate (eGFR) in patients with PAH.   Methods:  74 patients underwent baseline right heart catheterization to determine CO and RAP and blood sampling to calculate eGFR. These measurements were repeated in 30 patients after 12±1 months of follow-up.   Results:  Mean age was 52±15 years and 73% of subjects were female. Mean eGFR was 88±24 ml/min/1.73m 2 , mean CO was 5.1±1.7 L/min and mean RAP was 7.0±5 mmHg. Low eGFR at baseline was associated with low CO (R=0.46; p  After 1 year follow-up, eGFR remained stable, RAP remained unchanged and CO slightly increased (0.9±2.7 L/min; p=0.045). Changes in eGFR were determined by changes in CO (R=0.45; p=0.011) and RAP (R=-0.370; p=0.031). Multivariate analysis revealed that changes in CO were independently related to changes in eGFR (p=0.043).   Conclusions:  CO is the main determinant of renal dysfunction in patients with pulmonary arterial hypertension and RV dysfunction.   References:   1Benza et al. Circulation 2010.
AKI after Transcatheter or Surgical Aortic Valve Replacement
Authors: Charat Thongprayoon, Wisit Cheungpasitporn, Narat Srivali, Andrew M. Harrison, Tina M. Gunderson, Wonngarm Kittanamongkolchai, Kevin L. Greason, Kianoush B. Kashani
Journal: Journal of the American Society of Nephrology (2015)

Transcatheter aortic valve replacement (TAVR) is an alternative to surgical aortic valve replacement (SAVR) for patients with symptomatic severe aortic stenosis who are at high risk of perioperative mortality. Previous studies showed increased risk of postoperative AKI with TAVR, but it is unclear whether differences in patient risk profiles confounded the results. To conduct a propensity-matched study, we identified all adult patients undergoing isolated aortic valve replacement for aortic stenosis at Mayo Clinic Hospital in Rochester, Minnesota from January 1, 2008 to June 30, 2014. Using propensity score matching on the basis of clinical characteristics and preoperative variables, we compared the postoperative incidence of AKI, defined by Kidney Disease Improving Global Outcomes guidelines, and major adverse kidney events in patients treated with TAVR with that in patients treated with SAVR. Major adverse kidney events were the composite of in-hospital mortality, use of RRT, and persistent elevated serum creatinine ≥200% from baseline at hospital discharge. Of 1563 eligible patients, 195 matched pairs (390 patients) were created. In the matched cohort, baseline characteristics, including Society of Thoracic Surgeons risk score and eGFR, were comparable between the two groups. Furthermore, no significant differences existed between the TAVR and SAVR groups in postoperative AKI (24.1% versus 29.7%; P =0.21), major adverse kidney events (2.1% versus 1.5%; P =0.70), or mortality &gt;6 months after surgery (6.0% versus 8.3%; P =0.51). Thus, TAVR did not affect postoperative AKI risk. Because it is less invasive than SAVR, TAVR may be preferred in high-risk individuals.
Prioritising women’s, children’s, and adolescents’ health in the post-2015 world
Authors: Lori McDougall, Anita Sharma, Jennifer Franz-Vasdeki, Allison Eva Beattie, Kadidiatou Touré, Kaosar Afsana, Amy Boldosser-Boesch, Lola Dare, Flavia Draganus, Kate Eardley, Cecilia Garcia Ruiz, Lars Gronseth, Katja Iversen, Shyama Kuruvilla, Allison Marshall, Betsy McCallon, Susan Papp
Journal: BMJ (2015)

<b>Lori McDougall and colleagues</b> set out a three point agenda for strengthening advocacy: investing in multipartner national platforms for action; innovative communication circuits to unite advocacy; and multidonor funding mechanisms to scale up advocacy efforts
Is adjuvant tamoxifen used optimally in the treatment of breast cancer? Results of an Italian survey
Authors: M. Valentini, E. Mari, M. Belfiglio, A. Nicolucci
Journal: Annals of Oncology (1999)

Background: Institutional and physician-related factors can influence the way in which physicians interpret research results.The aim of this study was to determine what physicians know about, and their opinions of, hormone treatment in breast cancer patients, and the factors comprising their medical decision-making.Materials and methods: A questionnaire was mailed to a random sample of physicians inquiring as to their preferences with respect to adjuvant tamoxifen, and the usual duration of the treatment applied in various clinical scenarios (according to a woman's menopausal status, the oestrogen receptor status and the stage of disease).Results: Of 500 physicians identified, 38% returned the questionnaire.Of the non-responders, a random sample of 60 physicians was interviewed by phone.The total number of available questionnaires was 250 (50%).About 3/4 of the doctors would prescribe tamoxifen in older ER+ women and 30%-40% in post-menopausal ERpatients, but only 2/5 would do so in younger ER+ women.The vast majority of physicians considered five years as standard for ER+ patients.Nevertheless, about 1/4 of the doctors chose a shorter treatment duration for node-negative, pre-menopausal patients.A minority of physicians used tamoxifen for longer than five years.Older clinicians were less likely to prescribe tamoxifen, particularly for low-risk patients.Conclusions: According to the data of the recent EBCTG overview, an additional 20,000 lives could be saved worldwide each year if tamoxifen were given to all early breast cancer patients with hormone-sensitive disease, irrespective of age and disease stage, and for a minimum of five years.Our study, involving a representative sample of physicians practicing in Italy, shows that tamoxifen is not used optimally, with a substantial under-use in younger women and women with node-negative disease.
Repeatability of FeNO measurements with an airway inflammation monitor using the 6 second (6s) and the 10 second (10s) exhalation modes in children 6 to 10 years of age with asthma
Authors: Neal Jain, Chelsea Bradshaw, Nancy Herje, Glenn Crater
Journal: European Respiratory Journal (2014)

Introduction: Interpretation of FeNO profiles is based on the nitric oxide plateau. To achieve plateau, the duration of exhalation must be sufficient (at least 4 seconds for children ‹ 12 years and › 6s for children › 12 years (Am J Respir Crit Care Med 2005).

Objectives: To assess repeatability and degree of agreement of FeNO measurements performed with the NIOX VERO® in the same subject using both the 6s and the 10s exhalation modes.

Methods: Randomized, single-center, single-visit, clinical validation study conducted in children 4 to 10y with asthma. Repeatability of FeNO was measured as the intra-subject standard deviation in a subset of children 6 to 10y of age with two observations collected for both the 6s and the 10s assessments. Degree of agreement was measured through assessment of the bias at the 35ppb cut-off using a weighted Deming Regression analysis.

Results: Subjects were predominantly male (71.7%) with a mean age of 8.1y. Mean average FeNO was 34ppb (6s mode) and 33ppb (10s mode). FeNO measurements were repeatable; intra-subject SDs were very similar between the modes with a median pared difference of 0.0 (p=0.3090). The degree of agreement was high; the weighted Deming regression analysis parameter estimates for the intercept (-0.564; p=0.3642) and slope (1.057; p-0.0912) were not significantly different from zero and one, respectively.

Conclusions: FeNO measurements were repeatable and consistent and the degree of agreement between the 6s and the 10s modes was high. Results from this study support reliable and safe use of the NIOX VERO® to measure FeNO in children with asthma.