tbuckley/cabot-search huggingface dataset:
<sup>90</sup>Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide
Authors: David L. Bushnell, Thomas M. O'Dorisio, M. Sue O'Dorisio, Yusuf Menda, Rodney J. Hicks, Eric Van Cutsem, Jean-Louis Baulieu, Francoise Borson-Chazot, Lowell Anthony, Al B. Benson, Kjell Oberg, Ashley B. Grossman, Mary Connolly, Hakim Bouterfa, Yong Li, Katherine A. Kacena, Norman LaFrance, Stanislas A. Pauwels
Journal: Journal of Clinical Oncology (2010)

Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors.Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks.Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days.(90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.
Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation
Authors: M Auroux
Journal: Human Reproduction Update (2000)

In addition to gross malformations, many problems relating to the formation of gametes and embryos can generate, within a continuum of abnormalities, a number of problems that are less evident. On the basis of genetic and/or biochemical or cytological changes, these effects generally appear long after birth as functional difficulties that range from growth changes and altered endocrine functions and cancer to very late behavioural disorders. Such problems may have effects on males and females before conception, on the embryo during gestation, and may also impact on the success of assisted reproduction techniques. For this reason, we have examined the experimental and clinical data that indicate the long-term consequences, for progeny, of iatrogenic and toxic environmental factors on the male reproductive system, and in particular the effect that one specific condition–-cryopreservation–-may have on gametes and the conceptus. We then focus on the interpretation given to these data which, in general, emphasize the need not only for further experiments to help understand the mechanism of anomalies and increase the level of vigilance in humans, but also to extend follow-up investigations in children.
Cost‐effectiveness of natriuretic peptide‐based screening and collaborative care: a report from the STOP‐HF (St Vincent's Screening TO Prevent Heart Failure) study
Authors: Mark T. Ledwidge, Eoin O'Connell, Joseph Gallagher, Lesley Tilson, Stephanie James, Victor Voon, Margaret Bermingham, Elaine Tallon, Chris Watson, Rory O'Hanlon, Michael Barry, Kenneth McDonald
Journal: European Journal of Heart Failure (2015)
Endothelins Induce CCR7 Expression by Breast Tumor Cells via Endothelin Receptor A and Hypoxia-Inducible Factor-1
Authors: Julia L. Wilson, Joy Burchell, Matthew J. Grimshaw
Journal: Cancer Research (2006)

Abstract Endothelin expression is increased in breast tumors and is associated with invasion and metastasis, whereas CCR7 expression by breast tumor cells may have a role in the organ specificity of breast cancer spread. In this article, we have analyzed whether endothelins influence breast tumor cell expression of the chemokine receptor CCR7. Stimulation of human breast tumor cell lines with endothelins increased cell surface expression of CCR7 via endothelin receptor A. The iron chelators desferrioxamine and cobalt chloride, which induce hypoxia-inducible factor (HIF)-mediated transcription, also increased CCR7 expression; transfection of a dominant-negative version of the HIF regulatory subunit, HIF-1α, into MCF-7 cells abolished CCR7 induction by endothelins, indicating that increased expression is due to HIF-1 stabilization. Endothelin stimulation promoted invasion toward the CCR7 ligands CCL19 and CCL21. Endothelin-mediated chemokine-independent invasion itself is dependent on CCR7 activity and could be abolished using a CCR7-neutralizing monoclonal antibody. In human breast carcinomas, mRNA expression of endothelins correlated with the level of CCR7 expression, both of which were associated with the presence of lymph node metastases. Expression of the CCR7 ligands CCL19 and CCL21 was also higher in breast cancer patients with lymph node involvement compared with those without, but expression of these chemokines did not correlate with endothelin expression. These data show that CCR7 may be regulated by the breast tumor microenvironment and further support the use of endothelin receptor antagonists in the treatment of invasive and metastatic breast cancer. (Cancer Res 2006; 66(24): 11802-7)
Adverse events in surgery in Scotland show a steady fall
Authors: B. Christie
Journal: BMJ (2003)

Adverse events that contribute to deaths of patients while they are under surgical care have fallen steadily over the past five years in Scotland.

Figures from the 2002 Scottish Audit for Surgical Mortality show that poor standards of care caused the deaths of 12 patients who had been expected to survive and made a substantial contribution to a further 221 deaths.

The most common problems were delays in surgery, missed and delayed diagnoses, operations being done by inexperienced junior staff, and …
The “Sunshine Deficit” and Cardiovascular Disease
Authors: Diane E. Wallis, Sue Penckofer, Glen W. Sizemore
Journal: Circulation (2008)

I n past decades, the primary focus on vitamin D was the recognition and treatment of deficiency as it related to metabolic bone disease (rickets, osteomalacia, and secondary hyperparathyroidism).In the last 10 years, however, with the discovery of vitamin D receptors in multiple tissue types has come the recognition that the role of vitamin D extends beyond the musculoskeletal system. 1 The presence of abundant vitamin D receptors in myocardial tissue and vasculature and the observation that hypertension may be ameliorated with vitamin D suggest a greater role for vitamin D in the cardiovascular system. 2 Presently, large numbers of people are found to have hypovitaminosis D (a term chosen for this review to indicate any concentration below normal under substrate-saturated conditions) resulting in part from more indoor activities and the purposeful avoidance of sunshine.This review first describes why vitamin D, parathyroid hormone (PTH), and the skeleton are important to the heart and vasculature, then outlines why the epidemic of hypovitaminosis D deserves further scrutiny by the cardiovascular community, and finally suggests why treatment options for reducing hypovitaminosis D may favorably affect the morbidity and mortality of common cardiovascular disorders.
Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders
Journal: American Journal of Psychiatry (2009)

Objective: The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. Method: A literature review was carried out, power and other issues discussed, and planned studies assessed. Results: Most of the genomic DNA sequence differences between any two people are common (frequency >5%) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress. Conclusions: GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.
Polyfluoroalkyl Chemicals and Menopause among Women 20–65 Years of Age (NHANES)
Authors: Kyla W. Taylor, Kate Hoffman, Kristina A. Thayer, Julie L. Daniels
Journal: Environmental Health Perspectives (2013)

Polyfluoroalkyl chemicals (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) have been associated with early menopause. However, previous cross-sectional studies have lacked adequate data to investigate possible reverse causality (i.e., higher serum concentrations due to decreased excretion after menopause).We investigated the association between PFOS, PFOA, perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) and age at natural menopause among women 20-65 years of age in NHANES (National Health and Nutrition Examination Survey).We used proportional hazard models to estimate hazard ratios (HRs) for the onset of natural menopause as a function of age and serum PFC levels, and to investigate reverse causation by estimating associations between PFC levels and the rate of hysterectomy. We also used multivariable linear regression to determine whether time since menopause predicted serum PFC levels.After adjusting for age at survey, race/ethnicity, education, ever smoking, and parity, women with higher levels of PFCs had earlier menopause than did women with the lowest PFC levels. We observed a monotonic association with PFHxS: The HR was 1.42 (95% CI: 1.08, 1.87) for serum concentrations in tertile 2 versus tertile 1, and 1.70 (95% CI: 1.36, 2.12) for tertile 3 versus tertile 1. We also found evidence of reverse causation: PFCs were positively associated with rate of hysterectomy, and time since natural menopause was positively associated with serum PFCs.Our ﬁndings suggest a positive association between PFCs and menopause; however, at least part of the association may be due to reverse causation. Regardless of underlying cause, women appear to have higher PFC concentrations after menopause.
Regional volume distensibility of canine thoracic aorta during moderate treadmill exercise.
Authors: B J Gentile, C J Chuong, G A Ordway
Journal: Circulation Research (1988)

We characterized the in vivo mechanical properties of segments of upper descending thoracic aorta (UDTA) in terms of volume distensibility, which was derived from measurements of pulsatile intravascular pressure, inner wall radius, and length changes. Data for this analysis were obtained from six dogs at rest and during moderate treadmill exercise (8% grade, 4.5 miles/hr). Volume distensibility reflects the regional rheological properties of the UDTA at in vivo states. It was shown to be the sum of circumferential extensibility, longitudinal extensibility, and higher-order extensibilities. Circumferential extensibility and longitudinal extensibility are linear expressions of vessel kinematic changes which represent percent volume changes per pulse pressure and are due to circumferential and longitudinal dimensional changes alone. The higher-order extensibilities (second and third order), however, account for the coupling effect, which is the percentage volume change per millimeter mercury pulse pressure due to the interactions among radial, circumferential, and axial dimensional changes. The volume distensibility of the UDTA during exercise was significantly less than that at rest (0.67 +/- 0.12 vs. 0.91 +/- 0.11% V/mm Hg pressure). This was the result of a significant decrease in circumferential extensibility and higher-order extensibility in response to exercise with no change in longitudinal extensibility. The higher order extensibilities were also important since the volume distensibility of the UDTA was underestimated by 10% for both rest and exercise when they were ignored. We also evaluated radial extensibility by using pressure and wall thickness data and showed that this variable did not change in response to exercise.
Risk of Breast Cancer After Onset of Type 2 Diabetes
Authors: Samantha L. Bowker, Kathryn Richardson, Carlo A. Marra, Jeffrey A. Johnson
Journal: Diabetes Care (2011)

To examine the risk of breast cancer in pre- and postmenopausal women with type 2 diabetes (T2D).This was a population-based retrospective cohort study. Cox regression, stratified by pre- (<55 years) and postmenopausal (≥55 years) status, was used to estimate hazard ratios (HRs) for breast cancer, during earlier (0-3 months) and later (3 months to 10 years) time windows after diabetes index date.Compared with women without T2D, HRs for breast cancer were 0.95 (95% CI 0.48-1.86; P = 0.88) and 1.31 (0.92-1.86; P = 0.14) in pre- and postmenopausal women with T2D, respectively, in the early time window, and 0.92 (0.75-1.13; P = 0.45) and 1.00 (0.90-1.11; P = 0.93) in pre- and postmenopausal women with T2D, respectively, in the later time window.We observed a trend toward an increased risk of breast cancer in postmenopausal women with T2D, but only in the time period immediately after diabetes index date.
Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer
Authors: Harold J. Burstein, Yan Sun, Luc Y. Dirix, Zefei Jiang, Robert Paridaens, Antoinette R. Tan, Ahmad Awada, Anantbhushan Ranade, Shunchang Jiao, Gary Schwartz, Richat Abbas, Christine Powell, Kathleen Turnbull, Jennifer Vermette, Charles Zacharchuk, Rajendra Badwe
Journal: Journal of Clinical Oncology (2010)

Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial.Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review.The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported.Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.
Prevention of Ventricular Arrhythmias With Sarcoplasmic Reticulum Ca <sup>2+</sup> ATPase Pump Overexpression in a Porcine Model of Ischemia Reperfusion
Authors: Fabrice Prunier, Yoshiaki Kawase, Davide Gianni, Cristina Scapin, Stephan B. Danik, Patric T. Ellinor, Roger J. Hajjar, Federica del Monte
Journal: Circulation (2008)

Background— Ventricular arrhythmias are life-threatening complications of heart failure and myocardial ischemia. Increased diastolic Ca 2+ overload occurring in ischemia leads to afterdepolarizations and aftercontractions that are responsible for cellular electric instability. We inquired whether sarcoplasmic reticulum Ca 2+ ATPase pump (SERCA2a) overexpression could reduce ischemic ventricular arrhythmias by modulating Ca 2+ overload. Methods and Results— SERCA2a overexpression in pig hearts was achieved by intracoronary gene delivery of adenovirus in the 3 main coronary arteries. Homogeneous distribution of the gene was obtained through the left ventricle. After gene delivery, the left anterior descending coronary artery was occluded for 30 minutes to induce myocardial ischemia followed by reperfusion. We compared this model with a model of permanent coronary artery occlusion. Twenty-four–hour ECG Holter recordings showed that SERCA2a overexpression significantly reduced the number of episodes of ventricular tachycardia after reperfusion, whereas no significant difference was found in the occurrence of sustained or nonsustained ventricular tachycardia and ventricular fibrillation in pigs undergoing permanent occlusion. Conclusions— We show that Ca 2+ cycling modulation using SERCA2a overexpression reduces ventricular arrhythmias after ischemia-reperfusion. Strategies that modulate postischemic Ca 2+ overload may have clinical promise for the treatment of ventricular arrhythmias.
High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study
Authors: A. Necchi, L. Mariani, M. Di Nicola, S. Lo Vullo, N. Nicolai, P. Giannatempo, D. Raggi, E. Farè, M. Magni, L. Piva, P. Matteucci, M. Catanzaro, D. Biasoni, T. Torelli, S. Stagni, C. Bengala, C. Barone, I. Schiavetto, S. Siena, C. Carlo-Stella, G. Pizzocaro, R. Salvioni, A.M. Gianni
Journal: Annals of Oncology (2014)
Modeling Breast Cancer–Associated c-Src and EGFR Overexpression in Human MECs: c-Src and EGFR Cooperatively Promote Aberrant Three-dimensional Acinar Structure and Invasive Behavior
Authors: Manjari Dimri, Mayumi Naramura, Lei Duan, Jing Chen, Cesar Ortega-Cava, Gengsheng Chen, Rasna Goswami, Norvin Fernandes, Qingshen Gao, Goberdhan P. Dimri, Vimla Band, Hamid Band
Journal: Cancer Research (2007)

Abstract Epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is overexpressed in as many as 60% cases of breast and other cancers. EGFR overexpression is a characteristic of highly aggressive molecular subtypes of breast cancer with basal-like and BRCA1 mutant phenotypes distinct from ErbB2-overexpressing breast cancers. Yet, EGFR is substantially weaker compared with ErbB2 in promoting the oncogenic transformation of nontumorigenic human mammary epithelial cells (human MEC), suggesting a role for cooperating oncogenes. Here, we have modeled the co-overexpression of EGFR and a biologically and clinically relevant potential modifier c-Src in two distinct immortal but nontumorigenic human MECs. Using a combination of morphologic analysis and confocal imaging of polarity markers in three-dimensional Matrigel culture together with functional analyses of early oncogenic traits, we show for the first time that EGFR and c-Src co-overexpression but not EGFR or c-Src overexpression alone unleashes an oncogenic signaling program that leads to hyperproliferation and loss of polarity in three-dimensional acinar cultures, marked enhancement of migratory and invasive behavior, and anchorage-independent growth. Our results establish that EGFR overexpression in an appropriate context (modeled here using c-Src overexpression) can initiate oncogenic transformation of nontumorigenic human MECs and provide a suitable in vitro model to interrogate human breast cancer–relevant oncogenic signaling pathways initiated by overexpressed EGFR and to identify modifiers of EGFR-mediated breast oncogenesis. [Cancer Res 2007;67(9):4164–72]
Self-healing hybrid nanocomposites consisting of bisphosphonated hyaluronan and calcium phosphate nanoparticles
Authors: M. Reza Nejadnik, Xia Yang, Matilde Bongio, Hamdan S. Alghamdi, Jeroen J.J.P. van den Beucken, Marie C. Huysmans, John A. Jansen, Jöns Hilborn, Dmitri Ossipov, Sander C.G. Leeuwenburgh
Journal: Biomaterials (2014)
A LC3-Interacting Motif in the Influenza A Virus M2 Protein Is Required to Subvert Autophagy and Maintain Virion Stability
Authors: Rupert Beale, Helen Wise, Amanda Stuart, Benjamin J. Ravenhill, Paul Digard, Felix Randow
Journal: Cell Host & Microbe (2014)

Autophagy recycles cellular components and defends cells against intracellular pathogens. While viruses must evade autophagocytic destruction, some viruses can also subvert autophagy for their own benefit. The ability of influenza A virus (IAV) to evade autophagy depends on the Matrix 2 (M2) ion-channel protein. We show that the cytoplasmic tail of IAV M2 interacts directly with the essential autophagy protein LC3 and promotes LC3 relocalization to the unexpected destination of the plasma membrane. LC3 binding is mediated by a highly conserved LC3-interacting region (LIR) in M2. The M2 LIR is required for LC3 redistribution to the plasma membrane in virus-infected cells. Mutations in M2 that abolish LC3 binding interfere with filamentous budding and reduce virion stability. IAV therefore subverts autophagy by mimicking a host short linear protein-protein interaction motif. This strategy may facilitate transmission of infection between organisms by enhancing the stability of viral progeny.
Negative Regulation of p53 by the Long Isoform of ErbB3 Binding Protein Ebp1 in Brain Tumors
Authors: Chung Kwon Kim, Truong L.X. Nguyen, Kyeung Min Joo, Do-Hyun Nam, Jihye Park, Kyung-Hoon Lee, Sung-Woo Cho, Jee-Yin Ahn
Journal: Cancer Research (2010)

The ErbB3 binding protein Ebp1 has been implicated in a number of human cancers. Ebp1 includes 2 isoforms, p48 and p42, that exhibit different cellular activities. Here we show that the larger p48 isoform is transforming and that it promotes cell growth, clonogenicity, and invasion in human glioblastoma (GBM). P48 overexpression in GBM cells facilitated tumorigenesis and enhanced tumor growth in mouse xenograft models. Human GBM tissues displayed elevated levels of p48 compared with surrounding normal tissues or low-grade tumors. Notably, p48 levels were inversely correlated with poor prognosis in GBM patients. We determined that p48 binds to the p53 E3 ligase HDM2, enhancing HDM2-p53 association and thereby promoting p53 polyubiquitination and degradation to reduce steady-state p53 levels and activity. Together, our findings suggest that p48 functions as an oncogene by promoting glioma tumorigenicity via interactions with HDM2 that contribute to p53 downregulation.