tbuckley/cabot-search huggingface dataset:
Analysis of <i>PTEN</i>, <i>BRAF</i>, and <i>EGFR</i> Status in Determining Benefit From Cetuximab Therapy in Wild-Type <i>KRAS</i> Metastatic Colon Cancer
Authors: Pierre Laurent-Puig, Anne Cayre, Gilles Manceau, Emmanuel Buc, Jean-Baptiste Bachet, Thierry Lecomte, Philippe Rougier, Astrid Lievre, Bruno Landi, Valérie Boige, Michel Ducreux, Marc Ychou, Fréderic Bibeau, Olivier Bouché, Julia Reid, Steven Stone, Frédérique Penault-Llorca
Journal: Journal of Clinical Oncology (2009)

Purpose The occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti–epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy. Patients and Methods We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry. Results In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P &lt; .001) and shorter overall survival (OS; P &lt; .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS. Conclusion BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.
Estrogen Receptor-α and Endothelial Nitric Oxide Synthase Nuclear Complex Regulates Transcription of Human Telomerase
Authors: Annalisa Grasselli, Simona Nanni, Claudia Colussi, Aurora Aiello, Valentina Benvenuti, Gianluca Ragone, Fabiola Moretti, Ada Sacchi, Silvia Bacchetti, Carlo Gaetano, Maurizio C. Capogrossi, Alfredo Pontecorvi, Antonella Farsetti
Journal: Circulation Research (2008)

We report that in endothelial cells, the angiogenic effect of 17beta-estradiol (E2) is inhibited by the estrogen receptor (ER) antagonist ICI or the NO synthase (NOS) inhibitor 7-nitroindazole via downregulation of hTERT, the telomerase catalytic subunit, suggesting that E2 and NO are involved in controlling hTERT transcription. Quantitative Real-Time PCR and chromatin immunoprecipitations in E2-treated human umbilical vein endothelial cells, showed recruitment of ERs on the hTERT promoter and concomitant enrichment in histone 3 methylation at Lysine 79, a modification associated with transcription-competent chromatin. Confocal microscopy and re-chromatin immunoprecipitations revealed that on E2 induction, endothelial (e)NOS rapidly localized into the nucleus and associated with ERalpha on the hTERT promoter. Transfections of a constitutively active eNOS mutant (S1177D) strongly induced the hTERT promoter, indicating a direct role of the protein in hTERT transcriptional regulation. Mutation of the estrogen response element in the promoter abolished response to both ERs and active eNOS, demonstrating that the estrogen response element integrity is required for hTERT regulation by these factors. To investigate this novel regulation in a reduced NO environment, pulmonary endothelial cells were isolated from eNOS(-/-) mice and grown with/without E2. In wild-type cells, E2 significantly increased telomerase activity. In eNOS(-/-) cells, basal telomerase activity was rescued by exogenous eNOS or an NO donor, whereas responsiveness to E2 demanded the active protein. In conclusion, we document the novel findings of a combinatorial eNOS/ERalpha complex at the hTERT estrogen response element site and that active eNOS and ligand-activated ERs cooperate in regulating hTERT expression in the endothelium.
The Cost of HIPAA Compliance
Authors: Peter Kilbridge
Journal: New England Journal of Medicine (2003)

The deadline for compliance with the regulations for patient privacy in the Health Insurance Portability and Accountability Act of 1996 (HIPAA) is now upon us, and hospitals and physician groups are in the throes of working to meet it. This is an enormous chore, affecting numerous areas of hospital operations and, ultimately, every employee.Meeting the requirements of the extensive privacy regulations — the deadline for which is April 14, 2003 — has been consuming substantial time, resources, and energy from hospitals and physician groups. For example, essentially all employees must be trained in the protection of patients' privacy, and . . .
Identification of a recombinogenic major histocompatibility complex Q gene with diverse alleles.
Authors: M K Cullen, L A Lapierre, K V Kesari, J Geliebter
Journal: The Journal of Experimental Medicine (1993)

Structural diversity enables class Ia molecules to present a diverse repertoire of peptides to the T cell receptor. This diversity is thought to be generated by recombinations between class I genes. We have found that two class Ib Q2 alleles exhibit extremely high sequence diversity, even higher than class Ia alleles. Clustered nucleotide differences between Q2b and Q2k suggest that this sequence diversity was generated by microrecombinations between Q2 genes and other class I genes. The relatively high expression of Q2b in the thymus may be significant and perhaps suggests a novel role for a Q2b product in the education and selection of the T cell repertoire.
Update on the Effect of a Multidisciplinary Team (MDT) Clinic on Asthma Outcome for Medicaid-Eligible Inner City Children with Moderate to High-Risk Asthma
Authors: P.P. Patel, G. Dhillon, J. Mellesmoen, P. Seigel, P. Munzenberger, R. Rich, E. Secord
Journal: Journal of Allergy and Clinical Immunology (2006)
Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of <i>Braf</i>V600E–Driven Lung Tumors
Authors: Anne M. Strohecker, Jessie Yanxiang Guo, Gizem Karsli-Uzunbas, Sandy M. Price, Guanghua Jim Chen, Robin Mathew, Martin McMahon, Eileen White
Journal: Cancer Discovery (2013)

Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BrafV600E-induced lung cancer in the presence or absence of the tumor suppressor Trp53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect, suggesting that both genes modulate tumorigenesis by regulating oxidative stress and revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse life span. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire and survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BrafV600E tumor growth and metabolism.The essential autophagy gene Atg7 functions to promote BrafV600E-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating BrafV600E-driven cancers.
The Economic Cost of Pelvic Inflammatory Disease
Authors: A. Eugene Washington
Journal: JAMA (1986)

Pelvic inflammatory disease (PID) is one of the most widespread and debilitating diseases affecting women today. To calculate the economic costs of PID and PID-associated ectopic pregnancy and infertility in the United States, we analyzed data from local hospitals and from several state and national sources. Direct and indirect costs were computed. We found that the total cost of PID and PID-associated ectopic pregnancy and infertility exceeded +2.6 billion in 1984. By 1990, the estimated cost of PID and its sequelae will total +3.50 billion per year, if the annual medical care inflation is 5% and the incidence of PID remains constant during this six-year period. These estimated costs of PID and its associated sequelae emphasize the urgent need for effective programs to prevent PID.
COPD is associated with increased mortality in patients with community-acquired pneumonia
Authors: M. I. Restrepo, E. M. Mortensen, J. A. Pugh, A. Anzueto
Journal: European Respiratory Journal (2006)

Patients with chronic obstructive pulmonary disease (COPD) who develop community-acquired pneumonia (CAP) may experience worse clinical outcomes. However, COPD is not included as a distinct diagnosis in validated instruments that predict mortality in patients with CAP. The aim of the present study was to evaluate the impact of COPD as a comorbid condition on 30- and 90-day mortality in CAP patients. A retrospective observational study was conducted at two hospitals. Eligible patients had a discharge diagnosis and radiological confirmation of CAP. Among 744 patients with CAP, 215 had a comorbid diagnosis of COPD and 529 did not have COPD. The COPD group had a higher mean pneumonia severity index score (105+/-32 versus 87+/-34) and were admitted to the intensive care unit more frequently (25 versus 18%). After adjusting for severity of disease and processes of care, CAP patients with COPD showed significantly higher 30- and 90-day mortality than non-COPD patients. Chronic obstructive pulmonary disease patients hospitalised with community-acquired pneumonia exhibited higher 30- and 90-day mortality than patients without chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease should be evaluated for inclusion in community-acquired pneumonia prediction instruments.
Thromboxane A <sub>2</sub> Receptor Signaling Inhibits Vascular Endothelial Growth Factor–Induced Endothelial Cell Differentiation and Migration
Authors: Anthony W. Ashton, J. Anthony Ware
Journal: Circulation Research (2004)

Vascular endothelial growth factor (VEGF) is an important patho-physiological mediator of angiogenesis. VEGF-induced endothelial cell (EC) migration and angiogenesis often occur in complicated environments containing multiple agents capable of modifying the response. Thromboxane (TX) A2 is released from multiple cell types and is a prime mediator of pathogenesis of many vascular diseases. Human EC express both TXA2 receptor (TP) isoforms; however, the effects of individual TP isoforms on VEGF-induced EC migration and angogenesis are unknown. We report here that the TXA2 mimetic [1S-(1alpha, 2beta(5Z), 3alpha(1E, 3R), 4alpha]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxab icyclo-[2.2.1]heptan-2yl]-5'-heptenoic acid (IBOP) (100 nmol/L) is a potent antagonist (IC50 30 nmol/L) of VEGF-induced EC migration and differentiation. TPbeta, but not TPalpha, expression is required for the inhibition of VEGF-induced migration and angiogenesis. IBOP costimulation suppressed nitric oxide (NO) release from VEGF-treated EC through decreased activation of Akt, eNOS, and PDK1. TPbeta costimulation also ablated the increase in focal adhesion formation in response to VEGF. This mechanism was characterized by decreased recruitment of focal adhesion kinase (FAK) and vinculin to the alpha(v)beta3 integrin and reduced FAK and Src activation in response to VEGF. Addition of NO donors together with transfection of a constitutively active Src construct could circumvent the blockade of VEGF-induced migration by TP; however, neither intervention alone was sufficient. Thus, TP stimulation appears to limit angiogenesis, at least in part, by inhibiting the pro-angiogenic cytokine VEGF. These data further support a role for antagonism of TP activation in enhancing the angiogenic response in tissues exposed to elevated TXA2 levels in which revascularization is important.
A Novel Orally Bioavailable Inhibitor of Kinase Insert Domain-Containing Receptor Induces Antiangiogenic Effects and Prevents Tumor Growth <b> <i>in Vivo</i> </b>
Authors: Laura Sepp-Lorenzino, Elaine Rands, Xianzhi Mao, Brett Connolly, Jennifer Shipman, Joanne Antanavage, Susan Hill, Lenora Davis, Stephen Beck, Keith Rickert, Kathleen Coll, Patrice Ciecko, Mark Fraley, William Hoffman, George Hartman, David Heimbrook, Jackson Gibbs, Nancy Kohl, Kenneth Thomas
Journal: Cancer Research (2004)

A strategy for antagonizing vascular endothelial growth factor (VEGF) -induced angiogenesis is to inhibit the kinase activity of its receptor, kinase insert domain-containing receptor (KDR), the first committed and perhaps the last unique step in the VEGF signaling cascade. We synthesized a novel ATP-competitive KDR tyrosine kinase inhibitor that potently suppresses human and mouse KDR activity in enzyme (IC(50) = 7.8-19.5 nM) and cell-based assays (IC(50) = 8 nM). The compound was bioavailable in vivo, leading to a dose-dependent decrease in basal- and VEGF-stimulated KDR tyrosine phosphorylation in lungs from naïve and tumor-bearing mice (IC(50) = 23 nM). Pharmacokinetics and pharmacodynamics guided drug dose selection for antitumor efficacy studies. HT1080 nude mice xenografts were treated orally twice daily with vehicle, or 33 or 133 mg/kg of compound. These doses afforded trough plasma concentrations approximately equal to the IC(50) for inhibition of KDR autophosphorylation in vivo for the 33 mg/kg group, and higher than the IC(99) for the 133 mg/kg group. Chronic treatment at these doses was well-tolerated and resulted in dose-dependent inhibition of tumor growth, decreased tumor vascularization, decreased proliferation, and enhanced cell death. Antitumor efficacy correlated with inhibition of KDR tyrosine phosphorylation in the tumor, as well as in a surrogate tissue (lung). Pharmacokinetics and pharmacodynamics assessment indicated that the degree of tumor growth inhibition correlated directly with the extent of inhibition of KDR tyrosine phosphorylation in tumor or lung at trough. These observations highlight the need to design antiangiogenic drug regimens to ensure constant target suppression and to take advantage of PD end points to guide dose selection.
La menstruation apparente au cours de la grossesse
Authors: G. Kambourakis
Journal: Psychotherapy and Psychosomatics (1972)

The menstruation-like bleeding (M-LB) during pregnancy is, according to my clinical observations (1952, 1953), a psychosomatic phenomenon, because it occurs in emotional women, especially when they are under the effect of strong and prolonged emotional stresses. Moreover, the extremely evident clinical entity of this phenomenon (M-LB) and its striking similarity to the menstruation in the same woman led me to the conclusion, that a little time before menstruation as well in its beginning the hypothalamic part of the sympathetic system is in a state of increased activtiy, to which the menstruation, the menstruation-like bleeding during pregnancy (M-LB) and the premenstrual tension is related. The adrenalin and the not-adrenalin are one of the factors producing the hemorrhagic phenomena of the endometrium in menstruation.
Treatment of High-Risk Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia in Adolescents and Adults According to Early Cytologic Response and Minimal Residual Disease After Consolidation Assessed by Flow Cytometry: Final Results of the PETHEMA ALL-AR-03 Trial
Authors: Josep-Maria Ribera, Albert Oriol, Mireia Morgades, Pau Montesinos, Josep Sarrà, José González-Campos, Salut Brunet, Mar Tormo, Pascual Fernández-Abellán, Ramon Guàrdia, María-Teresa Bernal, Jordi Esteve, Pere Barba, María-José Moreno, Arancha Bermúdez, Antonia Cladera, Lourdes Escoda, Raimundo García-Boyero, Eloy del Potro, Juan Bergua, María-Luz Amigo, Carlos Grande, María-José Rabuñal, Jesús-María Hernández-Rivas, Evarist Feliu
Journal: Journal of Clinical Oncology (2014)

Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation.Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 × 10(-4) at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level ≥ 5 × 10(-4).Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (≥ 1 × 10(-3) after induction and ≥ 5 × 10(-4) after early consolidation) as the only prognostic factor for DFS and OS.Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.
Prevalence and Major Risk Factors of Reduced Flow Volume in Lower Extremities With Normal Ankle-Brachial Index in Japanese Patients With Type 2 Diabetes
Authors: Eiji Suzuki, Katsuya Egawa, Yoshihiko Nishio, Hiroshi Maegawa, Masanobu Tsuchiya, Masakazu Haneda, Hitoshi Yasuda, Shigehiro Morikawa, Toshiro Inubushi, Atsunori Kashiwagi
Journal: Diabetes Care (2003)

OBJECTIVE—To clarify the prevalence and major risk factors of reduced flow volume in lower extremities with normal ankle-brachial index (ABI) in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—We recruited 208 consecutive type 2 diabetic patients and 33 age-matched nondiabetic subjects (control group) admitted to our hospital. Thirty-two of the patients had low ABI (&amp;lt;0.90) and intermittent claudication (peripheral arterial disease [PAD] group), and 176 patients had normal ABI (&amp;gt;0.9) (non-PAD group). We evaluated flow volume and resistive index, as an index of arterial resistance to blood flow, at the popliteal artery using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. RESULTS—Simple linear regression analysis showed a negative correlation between resistive index and total flow volume in the non-PAD group (r = −0.714, P &amp;lt; 0.001). We defined the means ± 2 SD of these parameters in the control group as the normal range; abnormal resistive index was &amp;gt;1.017, and abnormal flow volume was &amp;lt;50.8 ml/min. The non-PAD group was divided according to the levels of these parameters: 80 patients had both normal resistive index and normal flow volume (normal group); of 96 patients with higher resistive index, 63 had normal flow volume (borderline group) and 33 had reduced flow volume (reduced group). Multiple regression analysis demonstrated that the major risk factors for reduced flow volume were age, hypertension, and diabetic nephropathy (r2 = 0.303, P &amp;lt; 0.001). CONCLUSIONS—The prevalence of patients without PAD with reduced flow volume in the lower extremities was 16% (n = 33) and comparable with that of patients with PAD with intermittent claudication (n = 32), suggesting that increase in arterial resistance to blood flow may be one of the major causes of lower extremity arterial disease in Japan.
Simple method for α1-antitrypsin deficiency screening by use of dried blood spot specimens
Authors: X. Costa, R. Jardi, F. Rodriguez, M. Miravitlles, M. Cotrina, C. Gonzalez, C. Pascual, R. Vidal
Journal: European Respiratory Journal (2000)

The use of dried blood spot (DBS) specimens in quantitative alpha1-antitrypsin (alpha1-AT) detection or genetic analysis is limited because protein levels in the samples are low and they contain components that can interfere with polymerase chain reaction amplification. A methodological adaptation was developed to overcome these drawbacks which is discussed here. The study population consisted of 200 healthy volunteers and 300 patients with chronic obstructive pulmonary disease (COPD). DBS specimens were tested for alpha1-AT concentration using a modified nephelometric assay and phenotyped with an isoelectric focusing method. Genetic diagnosis was established by deoxyribonucleic acid sequencing using a simple purification procedure to remove contaminants. The nephelometric method showed a detection limit of 0.284 mg x dL(-1), corresponding to a serum concentration of 13 mg x dL(-1). The correlation coefficient between alpha1-AT concentrations in DBS versus serum samples was R2=0.8674 (p&lt;0.0001). All 200 healthy individuals had DBS alpha1-AT concentrations &gt;1.9 mg x dL(-1), corresponding to 114 mg x dL(-1) in serum samples. One hundred and twenty-five COPD patients (42%) showed alpha1-AT values &lt;1.8 mg x dL(-1). Twenty patients with the PIZ phenotype had alpha1-AT values lower than 0.64 mg x dL(-1). On the basis of genotyping, one COPD patient was classified as heterozygous (PIMM(heerlen)). Selective elution of contaminants resulted in optimal alpha(1)1-antitrypsin genotyping. Because of its sensitivity and excellent correlation with the standard method, the dried blood spot quantitative assay is a reliable tool for routine measurement of alpha1-antitrypsin.
Re: Regionalization of Perinatal Services
Authors: Herman A. Hein
Journal: JAMA (1985)

<h3>To the Editor.—</h3> McCormick et al<sup>1</sup>recently published an evaluation of a national demonstration program of regionalized perinatal services sponsored by The Robert Wood Johnson Foundation (RWJF). Program regions were compared with control areas and the authors report that no special effect of the RWJF program could be detected. Based on the information provided in the article, the reader is helpless to determine either the nature of the demonstration program or the characteristics of the program and comparison regions. The actual locations of the program regions are confusing since the text notes eight regions but Table 1 lists 16. Also, the same table lists comparison areas and these do not correspond with information in the text, eg, the comparison area for Arizona is Oklahoma (text) or Arizona (Table 1). The method of determining outcome involved evaluation of birth and mortality data from 1970-1971, 1974-1975, and 1978-1979 for the program and