tbuckley/cabot-search huggingface dataset:
A Lesser Evil: Prophylactic Mastectomy for Women at High Risk for Breast Cancer
Authors: Leslie R. Schover
Journal: Journal of Clinical Oncology (2008)

TheidentificationoftheBRCA1andBRCA2genemutationswas amilestoneinthefighttoeradicatebreastcancer.Wehopedwewould soonbeabletopreventnotonlyhereditarybreastandovariancancers (HBOC), but sporadic tumors as well. In this struggle, unfortunately, victories are rarely as sweeping as they first appear. It has been more than 10 years since genetic tests for HBOC became commercially available. A recent analysis of surveillance for women with familial breast cancer in Norway and the United Kingdom revealed that, once diagnosed with apparently early-stage breast cancer, BRCA2 carriers and women who tested negative for BRCA mutations had 5-year survival rates of 96% and 90% respectively, compared with only 70% for women carrying BRCA1 mutations. 1 Howcanweimprovepreventionforwomenathighriskofbreast cancer? Surveillance can be enhanced by use of magnetic resonance imaging of the breasts. 2 Tamoxifen also reduces breast cancer risk in BRCA2 mutation carriers and the risk of contralateral second primaries in both BRCA2 and BRCA1 carriers, 2 but the intervention that most effectively prevents breast cancer is bilateral prophylactic mastectomy(BPM). 2,3 Bilateralprophylacticoophorectomybeforeage40 and contralateral prophylactic mastectomy also reduce breast cancer risk substantially. Womenwhoaremutationcarriersorhavefamilialcancerarefar morelikelytohavebilateralprophylacticoophorectomythanBPM. 2,3 At-risk women in the United States have one of the highest BPM rates (36%), with such surgery much less frequent among European women. 2 Factors predictive of choosing BPM include having a sister who had breast cancer, 4 being a BRCA1/2 mutation carrier, havingapersonalhistoryofbreastcancer,beingyoungeratthetimeof surgery than women who choose surveillance, and having high anxiety and exaggerated perceptions about risk of breast cancer. 5 Women with young children may choose BPM to maximize their chances of long-term survival. 6
The Pharmacokinetics and Pharmacodynamics of Pulmonary <i>Mycobacterium avium</i> Complex Disease Treatment
Authors: Jakko van Ingen, Eric F. Egelund, Adrah Levin, Sarah E. Totten, Martin J. Boeree, Johan W. Mouton, Rob E. Aarnoutse, Leonid B. Heifets, Charles A. Peloquin, Charles L. Daley
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs.To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease.We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations.We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin.Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.
Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial
Authors: Susan M. Blaney, Frank M. Balis, Stacey Berg, Carola A.S. Arndt, Richard Heideman, J. Russell Geyer, Roger Packer, Peter C. Adamson, Kurt Jaeckle, Renee Klenke, Alberta Aikin, Robert Murphy, Cynthia McCully, David G. Poplack
Journal: Journal of Clinical Oncology (2005)

Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials.In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs.The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease.The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.
Prognostic Significance of <i>MMP-1</i> and <i>MMP-3</i> Functional Promoter Polymorphisms in Colorectal Cancer
Authors: Franck Zinzindohoué, Thierry Lecomte, Jean-Marc Ferraz, Anne-Marie Houllier, Paul-Henri Cugnenc, Anne Berger, Hélène Blons, Pierre Laurent-Puig
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Matrix metalloproteinase (MMP) belongs to a large group of proteases capable of breaking essentially all components of the extracellular matrix. They are implicated in all steps of tumorogenesis, cancer invasion, and metastasis. Among them, metalloproteinase type 1 (MMP-1) is implicated in tumor invasion and metastasis in different types of cancers including colorectal cancer in which its expression was correlated with poor prognosis. A polymorphism in the promoter region of the MMP-1 gene leads to a variation of its level of transcription. Study Design: MMP-1 -1607ins/delG and MMP-3 - 1612 ins/delA promoter polymorphisms were genotyped by multiplex PCR from 201 colorectal cancer patients. The median follow-up of patients was 30 months. The MMP genotypes were correlated to clinical outcome. Results: Patients with the -1607insG/-1607insG MMP-1 genotype had significantly worse specific survival than the others in the whole series (P &amp;lt; 0.04), in stage I to III patients (P &amp;lt; 0.001), and in patients stage I and II (P &amp;lt; 0.01). In multivariate analysis, MMP-1-1607insG allele showed to be an independent poor prognostic factor after adjustment on stage, age, and the use of adjuvant chemotherapy. MMP-3 polymorphism was not associated with survival. Conclusions: In the subgroups of nondistant metatastic patients (stages I and II, and stages I-III), an inverse relation between the number of MMP-1-1607insG allele and survival was observed suggesting a gene dosage effect. Our results are consistent with the importance of MMP-1-1607ins/delG functional polymorphism in regulating transcription level and with the relationship between MMP-1 expression and cancer invasion, metastasis, and prognosis.
The Pharmacological Control of Immediate Hypersensitivity
Authors: J C Foreman
Journal: The Annual Review of Pharmacology and Toxicology (1981)

Immediate hypersensitivity is a reaction to a foreign substance and is im­ munological in nature. Initial challenge with the foreign material stimu­ lates, by interaction with T lymphocytes and macrophages, the immune system. The response is the generation of B lymphocytes which recognize the antigenic determinants of the foreign material; these B cells then differentiate into plasma cells which elaborate IgE-class antibodies directed against the antigens. The IgE antibodies so formed become fixed to tissue mast cells or circulating basophil leucocytes. In man, rat, and mouse the antibody which fixes to mast cells and basophils is of the IgE class whereas in other species such as guinea pig it appears to be a subclass of IgG antibodies. In either case the production of antibody which specifically binds to mast cells and basophils is fundamental to the immediate hypersen­ sitivity reaction. Second and subsequent challenges with foreign antigen lead to an antigen-antibody reaction on the mast cell and basophil mem­ brane. The immunological and the pharmacological control of IgE produc­ tion has been the subject of earlier reviews (1-4). Stimulation of the mast cell and basophil membranes initiates a sequence of cellular events leading to the release of the mediators of the immediate hypersensitivity reaction. The mediators have long been known to include histamine, slow reacting substance (SRS), and, in some species, 5-hydroxy­ tryptamine. Other putative mediators include prostaglandins, kinins, chemotactic factors, and platelet activating factor. The smooth muscle contraction, glandular secretion, cell accumulation, increased capillary
Characteristics of Urologists Predict the Use of Androgen Deprivation Therapy for Prostate Cancer
Authors: Vahakn B. Shahinian, Yong-fang Kuo, Jean L. Freeman, Eduardo Orihuela, James S. Goodwin
Journal: Journal of Clinical Oncology (2007)

Purpose We previously have reported wide variations among urologists in the use of androgen deprivation for prostate cancer. Using the Surveillance, Epidemiology, and End Results–Medicare linked database, we examined how individual urologist characteristics influenced the use of androgen deprivation therapy. Methods Participants included 82,375 men with prostate cancer who were diagnosed from January 1, 1992, through December 31, 2002, and the 2,080 urologists who provided care to them. Multilevel analyses were used to estimate the likelihood of androgen deprivation use within 6 months of diagnosis in the overall cohort, in a subgroup in which use would be of uncertain benefit (primary therapy for localized prostate cancer), and in a subgroup in which use would be evidence-based (adjuvant therapy with radiation for locally advanced disease). Results In the overall cohort of patients, a multilevel model adjusted for patient characteristics, tumor characteristics, and urologist characteristics (eg, board certification, academic affiliation, patient panel size, years since medical school graduation) showed that the likelihood of androgen deprivation use was significantly greater for patients who saw urologists without an academic affiliation. This pattern also was noted when the analysis was limited to settings in which androgen deprivation would have been of uncertain benefit. Odds ratios for use in that context were 1.66 (95% CI, 1.27 to 2.16) for urologists with no academic affiliation and 1.45 (95% CI, 1.13 to 1.85) for urologists with minor versus major academic affiliations. Conclusion Use of androgen deprivation for prostate cancer varies by the characteristics of the urologist. Patients of non–academically affiliated urologists were significantly more likely to receive primary androgen deprivation therapy for localized prostate cancer, a setting in which the benefits are uncertain.
Increased capillary hydraulic conductivity induced by atrial natriuretic peptide.
Authors: V H Huxley, V L Tucker, K M Verburg, R H Freeman
Journal: Circulation Research (1987)

The small molecular weight peptide, atrial natriuretic peptide (ANP), produces marked sodium and water excretion. The peptide, extracted from several species of vertebrate heart, also has been shown to increase glomerular filtration and reduce plasma volume. Several mechanisms have been proposed to account for the action of the peptide but remain undefined. In the present report, the ANP-induced alterations in transcapillary water movement were directly assessed. The modified Landis technique was used to measure single capillary hydraulic conductivity (Lp) of vessels from the frog mesenteric circulation. In 6 individual microvessels, Lp was measured under control conditions and again during perfusion with 10 X 10(-6) M ANP. The Lp increased in each vessel by a mean of 3.79-fold (+/- 2.09 SD). In 4 of these vessels, an additional measurement of Lp was repeated under control conditions; the capillary filtration coefficient returned to control levels. It was concluded that ANP directly and reversibly elevates capillary hydraulic conductivity; this response is independent of changes in capillary hydrostatic pressure or surface area.
Phylogenetic and Biochemical Evidence Supports the Recruitment of an ADP-Glucose Translocator for the Export of Photosynthate during Plastid Endosymbiosis
Authors: C. Colleoni, M. Linka, P. Deschamps, M. G. Handford, P. Dupree, A. P. M. Weber, S. G. Ball
Journal: Molecular Biology and Evolution (2010)

The acquisition of photosynthesis by eukaryotic cells through enslavement of a cyanobacterium represents one of the most remarkable turning points in the history of life on Earth. In addition to endosymbiotic gene transfer, the acquisition of a protein import apparatus and the coordination of gene expression between host and endosymbiont genomes, the establishment of a metabolic connection was crucial for a functional endosymbiosis. It was previously hypothesized that the first metabolic connection between both partners of endosymbiosis was achieved through insertion of a host-derived metabolite transporter into the cyanobacterial plasma membrane. Reconstruction of starch metabolism in the common ancestor of photosynthetic eukaryotes suggested that adenosine diphosphoglucose (ADP-Glc), a bacterial-specific metabolite, was likely to be the photosynthate, which was exported from the early cyanobiont. However, extant plastid transporters that have evolved from host-derived endomembrane transporters do not transport ADP-Glc but simple phosphorylated sugars in exchange for orthophosphate. We now show that those eukaryotic nucleotide sugar transporters, which define the closest relatives to the common ancestor of extant plastid envelope carbon translocators, possess an innate ability for transporting ADP-Glc. Such an unexpected ability would have been required to establish plastid endosymbiosis.
A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation
Authors: Elizabeth Clayton, Giuseppe Bardi, Sarah E. Bell, David Chantry, C. Peter Downes, Alexander Gray, Lisa A. Humphries, David Rawlings, Helen Reynolds, Elena Vigorito, Martin Turner
Journal: The Journal of Experimental Medicine (2002)

Mice lacking the p110δ catalytic subunit of phosphatidylinositol 3-kinase have reduced numbers of B1 and marginal zone B cells, reduced levels of serum immunoglobulins, respond poorly to immunization with type II thymus-independent antigen, and are defective in their primary and secondary responses to thymus-dependent antigen. p110δ−/− B cells proliferate poorly in response to B cell receptor (BCR) or CD40 signals in vitro, fail to activate protein kinase B, and are prone to apoptosis. p110δ function is required for BCR-mediated calcium flux, activation of phosphlipaseCγ2, and Bruton's tyrosine kinase. Thus, p110δ plays a critical role in B cell homeostasis and function.
Phase II Clinical Trial of the Epothilone B Analog, Ixabepilone, in Patients With Non–Small-Cell Lung Cancer Whose Tumors Have Failed First-Line Platinum-Based Chemotherapy
Authors: Johan Vansteenkiste, Primo N. Lara, Thierry Le Chevalier, Jean-Luc Breton, Philip Bonomi, Alan B. Sandler, Mark A. Socinski, Catherine Delbaldo, Brent McHenry, David Lebwohl, Ronald Peck, Mark Edelman
Journal: Journal of Clinical Oncology (2007)

Ixabepilone is the first in a new class of antineoplastic agents, the epothilones and their analogs. This international, randomized, phase II trial assessed two administration schedules of ixabepilone as second-line therapy in patients with non-small-cell lung cancer (NSCLC).Patients had experienced disease progression after one prior cisplatin- or carboplatin-based chemotherapy regimen. Ixabepilone was administered as a single 32 mg/m(2) 3-hour infusion (77 patients; arm A) or a 6 mg/m(2) 1-hour infusion daily for 5 consecutive days (69 patients; arm B) in a 3-week cycle.The intent-to-treat objective response rate was 14.3% in arm A and 11.6% in arm B. Median duration of response was 8.7 months (95% CI, 5.3 to 9.5 months) in arm A and 9.6 months (95% CI, 6.1 to 19.7 months) in arm B. Median time to progression was 2.1 months (95% CI, 1.4 to 2.8 months) for arm A and 1.5 months (95% CI, 1.4 to 2.8 months) for arm B. Median survival was 8.3 months (95% CI, 5.8 to 11.5 months) for arm A, and 7.3 months (95% CI, 5.7 to 11.7 months) for arm B; the 1-year survival rate (both cohorts) was 38%. Responses occurred in patients with taxane-pretreated and platinum-refractory tumors. Both regimens had an acceptable toxicity profile. Myelosuppression was manageable, manifesting primarily as neutropenia and leukopenia. Neuropathy was primarily sensory, generally mild to moderate in severity, and mostly reversible (both regimens).Single-agent ixabepilone had clinically relevant activity and an acceptable safety profile in patients with advanced NSCLC whose tumors had failed one prior platinum-based chemotherapy regimen.
Genetic Mutation of p53 and Suppression of the miR-17∼92 Cluster Are Synthetic Lethal in Non–Small Cell Lung Cancer due to Upregulation of Vitamin D Signaling
Authors: Robert Borkowski, Liqin Du, Zhenze Zhao, Elizabeth McMillan, Adam Kosti, Chin-Rang Yang, Milind Suraokar, Ignacio I. Wistuba, Adi F. Gazdar, John D. Minna, Michael A. White, Alexander Pertsemlidis
Journal: Cancer Research (2014)

Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We used a library of oligonucleotide inhibitors of microRNAs, a class of posttranscriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in non-small cell lung cancer (NSCLC). Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific downregulation of the miR-17∼92 polycistron, and this downregulation was toxic only in the context of p53 loss. Mechanistic studies indicated that the selective toxicity of miR-17∼92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1, a rate-limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach used in this study can identify clinically relevant synthetic lethal interactions and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients.
Diabetes prevalence, process of care and outcomes in relation to practice size, caseload and deprivation: national cross-sectional study in primary care
Authors: Christopher Millett, Josip Car, Darren Eldred, Kamlesh Khunti, Arch G Mainous, Azeem Majeed
Journal: Journal of the Royal Society of Medicine (2007)

Objective To examine the association between practice list size, deprivation and the quality of care of patients with diabetes. Design Population-based cross-sectional study using Quality and Outcomes Framework data. Setting England and Scotland. Participants 55 522 778 patients and 8970 general practices with 1 852 762 people with diabetes. Interventions None. Main outcome measures Seventeen process and surrogate outcome measures of diabetes care. Results The prevalence of diabetes was 3.3%. Prevalence differed with practice list size and deprivation: smaller and more deprived practices had a higher mean prevalence than larger and more affluent practices (3.8% versus 2.8%). Practices with large patient list sizes had the highest quality of care scores, even after stratifying for deprivation. However, with the exception of retinal screening, peripheral pulses and neuropathy testing, differences in achievement between small and large practices were modest (&lt;5%). Small practices performed nearly as well as the largest practices in achievement of intermediate outcome targets for HbA1c, blood pressure and cholesterol (smallest versus largest practices: 57.4% versus 58.7%; 70.7% versus 70.7%; and 69.5% versus 72.7%, respectively). Deprivation had a negative effect on the achieved scores and this was more pronounced for smaller practices. Conclusion Our study provides some evidence of a volume-outcome association in the management of diabetes in primary care; this appears most pronounced in deprived areas.
Cardiovascular and pulmonary effects of thromboxane B2 in the dog.
Authors: L S Friedman, T M Fitzpatrick, M F Bloom, P W Ramwell, J C Rose, P A Kot
Journal: Circulation Research (1979)

The hemodynamic properties of thromboxane B2 (TxB2), a product of prostaglandin endoperoxide metabolism, have not been thoroughly described. TxB2 is a bronchoconstrictor, but its effects on the systemic circulation and circulating platelets are unknown. Its precursor, thromboxane A2(TxA2), is a potent vasoconstrictor as well as a platelet-aggregating agent. Using intact anesthetized dogs, we investigated the effects of TxB2 on pulmonary artery pressure (PAP), airway pressure (AP), systemic arterial pressure (SAP), and myocardial contractility (MC). Vascular responses were evaluated in relation to changes in platelet population and aggregability. Intravenous TxB2 (25 and 50 micrograms/kg) increased AP (mean 62% and 69%) and PAP (50% and 86%), respectively, whereas SAP and MC responses were inconsistent. Left ventricular injections (25 micrograms/kg) also increased AP (36%) and PAP responses were inconsistent. Left ventricular injections (25 micrograms/kg) also increased AP (36%) and PAP (36%). Intraventricular administration of TxB2 produced a consistent elevation of SAP (10%) with a concomitant fall in MC (11%). These vascular responses were not consistent with alterations in platelet number or aggregability. A tachyphylactic response to TxB2 developed in AP and PAP at both dose levels and with both routes of administration. Intravenous and intraventricular TxB2 (25 micrograms/kg) produced a parallel decreasing response in PAP, suggesting the possible saturation of TxB2 binding sites or the depletion of a catabolic enzyme in the lung.