tbuckley/cabot-search huggingface dataset:
Contralateral Prophylactic Mastectomy: Caveat Emptor
Authors: Abram Recht
Journal: Journal of Clinical Oncology (2009)

In this issue of Journal of Clinical Oncology, Tuttle et al 1 show that the use of contralateral prophylactic mastectomy (CPM) in patients with newly diagnosed ductal carcinoma in situ (DCIS) increased from 2.1% in 1998 to 5.2% in 2005.This finding is similar to their previous study for patients with stage I to III invasive cancer, for whom the rate of CPM increased from 1. 8% in 1998 to 4.5% in 2003. 2 This development is even more striking in view of the modest but statistically significant increased rates of ipsilateral breast-conserving therapy (BCT) both studies observed over the same time.Further, these are likely underestimates of the ultimate rates of CPM, as the Surveillance, Epidemiology, and End Results database only captured surgeries occurring within 6 months of initial diagnosis.Is this development justified by what we know about CPM?CPM nearly eliminates patients' risk of developing contralateral breast cancer (CBC). [3]4][5][6][7] However, it is much less clear whether or by how much CPM improves long-term breast cancer-specific survival (BCSS) rates.Such an effect would seem most likely for patients with proven BRCA1 or BRCA2 mutations, whose risk of developing CBC (without intervention) is 25% to 30% at 10 years. 8-10A study from Rotterdam of 223 patients with breast cancer (51 of whom had CPM) with a median follow-up of 5.1 years found that CPM did not affect BCSS on multivariate analysis. 10 Another study from this group with similar follow-up that included 260 patients (38 of whom had CPM) who underwent genetic testing within 2 years of diagnosis came to the same conclusion. 11 Two studies of women not uniformly having genetic testing found improved outcome in patients undergoing CPM.One, performed at the City of Hope National Medical Center in Duarte, CA, compared 64 patients undergoing CPM with 182 patients matched for decade of treatment, age, stage, the presence of lobular carcinoma in situ, type of ipsilateral surgery, and use of chemotherapy and hormonal therapy. 12With a mean follow-up time of 6.8 years, the risk of distant failure in the CPM group was 19%, compared with 29% for the control group.The 15-year overall survival rates in the two groups were 64% and 49%, respectively; BCSS rates were 71% and 53%, respectively, for the 59 CPM and 170 control patients with stage 0 to II disease.However, patients were not matched for length of follow-up before CPM.A much larger retrospective study used the tumor registries of four American health maintenance organizations to compare cancer-specific outcome of 908 patients who had CPM with that of 46,368 patients who did not. 13 With median follow-up times of 5.7 years and 4.8 years in the two groups, their respective rates of breast
A Prospective Study of the Associations Between Treated Diabetes and Cancer Outcomes
Authors: Hsin-Chieh Yeh, Elizabeth A. Platz, Nae-Yuh Wang, Kala Visvanathan, Kathy J. Helzlsouer, Frederick L. Brancati
Journal: Diabetes Care (2011)

To quantify the association of treated diabetes with cancer incidence and cancer mortality as well as cancer case fatality and all-cause mortality in adults who subsequently develop cancer and to calculate attributable fractions due to diabetes on various cancer outcomes.Prospective data on 599 diabetic and 17,681 nondiabetic adults from the CLUE II (Give Us a Clue to Cancer and Heart Disease) cohort in Washington County, Maryland, were analyzed. Diabetes was defined by self-reported use of diabetes medications at baseline. Cancer incidence was ascertained using county and state cancer registries. Mortality data were obtained from death certificates.From 1989 to 2006, 116 diabetic and 2,365 nondiabetic adults developed cancer, corresponding to age-adjusted incidence of 13.25 and 10.58 per 1,000 person-years, respectively. Adjusting for age, sex, education, BMI, smoking, hypertension treatment, and high cholesterol treatment using Cox proportional hazards regression, diabetes was associated with a higher risk of incident cancer (hazard ratio 1.22 [95% CI 0.98-1.53]) and cancer mortality (1.36 [1.02-1.81]). In individuals who developed cancer, adults with diabetes had a higher risk of cancer case fatality (1.34 [1.002-1.79]) and all-cause mortality (1.61 [1.29-2.01]). For colorectal, breast, and prostate cancers, the attributable fractions resulting from diabetes were larger for cancer fatality and mortality than cancer incidence.In this prospective cohort, diabetes appears to exert a greater influence downstream on the risk of mortality in people with cancer than on upstream risk of incident cancer.
Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness.
Authors: E H Ramsdale, M M Morris, R S Roberts, F E Hargreave
Journal: Thorax (1984)

The response to inhaled methacholine is increased in patients with chronic airflow obstruction, but it is not known whether this is due to true hyperresponsiveness or is a result of the airflow obstruction. In asthmatics the response to methacholine correlates with the bronchoconstriction produced by hyperventilation of cold dry air. We studied 27 patients with a history of smoking and chronic bronchitis with a range of severity of airflow obstruction. Bronchial responses to methacholine (expressed as the provocation concentration causing a fall in FEV1 of 20%-PC20) and isocapnic hyperventilation of cold dry air were measured. In 19 patients the PC20 was less than 8 mg/ml (that is, in the asthmatic range) but only three developed bronchoconstriction in response to hyperventilation. There was a linear correlation between the log PC20 and the FEV1 (r = 0.86, p less than 0.001). The results suggest that in patients with chronic airflow obstruction the response to methacholine is determined by the degree of airflow obstruction, and cannot be used in the diagnosis of asthma in the absence of additional information.
Targeting V600EB-Raf and Akt3 Using Nanoliposomal-Small Interfering RNA Inhibits Cutaneous Melanocytic Lesion Development
Authors: Melissa A. Tran, Raghavendra Gowda, Arati Sharma, Eun-Joo Park, James Adair, Mark Kester, Nadine Barrie Smith, Gavin P. Robertson
Journal: Cancer Research (2008)

Abstract Most events promoting early melanoma development are yet to be identified, but deregulation of the B-Raf and Akt3 signaling cascades is an important regulator of this process. Approximately 90% of normal moles and ∼60% of early invasive cutaneous melanomas contain a T1799A B-Raf mutation (V600EB-Raf), leading to 10 times higher enzyme activity and constitutive activation of the mitogen-activated protein kinase pathway. Furthermore, ∼70% of melanomas have elevated Akt3 signaling due to increased gene copy number and PTEN loss. Therefore, targeting V600EB-Raf and Akt3 signaling is necessary to prevent or treat cutaneous melanocytic lesions. Agents specifically targeting these proteins are needed, having fewer side effects than those inhibiting both normal and mutant B-Raf protein or targeting all three Akt isoforms. In this study, a unique nanoliposomal-ultrasound–mediated approach has been developed for delivering small interfering RNA (siRNA) specifically targeting V600EB-Raf and Akt3 into melanocytic tumors present in skin to retard melanoma development. Novel cationic nanoliposomes stably encapsulate siRNA targeting V600EB-Raf or Akt3, providing protection from degradation and facilitating entry into melanoma cells to decrease expression of these proteins. Low-frequency ultrasound using a lightweight four-cymbal transducer array enables penetration of nanoliposomal-siRNA complex throughout the epidermal and dermal layers of laboratory-generated or animal skin. Nanoliposomal-mediated siRNA targeting of V600EB-Raf and Akt3 led to a cooperatively acting ∼65% decrease in early or invasive cutaneous melanoma compared with inhibition of each singly with negligible associated systemic toxicity. Thus, cationic nanoliposomes loaded with siRNA targeting V600EB-Raf and Akt3 provide an effective approach for targeted inhibition of early or invasive cutaneous melanomas. [Cancer Res 2008;68(18):7638–49]
Retinoblastoma Tumor Suppressor Status Is a Critical Determinant of Therapeutic Response in Prostate Cancer Cells
Authors: Ankur Sharma, Clay E.S. Comstock, Erik S. Knudsen, Khanh H. Cao, Janet K. Hess-Wilson, Lisa M. Morey, Jason Barrera, Karen E. Knudsen
Journal: Cancer Research (2007)

The retinoblastoma tumor suppressor protein (RB), a critical mediator of cell cycle progression, is functionally inactivated in the majority of human cancers, including prostatic adenocarcinoma. The importance of RB tumor suppressor function in this disease is evident because 25% to 50% of prostatic adenocarcinomas harbor aberrations in RB pathway. However, no previous studies challenged the consequence of RB inactivation on tumor cell proliferation or therapeutic response. Here, we show that RB depletion facilitates deregulation of specific E2F target genes, but does not confer a significant proliferative advantage in the presence of androgen. However, RB-deficient cells failed to elicit a cytostatic response (compared with RB proficient isogenic controls) when challenged with androgen ablation, AR antagonist, or combined androgen blockade. These data indicate that RB deficiency can facilitate bypass of first-line hormonal therapies used to treat prostate cancer. Given the established effect of RB on DNA damage checkpoints, these studies were then extended to determine the impact of RB depletion on the response to cytotoxic agents used to treat advanced disease. In this context, RB-deficient prostate cancer cells showed enhanced susceptibility to cell death induced by only a selected subset of cytotoxic agents (antimicrotubule agents and a topoisomerase inhibitor). Combined, these data indicate that RB depletion dramatically alters the cellular response to therapeutic intervention in prostate cancer cells and suggest that RB status could potentially be developed as a marker for effectively directing therapy.
Successful control of bleeding from gastric antral vascular ectasia (watermelon stomach) by laser photocoagulation.
Authors: H H Tsai, J Smith, B J Danesh
Journal: Gut (1991)

We report a case of gastric antral vascular ectasia in a patient with primary biliary cirrhosis in whom chronic blood loss was a major problem. She required repeated blood transfusions that were complicated by reactions and still had persistent anaemia. She was treated with laser phototherapy in the form of quadrantic photocoagulation with a neodynium yttrium-aluminium-garnet laser. This greatly improved the endoscopic appearance of the gastric lesions and effectively controlled blood loss. She required no further transfusions. Bleeding recurred after 11 months which was controlled by further laser photocoagulation.
Gastric H,K-ATPASE as Therapeutic Target
Authors: G Sachs, E Carlsson, P Lindberg, B Wallmark
Journal: The Annual Review of Pharmacology and Toxicology (1988)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Hepatic toxicity of ketoconazole
Authors: O. Rollman, L. Lloof
Journal: British Journal of Dermatology (1983)

Journal Article Hepatic toxicity of ketoconazole Get access O. Rollman, O. Rollman Department of Dermatology, Department of Internal Medicine, University Hospital, 750 14 Uppsala, Sweden Search for other works by this author on: Oxford Academic Google Scholar L. Lloof L. Lloof Department of Dermatology, Department of Internal Medicine, University Hospital, 750 14 Uppsala, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 108, Issue 3, 1 March 1983, Pages 376–378, https://doi.org/10.1111/j.1365-2133.1983.tb03981.x Published: 01 March 1983
Vascular Endothelial Growth Factor (VEGF) and VEGF-C Show Overlapping Binding Sites in Embryonic Endothelia and Distinct Sites in Differentiated Adult Endothelia
Authors: Athina Lymboussaki, Birgitta Olofsson, Ulf Eriksson, Kari Alitalo
Journal: Circulation Research (1999)

Abstract —Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis during development and in adult tissues, whereas the related VEGF-C has been shown to induce both lymphangiogenesis and angiogenesis. To better understand the specific functions of these growth factors, we have here analyzed their binding to sections of mouse embryonic and adult tissues and compared the distribution of the bound growth factors with the expression patterns of the 3 known members of the VEGF receptor family as well as with neuropilin-1, a coreceptor for VEGF 165 . Partially overlapping patterns of VEGF and VEGF-C binding were obtained in embryonic tissues, consistent with the expression of all known VEGF receptors by vascular endothelial cells. However, the most striking differences of binding were observed in the developing and adult heart, in which VEGF decorated all vessels, whereas strong VEGF-C signals were obtained only from epicardial vessels. In the lymph nodes, VEGF and VEGF-C showed distinct binding patterns in agreement with the differential location of their specific receptors. These results show that both VEGF-C and VEGF target embryonic blood vessels, whereas a more selective binding of VEGF-C occurs to its lymphatic vascular receptor in certain adult tissues. Our results suggest that VEGF and VEGF-C have both overlapping and distinct activities via their endothelial receptors.
p53-Dependent BRCA1 Nuclear Export Controls Cellular Susceptibility to DNA Damage
Authors: Juhong Jiang, Eddy S. Yang, Guochun Jiang, Somaira Nowsheen, Hong Wang, Tong Wang, Yihan Wang, Dean Billheimer, A. Bapsi Chakravarthy, Melissa Brown, Bruce Haffty, Fen Xia
Journal: Cancer Research (2011)

Subcellular localization regulates BRCA1 function, and BRCA1 is exported to the cytoplasm following DNA damage in a p53-dependent manner. Because more than 50% of solid tumors harbor p53 mutations, it is possible that genetically wild-type (wt) BRCA1 is functionally abnormal through compromised nuclear-cytoplasmic shuttling in sporadic breast cancer patients with dysfunctional p53. In this study, we have investigated the mechanisms of p53-dependent BRCA1 subcellular distribution and DNA damage-induced nuclear export, as well as the impact on the resulting cytotoxic response to therapy in human breast cancer. We first show that p53 mediates BRCA1 nuclear export via protein-protein binding, rather than by modulation of its transcription. Furthermore, it is the C-terminal (BRCT) region of BRCA1 that is critical for its interaction with p53, and p53 may promote BRCA1 nuclear export by interrupting the association of BRCA1 with BARD1. In sporadic breast cancer specimens, dysfunctional p53 strongly correlates with nuclear retention of sequence-verified wt BRCA1. This p53-dependent BRCA1 shuttling determines cellular susceptibility to DNA damage as augmentation of cytosolic BRCA1 significantly enhances cancer cell susceptibility to ionizing radiation. Taken together, our data suggest that p53 dysfunction compromises nuclear export of wt BRCA1 as a mechanism to increase cellular resistance to DNA damage in sporadic breast cancer. We propose that targeting nuclear BRCA1 to the cytoplasm may offer a unique strategy to sensitize p53-deficient sporadic breast cancers to DNA damage-based therapy.
Congenital cytomegalovirus infection: patterns of fetal brain damage
Authors: L. Gabrielli, M.P. Bonasoni, D. Santini, G. Piccirilli, A. Chiereghin, E. Petrisli, R. Dolcetti, B. Guerra, M. Piccioli, M. Lanari, M.P. Landini, T. Lazzarotto
Journal: Clinical Microbiology and Infection (2012)
Effects of a Residential Exercise Training on Baroreflex Sensitivity and Heart Rate Variability in Patients With Coronary Artery Disease
Authors: Ferdinando Iellamo, Jacopo M. Legramante, Michele Massaro, Gianfranco Raimondi, Alberto Galante
Journal: Circulation (2000)

Background —Myocardial ischemia and infarction impair baroreflex sensitivity (BRS), which when depressed is predictive of future cardiac events after myocardial infarction (MI). The main objective of this study was to determine whether exercise training improves BRS in patients with coronary artery disease. Methods and Results —Ninety-seven male patients with and without a previous MI were recruited after myocardial revascularization surgery and randomized into trained (TR) or untrained (UTR) groups. TR patients underwent a residential exercise program at 85% of maximum heart rate (HRmax) consisting of 2 daily sessions 6 times a week for 2 weeks. Eighty-six patients (45 TR and 41 UTR) completed the study. BRS was assessed at baseline and at the end of the protocol by the spontaneous baroreflex method. The standard deviation of mean R-R interval (RRSD) was also assessed as a measure of heart rate variability. At baseline, there were no significant differences between TR and UTR patients in any variable. In TR patients, BRS increased from 3.0±0.3 to 5.3±0.7 ms/mm Hg ( P &lt;0.001), RRSD from 18.7±1.4 to 23.6±1.6 ms ( P &lt;0.01), and R-R interval from 792.0±15.5 to 851.3±20.5 ms ( P &lt;0.001). No significant changes occurred in UTR patients. Increases in BRS and RRSD were significant in patients either with or without a previous MI. Conclusions —Exercise training increases BRS and heart rate variability in patients with coronary artery disease. Improved cardiac autonomic function might add to the other benefits of exercise training in secondary prevention of ischemic heart disease.
Effect of High Extracellular Phosphate Concentration on Arachidonic Acid Production by Parathyroid Tissue In Vitro
Authors: YOLANDA ALMADÉN, ANTONIO CANALEJO, EVARISTO BALLESTEROS, GRACIA AN[Combining Tilde]ÓN, MARIANO RODRÍGUEZ
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Recent in vivo and in vitro studies show that high phosphate directly stimulates parathyroid hormone (PTH) secretion. However, little is known about the intracellular signaling system involved in the regulation of PTH secretion by extracellular phosphate. High extracellular calcium is coupled to the activation of phospholipase A 2 (PLA 2 ) and the formation of arachidonic acid (AA), a potent inhibitor of PTH release. The present study was designed to evaluate whether a high phosphate concentration has an effect on the PLA 2 -AA pathway in parathyroid cells. In vitro experiments were performed in parathyroid tissue obtained from normal rats and dogs. AA production was measured in parathyroid tissue in response to 1- and 4-mM phosphate concentration and after addition of PLA 2 to the medium. To determine whether the effect of phosphate on AA production in parathyroid cells was tissue specific, separate experiments were performed to test the effect of phosphate in rat adrenal glomerulosa cells, which are known to increase AA production in response to angiotensin II. The effect of sulfate, an ion with chemical characteristics similar to phosphate, on PTH secretion was also evaluated. In parathyroid tissue, a high phosphate concentration decreased the high calcium-induced AA production. This effect of phosphate was associated with an increase in PTH secretion. The addition of AA reversed the stimulatory effect of phosphate on PTH secretion. In another type of AA-responsive tissue, the adrenal glomerulosa, a high phosphate concentration did not affect the production of AA when stimulated by angiotensin II. In a normal phosphate concentration, the addition of PLA 2 stimulated AA production and decreased the PTH secretion. However, in a 4-mM phosphate concentration, the addition of PLA 2 did not reduce PTH secretion and did not stimulate AA production. Finally, sulfate did not affect PTH secretion. In conclusion, a high phosphate concentration affects the production of AA by parathyroid tissue. This effect of phosphate may be the mechanism by which a high phosphate concentration stimulates PTH secretion.
Inter- and intraobserver consistency in assessing eligibility for bevacizumab (BVZ) in non-small-cell lung cancer (NSCLC) patients with centrally located tumors
Authors: F. Barlési, C. Balleyguier, B. Besse, F. Bonodeau, F. Brenac, O. Corneloup, E. Dansin, G. Ferretti, J.Y. Gaubert, R. Gervais, C. Lacombe, A. Loundou, D. Moro-Sibilot, D. Planchard, A. Scherpereel, Y. Menu
Journal: Annals of Oncology (2010)
Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation
Authors: Linda L. Humphrey, Mark Deffebach, Miranda Pappas, Christina Baumann, Kathryn Artis, Jennifer Priest Mitchell, Bernadette Zakher, Rongwei Fu, Christopher G. Slatore
Journal: Annals of Internal Medicine (2013)

Background: Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial. Purpose: To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT). Data Sources: MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists. Study Selection: English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer. Data Extraction: One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria. Data Synthesis: Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common. Limitations: Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations. Conclusion: Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits. Primary Funding Source: Agency for Healthcare Research and Quality.