tbuckley/cabot-search huggingface dataset:
Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy
Authors: Masaaki Komatsu, Heather E. Wheeler, Suyoun Chung, Siew-Kee Low, Claudia Wing, Shannon M. Delaney, Lidija K. Gorsic, Atsushi Takahashi, Michiaki Kubo, Deanna L. Kroetz, Wei Zhang, Yusuke Nakamura, M. Eileen Dolan
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Paclitaxel is used worldwide in the treatment of breast, lung, ovarian, and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented, or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCL) and Asian patients. Methods: GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare with a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human-induced pluripotent stem cells were used for functional validation of candidate genes. Results: SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P &amp;lt; 10−6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphologic changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P &amp;lt; 0.05), including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphologic characteristics. Conclusions: We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy. Clin Cancer Res; 21(19); 4337–46. ©2015 AACR.
Phospho-Serine-118 Estrogen Receptor-α Expression Is Associated with Better Disease Outcome in Women Treated with Tamoxifen
Authors: Leigh C. Murphy, Yulian Niu, Linda Snell, Peter Watson
Journal: Clinical Cancer Research (2004)

The purpose of this research was to determine whether estrogen receptor alpha specifically phosphorylated at Ser(118) is associated with clinical outcome in primary breast tumors from estrogen receptor-positive and node-negative breast cancer patients.Estrogen receptor alpha specifically phosphorylated at Ser(118) was determined by immunohistochemistry in 117 primary breast tumors from node-negative patients who were subsequently treated with adjuvant tamoxifen. The relationship of estrogen receptor alpha specifically phosphorylated at Ser(118) expression to disease-free survival and overall survival was determined.Estrogen receptor alpha specifically phosphorylated at Ser(118) was limited to estrogen receptor alpha ligand binding assay-positive tumors and among this subset was expressed in 70 (62%) of these tumors. Estrogen receptor alpha specifically phosphorylated at Ser(118) expression was more frequently observed in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors (chi(2) test, P = 0.012, n = 113). A significant correlation was also seen between estrogen receptor alpha specifically phosphorylated at Ser(118) and progesterone receptor levels (Spearman r = 0.236, P = 0.0118, n = 113). Kaplan-Meier outcome analysis showed that patients whose primary tumors expressed estrogen receptor alpha specifically phosphorylated at Ser(118) had a longer disease-free survival (P = 0.0018, n = 113) and a trend toward better overall survival, but this was not statistically significant. Among the subset of progesterone receptor-positive tumors, progesterone receptor-positive/estrogen receptor alpha specifically phosphorylated at Ser(118)-positive patients had a significantly longer disease-free survival that progesterone receptor-positive/estrogen receptor alpha specifically phosphorylated at Ser(118)-negative patients (P = 0.0041).Our data suggest that estrogen receptor alpha specifically phosphorylated at Ser(118) is a marker of a functional, intact ligand-dependent estrogen receptor signaling pathway in breast cancer and that estrogen receptor alpha specifically phosphorylated at Ser(118) status has the potential to provide a more precise biomarker of responsiveness to endocrine therapy in conjunction with estrogen receptor alpha and progesterone receptor status.
The Sick Sinus Syndrome
Authors: M. IRENÉ FERRER
Journal: Circulation (1973)

A review of the sick sinus syndrome (SSS) is presented stressing its multifaceted expressions, with slow and fast heart rates, syncopal and dizzy attacks, and rather vague nature early in its course. All ages are affected and the diagnosis must be considered if there is a modest degree of sinus bradycardia (SB), even if asymptomatic, as SB is less benign than was heretofore thought. Inappropriate or relatively slow sinus rates (RSSR) under stressful conditions are equally as important as SB. Inadequacy of the sinoatrial node (SAN) may be manifested by one or more of the following: (1) persistent severe and unexpected sinus bradycardia; (2) cessation of sinus rhythm (sinus arrest) for short intervals during which no other (escape) rhythm arises, or for somewhat longer periods with replacement of sinus rhythm by an atrial or junctional rhythm; (3) long periods of sinus arrest without the appearance of a new pacemaker and resulting in total cardiac arrest (ventricular arrhythmias may then follow); (4) chronic atrial fibrillation because the SAN is permanently silent, or repeated episodes of transitory atrial fibrillation due to total cessation of sinus rhythm at these times. Atrial fibrillation is often, but not always, accompanied by a slow ventricular rate (not produced by digitalis but resulting from an accompanying organic A-V block and the patient has binodal disease); (5) inability of the heart to resume sinus rhythm following cardioversion for atrial fibrillation (most likely if the ventricular rate is slow as mentioned above); and (6) episodes of sinoatrial exit block which are not related to drug therapy. These six items form the indirect evidences for the SSS and represent primary physiologic manifestations. Provocative tests are of value although not wholly satisfactory. Therapy for the chronic form will eventually be a ventricular artificial pacemaker. The natural history of the SSS is imperfectly known but probably covers 5-10 years, at least.
Centromeric Repositioning of Coreceptor Loci Predicts Their Stable Silencing and the CD4/CD8 Lineage Choice
Authors: Matthias Merkenschlager, Shannon Amoils, Esther Roldan, Amin Rahemtulla, Eric O'Connor, Amanda G. Fisher, Karen E. Brown
Journal: The Journal of Experimental Medicine (2004)

The differentiation of CD4+ CD8+ double positive (DP) thymocytes requires the irreversible choice between two alternative lineages, distinguished by the mutually exclusive expression of either CD4 or CD8. Differentiating DP cells transiently down-regulate both CD4 and CD8, and this has complicated the debate whether the mechanism of CD4/CD8 lineage choice is instructive, stochastic/selective, or more complex in nature. Using fluorescence in situ hybridization, we show that the stable silencing of coreceptor loci, and ultimately lineage choice, is predicted by the spatial repositioning of coreceptor alleles to centromeric heterochromatin domains. These data provide evidence that lineage-specific developmental programs are established early during the transition from the DP to the single positive stage.
PSA screening leads to overdiagnosis, study says
Authors: D. Josefson
Journal: BMJ (2002)

Routine screening for prostate cancer using the prostate specific antigen (PSA) test, is responsible for the observed increased epidemiological incidence of the disease, says a new report ( Journal of the National Cancer Institute 2002;94:981-90).

Moreover, PSA screening causes overdiagnosis rates of the disease in about 29% of white men and 44% of black men, so many of those whose cancers were diagnosed through PSA screening would likely have died of something other than prostate cancer.

As prostate cancer treatment itself causes …
Photodynamic therapy reduces the histological features of actinic damage and the expression of early oncogenic markers
Authors: L. Bagazgoitia, J. Cuevas Santos, Á. Juarranz, P. Jaén
Journal: British Journal of Dermatology (2011)

Photodynamic therapy (PDT) has been shown to be effective in treating nonmelanoma skin cancer (NMSC), especially actinic keratosis (AK). Moreover, there is sufficient evidence of its effectiveness in preventing the appearance of premalignant and malignant lesions in organ transplant recipients.To describe the molecular and genetic changes underlying this preventive effect.Twenty-two patients with AK were treated with methyl aminolaevulinate and red light. Biopsies were performed before and 6 weeks after the treatment. Conventional histopathology and immunohistochemistry were carried out.Not only was a reduction in the dysplasia and elastosis observed, but also a decreased expression of Ki-67 and p53. The abnormal findings did not disappear completely in all cases. The expression of cyclin D₁ remained stable.These findings show that PDT has the potential to reduce the histological signs of photoageing. Moreover, the reduction of Ki-67, a marker of proliferation and of p53, a marker of early skin carcinogenesis, indicates a reversal of the carcinogenic process. On the other hand, the fact that one treatment does not clear dysplasia and expression of p53 completely, and the persistence of cyclin D₁, indicate that one single treatment, despite showing good clinical results, is not sufficient to clear completely the signs of chronic actinic damage, and thus the risk of NMSC.
Cost Implications of the Rapid Adoption of Newer Technologies for Treating Prostate Cancer
Authors: Paul L. Nguyen, Xiangmei Gu, Stuart R. Lipsitz, Toni K. Choueiri, Wesley W. Choi, Yin Lei, Karen E. Hoffman, Jim C. Hu
Journal: Journal of Clinical Oncology (2011)

Intensity-modulated radiation therapy (IMRT) and laparoscopic or robotic minimally invasive radical prostatectomy (MIRP) are costlier alternatives to three-dimensional conformal radiation therapy (3D-CRT) and open radical prostatectomy for treating prostate cancer. We assessed temporal trends in their utilization and their impact on national health care spending.Using Surveillance, Epidemiology, and End Results-Medicare linked data, we determined treatment patterns for 45,636 men age ≥ 65 years who received definitive surgery or radiation for localized prostate cancer diagnosed from 2002 to 2005. Costs attributable to prostate cancer care were the difference in Medicare payments in the year after versus the year before diagnosis.Patients received surgery (26%), external RT (38%), or brachytherapy with or without RT (36%). Among surgical patients, MIRP utilization increased substantially (1.5% among 2002 diagnoses v 28.7% among 2005 diagnoses, P < .001). For RT, IMRT utilization increased substantially (28.7% v 81.7%; P < .001) and for men receiving brachytherapy, supplemental IMRT increased significantly (8.5% v 31.1%; P < .001). The mean incremental cost of IMRT versus 3D-CRT was $10,986 (in 2008 dollars); of brachytherapy plus IMRT versus brachytherapy plus 3D-CRT was $10,789; of MIRP versus open RP was $293. Extrapolating these figures to the total US population results in excess spending of $282 million for IMRT, $59 million for brachytherapy plus IMRT, and $4 million for MIRP, compared to less costly alternatives for men diagnosed in 2005.Costlier prostate cancer therapies were rapidly and widely adopted, resulting in additional national spending of more than $350 million among men diagnosed in 2005 and suggesting the need for comparative effectiveness research to weigh their costs against their benefits.
Recommendations for the assessment and management of cough in children
Authors: M D Shields, A Bush, M L Everard, S McKenzie, R Primhak
Journal: Thorax (2007)

Step 1 MDS performed a database literature search (Medline, Embase, Cochrane Library and Google Scholar) initially using the terms ''cough'' AND ''child''.Exclusions included non-English language papers and papers on pertussis vaccine development.Also excluded were papers on specific diseases including asthma, cystic fibrosis and pneumonia for which management guidelines have already been published.Abstracts of papers were then reviewed and relevant papers obtained.The relevant studies to the UK population were largely performed in Europe, North America, Australia, New Zealand and South Africa.Specific searches of the databases were subsequently made adding the terms ''gastroesophageal reflux'', ''cough variant asthma'', ''isolated'' OR BTS guidelines
Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING
Authors: Christian K Holm, Søren B Jensen, Martin R Jakobsen, Natalia Cheshenko, Kristy A Horan, Hanne B Moeller, Regina Gonzalez-Dosal, Simon B Rasmussen, Maria H Christensen, Timur O Yarovinsky, Frazer J Rixon, Betsy C Herold, Katherine A Fitzgerald, Søren R Paludan
Journal: Nature Immunology (2012)
Stand up, sit down, keep moving: turning circles in physical activity research?
Authors: W J Brown, A E Bauman, N Owen
Journal: British Journal of Sports Medicine (2008)

This review tracks the evidence and associated recommendations and guidelines for optimal levels of physical activity for health benefit. In the 1950s, early epidemiological studies focused on the increased risk of cardiovascular disease and all-cause mortality associated with sitting at work. The period from the mid-seventies to the turn of the century saw an initial focus on the health benefits of vigorous exercise give way to mounting evidence for the benefits of moderate-intensity physical activity. As daily energy expenditure in most domains of human activity (travel, domestic and occupational work, and leisure) continues to decline, early 21st century researchers are starting to turn full circle, with a rekindling of interest in the health effects of sedentary behaviour at work, and indeed in the balance between activity and sedentariness in all aspects of daily life.
Dietary Carbohydrate (Amount and Type) in the Prevention and Management of Diabetes
Authors: Nancy F. Sheard, Nathaniel G. Clark, Janette C. Brand-Miller, Marion J. Franz, F. Xavier Pi-Sunyer, Elizabeth Mayer-Davis, Karmeen Kulkarni, Patti Geil
Journal: Diabetes Care (2004)

Diabetes has long been viewed as a disorder of carbohydrate metabolism due to its hallmark feature of hyperglycemia. Indeed, hyperglycemia is the cause of the acute symptoms associated with diabetes such as polydypsia, polyuria, and polyphagia (1). The long-term complications (retinopathy, nephropathy, and neuropathy) associated with diabetes are also believed to result from chronically elevated blood glucose levels (2–6). In addition, hyperglycemia may contribute to the development of macrovascular disease, which is associated with the development of coronary artery disease, the leading cause of death in individuals with diabetes (7–9). Thus, a primary goal in the management of diabetes is the regulation of blood glucose to achieve near-normal blood glucose.

Blood glucose concentration following a meal is determined by the rate of appearance of glucose into the blood stream (absorption) and its clearance/disappearance from the circulation (10). The rate of disappearance of glucose is largely influenced by insulin secretion and its action on target tissues (11).

The component of the diet that has the greatest influence on blood glucose is carbohydrate. Other macronutrients in the diet, i.e., fat and protein, can influence the postprandial blood glucose level, however. For example, dietary fat slows glucose absorption, delaying the peak glycemic response to the ingestion of a food that contains glucose (12–14). In addition, although glucose is the primary stimulus for insulin release, protein/amino acids augment insulin release when ingested with carbohydrate, thereby increasing the clearance of glucose from the blood (15–17).

Both the quantity and the type or source of carbohydrate found in foods influence postprandial glucose level (18,19). Although most experts agree that the total carbohydrate intake from a meal or snack is a relatively reliable predictor of postprandial blood glucose (18,20–22), the impact …
Landmarks in the History of Cancer Epidemiology
Authors: Peter Greenwald, Barbara K. Dunn
Journal: Cancer Research (2009)

Abstract The application of epidemiology to cancer prevention is relatively new, although observations of the potential causes of cancer have been reported for more than 2,000 years. Cancer was generally considered incurable until the late 19th century. Only with a refined understanding of the nature of cancer and strategies for cancer treatment could a systematic approach to cancer prevention emerge. The 20th century saw the elucidation of clues to cancer causation from observed associations with population exposures to tobacco, diet, environmental chemicals, and other exogenous factors. With repeated confirmation of such associations, researchers entertained for the first time the possibility that cancer, like many of the infectious diseases of the time, might be prevented. By the mid-20th century, with antibiotics successfully addressing the majority of infectious diseases and high blood pressure treatment beginning to affect the prevalence of heart disease in a favorable direction, the focus of much of epidemiology shifted to cancer. The early emphasis was on exploring, in greater depth, the environmental, dietary, hormonal, and other exogenous exposures for their potential associations with increased cancer risk. The first major breakthrough in identifying a modifiable cancer risk factor was the documentation of an association between tobacco smoking and lung cancer. During the past four decades, epidemiologic studies have generated population data identifying risk factors for cancers at almost every body site, with many cancers having multiple risk factors. The development of technologies to identify biological molecules has facilitated the incorporation of these molecular manifestations of biological variation into epidemiologic studies, as markers of exposure as well as putative surrogate markers of cancer outcome. This technological trend has, during the past two decades, culminated in emphasis on the identification of genetic variants and their products as correlates of cancer risk, in turn, creating opportunities to incorporate the discipline of molecular/genetic epidemiology into the study of cancer prevention. Epidemiology will undoubtedly continue contributing to cancer prevention by using traditional epidemiologic study designs to address broad candidate areas of interest, with molecular/genetic epidemiology investigations honing in on promising areas to identify specific factors that can be modified with the goal of reducing risk. [Cancer Res 2009;69(6):2151–62]
Proxy assessment of quality of life in patients with prostate cancer: how accurate are partners and urologists?
Authors: R Pearcy, D Waldron, C O'Boyle, R MacDonagh
Journal: Journal of the Royal Society of Medicine (2008)

To assess the ability of partners and clinicians to make proxy judgements on behalf of patients with prostate cancer relating to selection of life priorities and quality of life (QoL).47 consecutive patients with histologically proven adenocarcinoma, and their partners, were recruited. The partners were asked to assess, by proxy, the QoL of the patient by completion of a series of interview-led questionnaires assessing global QoL (SEIQoL-DW), health-related QoL (FACT-P) and overall QoL (visual analogue score [VAS]). The patients' clinicians were asked to complete the SEIQoL-DW and VAS by proxy as soon as possible after a consultation with the patient.Patients with histologically proven adenocarcinoma, their partners and their clinicians.Proxy scores for SEIQoL-DW, FACT-P and VAS, as provided by partners and clinicians.25 partners made a proxy assessment of the patients. The results showed that partners were able to select similar QoL cues to those of the patients (Spearman-Rank correlation 0.89). Comparison of the QoL scores obtained from patients and partners in proxy using the questionnaires showed no statistically significant difference (paired t-test). Urologists were poor predictors of areas of life (cues) that were important to their patients. The doctors overemphasized the importance of survival, postoperative complications, urinary symptoms, sexual ability, activities of daily living and finance, but underestimated the importance of wife, family, home and religion. Comparison of the QoL scores obtained from patients and urologists by proxy showed a significantly lower score when assessed by urologists using the SEIQoL-DW questionnaire.Partners are able to accurately assess, by proxy, the areas of life that are of importance to patients. Clinicians, however, who are charged with making decisions on behalf of patients, are very poor judges of their patients' life priorities and QoL. This illustrates that conventional views held by most doctors regarding the priorities patients set themselves when planning treatment should be called into question and consequently suggests that the way in which doctors and patients arrive at treatment decisions must be reviewed.
Impact of Age and Comorbidity on Non–Small-Cell Lung Cancer Treatment in Older Veterans
Authors: Sunny Wang, Melisa L. Wong, Nathan Hamilton, J. Ben Davoren, Thierry M. Jahan, Louise C. Walter
Journal: Journal of Clinical Oncology (2012)

Purpose Because comorbidity affects cancer treatment outcomes, guidelines recommend considering comorbidity when making treatment decisions in older patients with lung cancer. Yet, it is unclear whether treatment is targeted to healthier older adults who might reasonably benefit. Patients and Methods Receipt of first-line guideline-recommended treatment was assessed for 20,511 veterans age ≥ 65 years with non–small-cell lung cancer (NSCLC) in the Veterans Affairs (VA) Central Cancer Registry from 2003 to 2008. Patients were stratified by age (65 to 74, 75 to 84, ≥ 85 years), Charlson comorbidity index score (0, 1 to 3, ≥ 4), and American Joint Committee on Cancer stage (I to II, IIIA to IIIB, IIIB with malignant effusion to IV). Comorbidity and patient characteristics were obtained from VA claims and registry data. Multivariate analysis identified predictors of receipt of guideline-recommended treatment. Results In all, 51% of patients with local, 35% with regional, and 27% with metastatic disease received guideline-recommended treatment. Treatment rates decreased more with advancing age than with worsening comorbidity for all stages, such that older patients with no comorbidity had lower rates than younger patients with severe comorbidity. For example, 50% of patients with local disease age 75 to 84 years with no comorbidity received surgery compared with 57% of patients age 65 to 74 years with severe comorbidity (P &lt; .001). In multivariate analysis, age and histology remained strong negative predictors of treatment for all stages, whereas comorbidity and nonclinical factors had a minor effect. Conclusion Advancing age is a much stronger negative predictor of treatment receipt among older veterans with NSCLC than comorbidity. Individualized decisions that go beyond age and include comorbidity are needed to better target NSCLC treatments to older patients who may reasonably benefit.