tbuckley/cabot-search huggingface dataset:
Neoadjuvant Endocrine Therapy as a Drug Development Strategy
Authors: Matthew J. Ellis
Journal: Clinical Cancer Research (2004)

Abstract The aromatase inhibitors offer both toxicity and efficacy advantages over tamoxifen, but to date, their overall impact on breast cancer outcomes has been modest. Advanced breast cancer remains incurable, and for early stage disease, an improvement in survival with AI versus tamoxifen has yet to be demonstrated. Resistance to endocrine manipulation is at the core of the problem and must be overcome to make additional progress. A number of signal transduction inhibitors (STIs) are now under development as endocrine resistance modulators, including those targeting cyclooxygenase-2, HER1 and/or 2 kinase, mTOR, and farnesyl transferase. Developing STIs for this indication is a challenge, however, because we still do not have a clear understanding of the molecular basis of resistance. A complete understanding could translate into a series of endocrine therapy/STI combinations that would be tailored according to the biology of the individual tumor to achieve optimal efficacy and safety. The development of this strategy will require the ability to diagnose resistance mechanisms on a tumor-by-tumor basis, and this can only be attained through careful clinical investigation. Neoadjuvant endocrine therapy is an appealing context to conduct research in this area because clinical outcomes can be obtained within a few months of treatment, and repeated tumor sampling for biomarker analysis (pharmacodynamic tumor profiling) can be readily achieved. However, the optimal clinical investigative approaches, analytical techniques, and appropriate surrogate end points have yet to be identified and are the subject of several ongoing or planned clinical studies.
Renal clearance of pancreatic and salivary amylase relative to creatinine in patients with chronic renal insufficiency.
Authors: J B Keogh, K F McGeeney, M I Drury, T B Counihan, M D O'Donnell
Journal: Gut (1978)

Pancreatic and salivary amylase/creatinine clearance ratios in patients with various degrees of renal impairment were compared with those obtained for control subjects. In chronic renal insufficiency (mean GFR 30 ml/min +/- 15 SD; n = 13) the clearance ratios for pancreatic (mean 3.5 +/- 1.85 SD) and salivary (mean 2.3 +/- 1.3 SD) amylase were significantly higher (P less than 0.05) than those in controls. Corresponding control values (n = 26) were 2.64 +/- 0.86 (pancreatic) and 1.64 +/- 0.95 (salivary). Three patients showed values above the normal limit. In the diabetic group (mean GFR 41 ml/min +/- 22 SD; n = 10) salivary amylase/creatinine clearance ratios (mean 2.36 +/- 1.55 SD) were significantly higher than in controls (P less than 0.05). Three patients showed raised values. Pancreatic amylase clearance was raised in only one of these patients. Three patients with terminal disease (mean GFR 10 ml/min) showed markedly raised (two- to threefold) clearance ratios for both salivary and pancreatic amylase. Of a total of 26 patients, eight had increased total amylase/creatinine clearance ratios. Pancreatic amylase/creatinine clearance was increased in seven patients, while nine patients showed raised salivary amylase/creatinine ratios. Patients with raised clearance ratios did not have clinical evidence of pancreatitis. We suggest that, in the presence of impaired renal function, a high amylase/creatinine clearance ratio need not be indicative of pancreatic disease.
Phylogenetic Signal and its Decay in Mitochondrial SSU and LSU rRNA Gene Fragments of Anisoptera
Authors: B Misof, A M Rickert, T R Buckley, G Fleck, K P Sauer
Journal: Molecular Biology and Evolution (2001)

The phylogeny of Anisoptera, dragonflies in the strict sense, has proven to be notoriously difficult to resolve. Based on morphological characters, several recent publications dealing with the phylogeny of dragonflies proposed contradicting inter- and intrafamily relationships. We explored phylogenetic information content of mitochondrial large-subunit (LSU) and small-subunit (SSU) ribosomal gene fragments for these systematic problems. Starting at published universal primers, we developed primer sets suitable for amplifying large parts of the LSU and SSU rRNA genes within dragonflies. These fragments turned out to harbor sufficient phylogenetic information to satisfyingly resolve intrafamily relationships, but they contain insufficient phylogenetic structure to permit reliable conclusions about several interfamily relationships. We demonstrate that decay of phylogenetic signal progresses from intrafamily to interfamily to outgroup relationships and is correlated with an increase of genetic distances. As expected, signal decay is most pronounced in fast-changing sites. Additionally, base composition among fast-changing sites significantly deviates from the expected homogeneity. Homogeneity of base composition among all included taxa was restored only after removing fast-changing sites from the data set. The molecular data tentatively support interfamily relationships proposed by the most recent publication based on morphological characters of fossil and extant dragonflies.
Rare Variants in TP53 and Susceptibility to Neuroblastoma
Authors: Sharon J. Diskin, Mario Capasso, Maura Diamond, Derek A. Oldridge, Karina Conkrite, Kristopher R. Bosse, Mike R. Russell, Achille Iolascon, Hakon Hakonarson, Marcella Devoto, John M. Maris
Journal: JNCI Journal of the National Cancer Institute (2014)

TP53 is the most frequently mutated gene in human malignancies; however, de novo somatic mutations in childhood embryonal cancers such as neuroblastoma are rare. We report on the analysis of three independent case-control cohorts comprising 10290 individuals and demonstrate that rs78378222 and rs35850753, rare germline variants in linkage disequilibrium that map to the 3' untranslated region (UTR) of TP53 and 5' UTR of the Δ133 isoform of TP53, respectively, are robustly associated with neuroblastoma (rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6, P combined = 3.43×10(-12); rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9, P combined = 2.03×10(-11)). All statistical tests were two-sided. These findings add neuroblastoma to the complex repertoire of human cancers influenced by the rs78378222 hypomorphic allele, which impairs proper termination and polyadenylation of TP53 transcripts. Future studies using whole-genome sequencing data are likely to reveal additional rare variants with large effect sizes contributing to neuroblastoma tumorigenesis.
456 PROGNOSTIC FACTOR OF PATIETS UNDERGOING SURGERY FOR INTRAHEPATIC CHOLANGIOCARCINOMA – NO LYMPH NODE DISSECTION STATEGY IN PHERIPHERAL TYPE
Authors: J. Arita, K. Hasegawa, Y. Seyama, T. Aoki, Y. Beck, Y. Sugawara, N. Kokudo
Journal: Journal of Hepatology (2010)
Rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults
Authors: M.A. Marcos, M.T. Jiménez de Anta, J.P. de la Bellacasa, J. González, E. Martínez, E. García, J. Mensa, A. de Roux, A. Torres
Journal: European Respiratory Journal (2003)

Streptococcus pneumoniae is suspected to cause an important proportion of community-acquired pneumonia (CAP) whose aetiology cannot be detected with conventional tests. In this study, the authors evaluated the diagnostic yield of a new immunochromatographic membrane test (ICT) for the detection of the S. pneumoniae antigen in the urine of patients admitted with diagnosed CAP. ICT was performed in unconcentrated and concentrated urine from all the patients. ICT was repeated 1 month after discharge in a group initially testing positive. The authors also studied the ICT in clinically stable human immunodeficiency virus type 1 (HIV1)-infected patients. S. pneumoniae antigen was detected in all of the 68 (100%) patients tested with definitive pneumococcal pneumonia. In five of these cases ICT was only positive when it had been performed on the patients. The S. pneumoniae antigen was also detected in 36 (69.2%) of 52 patients with probable pneumococcal pneumonia and in 50 of 277 (18%) patients without pneumococcal pneumonia. ICT remained positive in 16 (69.5%) of 23 patients, 1 month after hospital discharge. Nasopharyngeal colonisation with S. pneumoniae was detected in 8 (12%) of 68 clinically stable HIV1 infected patients, but none tested ICT positive. The Binax NOW® immunochromatographic membrane test is a rapid, sensitive and specific test for detecting pneumococcal community-acquired pneumonia in adults. The test may remain positive for several weeks after pneumococcal pneumonia.
Expression of <b> <i>N</i> </b>-Acetylglucosaminyltransferase V Is Associated with Prognosis and Histology in Non-Small Cell Lung Cancers
Authors: Hirotoshi Dosaka-Akita, Eiji Miyoshi, Osamu Suzuki, Tomoo Itoh, Hiroyuki Katoh, Naoyuki Taniguchi
Journal: Clinical Cancer Research (2004)

N-Acetylglucosaminyltransferase V (GnT-V), a key enzyme in the formation of branching of asparagine-linked oligosaccharides, is strongly linked to tumor invasion and metastasis of colon and breast cancers. However, GnT-V is expressed in many tissues, including normal lung. GnT-V expression has not been examined previously in human lung cancers. The objective of this study is to examine GnT-V expression in non-small cell lung cancers (NSCLCs) and to determine its relationship to biological and clinicopathological characteristics and prognosis.GnT-V expression was studied by immunohistochemistry in 217 surgically resected NSCLCs and analyzed statistically in relation to various characteristics.High GnT-V expression was found in 113 (52.1%) NSCLCs, and low GnT-V expression was found in 104 (47.9%) NSCLCs. Multivariate logistic regression analysis revealed a significant association between low GnT-V expression and squamous cell carcinomas, as compared with nonsquamous cell carcinomas (P = 0.02). Among biological characteristics of tumors, Ki-67 labeling index was higher in tumors with low GnT-V expression than in those with high GnT-V expression, although this difference was not statistically significant (P = 0.09). Patients with tumors having low GnT-V expression had significantly shorter survival time than patients with tumors having high GnT-V expression in 103 patients with pStage I NSCLCs (5-year survival rates, 49% and 86%, respectively; P = 0.0009), as well as in 59 patients with pStage I non-squamous cell carcinomas (5-year survival rates, 54% and 89%, respectively; P = 0.007). Low GnT-V expression was a significant unfavorable prognostic factor in pStage I NSCLCs (hazard ratio, 2.86; P = 0.002) and in pStage I nonsquamous cell carcinomas (hazard ratio, 3.02; P = 0.02). Furthermore, beta1-6 branching of asparagine-linked oligosaccharides, which are products of GnT-V, were increased highly or moderately in 8 of 10 tumors with high GnT-V expression, as judged by leukoagglutinating phytohemagglutinin staining.GnT-V expression is associated with histology in NSCLCs. Low GnT-V expression is associated with shorter survival and poor prognosis in pStage I overall NSCLCs and non-squamous cell carcinomas.
A role for interleukin-2 trans-presentation in dendritic cell–mediated T cell activation in humans, as revealed by daclizumab therapy
Authors: Simone C Wuest, Jehad H Edwan, Jayne F Martin, Sungpil Han, Justin S A Perry, Casandra M Cartagena, Eiji Matsuura, Dragan Maric, Thomas A Waldmann, Bibiana Bielekova
Journal: Nature Medicine (2011)
On being wrong
Authors: A M. Barr
Journal: BMJ (1996)

<h3>ABSTRACT</h3> An important goal in molecular biology is to quantify both the patterns across a genomic sequence and the relationship between phenotype and underlying sequence. We propose a multivariate tensor-based orthogonal polynomial approach to characterize nucleotides or amino acids in a given sequence and map corresponding phenotypes onto the sequence space. We have applied this method to a previously published case of small transcription activating RNAs (STARs). Covariance patterns along the sequence showcased strong correlations between nucleotides at the ends of the sequence. However, when the phenotype is projected onto the sequence space, this pattern doesn’t emerge. When doing second order analysis and quantifying the functional relationship between the phenotype and pairs of sites along the sequence, we identified sites with high regressions spread across the sequence, indicating potential intramolecular binding. In addition to quantifying interactions between different parts of a sequence, the method quantifies sequence-phenotype interactions at first and higher order levels. We discuss the strengths and constraints of the method and compare it to computational methods such as machine learning approaches. An accompanying command line tool to compute these polynomials is provided. We show proof of concept of this approach and demonstrate its potential application to other biological systems.
Stanford Seven-Day Physical Activity Recall questionnaire in COPD
Authors: Benjamin E. Garfield, Jane L. Canavan, Cayley J. Smith, Karen A. Ingram, Ria P. Fowler, Amy L. Clark, Michael I. Polkey, William D-C. Man
Journal: European Respiratory Journal (2011)

Quantification of daily physical activity is of clinical interest in chronic obstructive pulmonary disease (COPD). Objective measures using activity monitors may take several days to obtain reliable results. The aim of our study was to evaluate the Stanford Seven-Day Physical Activity Recall questionnaire (PAR) against the SenseWear armband (SWA) and compare its validity with three other physical activity questionnaires. 43 COPD patients wore the SWA for 7 days. Patients completed the PAR, Baecke, Physical Activity Scale for the Elderly (PASE) and Zutphen questionnaires. Spearman rank correlation, intraclass correlation coefficients (ICC) and receiver-operating characteristics (ROC) curves were used to assess the relationship between the questionnaires and SWA. Assessed by PAR, time spent at ≥3.0 metabolic equivalents (METs) correlated significantly (r=0.54, p&lt;0.001) with equivalent measures from SWA, with an ICC of 0.40. No relationship was seen between the other questionnaires and the SWA. The PAR predicted active patients (≥30 min at ≥3.0 METs or a physical activity level (PAL) ≥1.55) and very inactive patients (PAL &lt;1.40) with an area under ROC curve of 0.83, 0.77 and 0.70, respectively. While the PAR did not measure physical activity sufficiently accurately to make individual recommendations, it was able to identify COPD patients at extremes of the physical activity spectrum, potentially reducing the number of patients requiring direct measurement.
Four pillars of occupational health.
Authors: J C McDonald
Journal: BMJ (1981)

Most occupational health services in this country and in the Western world are in private industry. They vary in quality and offer little cover for workers in companies with fewer than 300 or 400 employees. The main reason for their development was   interest; enlightened in that most employers had genuine concern for the wellbeing of their workers, and self interest in that they hoped to reduce absenteeism, lost time, and compensation claims, and to attract the best labour. These are valid reasons but may or may not result in the best services. Moreover, normal economic competition between companies may inhibit the level of frank collaboration necessary for epidemiological surveillance and research. As for the rest of those who work for a living?self-employed or in smaller companies?they have virtually no cover, apart from the limited advisory and enforcement services of the Health and Safety Executive (HSE): These men and women, comprising half the working population, probably experience far more than their share of accidents and occupational disease; this is not surprising, since conditions and health supervision in small work places are sometimes bad. Various approaches have been tried to cope with this problem. There are a few co-operative group schemes in the United Kingdom but they have proved difficult to finance and have had little impact. France, Finland, Norway, and Sweden all have programmes for small enterprises but progress has been slow, mainly through lack of professional staff. Not only are those at greatest risk insufficiently protected at work but they tend also to be omitted from systematic epidemiological sur? veillance. Responsibility for this task is seldom explicit and only the resources of HSE are available for the purpose. Generally speaking, private occupational health services are hierarchical structures with doctors at the top. Some are excellent, but the arrangement has its disadvantages. It is expensive and tends to inhibit the development of any service if no doctor can bf ' and, and it encourages clinical and therapeutic procedures at the expense of primary prevention. It tends to separate health from safety and is not really compatible with the multidisciplinary nature of occupational health. Usually the medical director is employed by the company, with little security of tenure, sometimes subordinate to the personnel manager. Too often he is seen by the work force as the mouth
Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention: Results of the coronary revascularization using integrilin and single bolus enoxaparin study
Authors: Deepak L Bhatt, Benjamin I Lee, Peter J Casterella, Mark Pulsipher, Matthew Rogers, Marc Cohen, Victor E Corrigan, Thomas J Ryan, Jeffrey A Breall, Jeffrey W Moses, Gregory M Eaton, Mitchel A Sklar, A.Michael Lincoff
Journal: Journal of the American College of Cardiology (2002)
Estrogen Receptor Status of Primary Breast Cancer Is Predictive of Estrogen Receptor Status of Contralateral Breast Cancer
Authors: Sandra M Swain, John W Wilson, Eleftherios P Mamounas, John Bryant, D Lawrence Wickerham, Bernard Fisher, Soon Paik, Norman Wolmark
Journal: JNCI Journal of the National Cancer Institute (2004)

Tamoxifen reduces the risk for contralateral breast cancer by approximately 30%-50%, with benefits probably limited to women with estrogen receptor (ER)-positive primary disease. In a retrospective analysis of data from National Surgical and Adjuvant Breast and Bowel Project trials B-18, B-22, and B-25, we determined whether the ER status of primary breast cancer predicts the ER status of a subsequent contralateral breast cancer and whether tamoxifen treatment affects this relationship. In these trials, tamoxifen at 20 mg/day had been administered only to women aged 50 years or older, rather than to those determined by the ER status of their primary tumor, allowing an assessment of the treatment's effects in ER-negative disease.Among the 5513 eligible patients, 176 patients developed a contralateral breast cancer. The ER status of the primary and contralateral tumor was determined and cross-classified for women who did not receive tamoxifen (i.e., those aged 49 years or younger) and for women who did (i.e., those aged 50 years or older). ER data were available for 110 evaluable invasive contralateral breast cancers.Among patients who did not receive tamoxifen (n = 62), 89% with an ER-positive primary cancer had an ER-positive contralateral breast cancer and 70% with an ER-negative primary breast cancer had an ER-negative contralateral breast cancer (odds ratio for the association between primary and contralateral ER status = 14.8, 95% confidence interval = 3.8 to 74.3; P<.001). Among patients who received tamoxifen (n = 48), 56% with an ER-positive primary cancer had an ER-positive contralateral breast cancer and 78% with an ER-negative primary cancer had an ER-negative contralateral breast cancer (odds ratio = 3.4, 95% confidence interval = 0.53 to 39.2; P =.25).The ER status of the primary breast cancer was associated with that of the contralateral breast for patients not receiving tamoxifen. Patients with an ER-positive primary cancer who received tamoxifen had a lower concordance rate with fewer ER-positive contralateral breast cancers, which may be a result of tamoxifen treatment.
Oscar B. Crofford: Clinician, Scientist, Educator, Advocate for People With Diabetes, and Godfather of Diabetes Control and Complications Trial
Authors: Bernard Zinman
Journal: Diabetes Care (2014)

It is not often that one individual is gifted with leadership skills encompassing basic science, clinical trials, diabetes clinical care, and political lobbying for diabetes. Oscar B. Crofford, MD, at various stages in his career, was a master in each of these disciplines. Although each endeavor required a somewhat unique skill set with different short-term goals, his singular overarching aim was always to improve the lives of people with diabetes. In this context, it is not difficult to weave together his major role in the establishment of the National Commission on Diabetes in the U.S., the development of diabetes research and training centers, and, ultimately, the planning and implementation of the Diabetes Control and Complications Trial (DCCT), one of the most highly cited type 1 diabetes studies, which set a new standard of care for the management of this condition.

Oscar B. Crofford was born in Chickasha, Oklahoma, in 1930, attended high school in Memphis, Tennessee, and obtained an undergraduate degree at Vanderbilt University where he also completed his medical degree in 1955. He met his wife, Jane Long Crofford, on a blind date in 1955, and they were married in 1957. Jane had just graduated from nursing school at Vanderbilt, and he was midway through his residency training. He and Jane have three children: daughter Leslie who is a distinguished rheumatologist and Professor of Medicine at Vanderbilt, son David is in the construction business, and son Stephen is a trial lawyer.



Oscar B. Crofford, MD 



To fulfill military obligations, Oscar entered the U.S. Navy Medical Corps immediately following his marriage to Jane and served 2 years as a medical officer. In 1959, he returned to Vanderbilt for a postdoctoral fellowship, training in clinical investigative physiology under the direction of Dr. Elliott V. Newman, a physician-scientist who had established a …
Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function
Authors: N.V. Rajeshkumar, Prasanta Dutta, Shinichi Yabuuchi, Roeland F. de Wilde, Gary V. Martinez, Anne Le, Jurre J. Kamphorst, Joshua D. Rabinowitz, Sanjay K. Jain, Manuel Hidalgo, Chi V. Dang, Robert J. Gillies, Anirban Maitra
Journal: Cancer Research (2015)

The "Warburg effect" describes a peculiar metabolic feature of many solid tumors, namely their increased glucose uptake and high glycolytic rates, which allow cancer cells to accumulate building blocks for the biosynthesis of macromolecules. During aerobic glycolysis, pyruvate is preferentially metabolized to lactate by the enzyme lactate dehydrogenase-A (LDH-A), suggesting a possible vulnerability at this target for small-molecule inhibition in cancer cells. In this study, we used FX11, a small-molecule inhibitor of LDH-A, to investigate this possible vulnerability in a panel of 15 patient-derived mouse xenograft (PDX) models of pancreatic cancer. Unexpectedly, the p53 status of the PDX tumor determined the response to FX11. Tumors harboring wild-type (WT) TP53 were resistant to FX11. In contrast, tumors harboring mutant TP53 exhibited increased apoptosis, reduced proliferation indices, and attenuated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WT TP53 tumors, with FX11 administration downregulating metabolic activity only in mutant TP53 tumors. Through a noninvasive quantitative assessment of lactate production, as determined by 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate, we confirmed that FX11 administration inhibited pyruvate-to-lactate conversion only in mutant TP53 tumors, a feature associated with reduced expression of the TP53 target gene TIGAR, which is known to regulate glycolysis. Taken together, our findings highlight p53 status in pancreatic cancer as a biomarker to predict sensitivity to LDH-A inhibition, with regard to both real-time noninvasive imaging by 13C MRS as well as therapeutic response.