tbuckley/cabot-search huggingface dataset:
Late-breaking abstract: Glutathione-S-transferase P1 Ile105Val polymorphism associated with elevated lung function and reduced risk of lung cancer and death in 66,000 individuals
Authors: Morten Dahl, Marianne Nørskov, Børge Nordestgaard, Anne Tybjærg-Hansen
Journal: European Respiratory Journal (2014)

Background: The enzyme glutathione-S-transferase (GST) P1 metabolises carcinogens from tobacco smoke in the lung. We tested whether genetically altered GSTP1 activity affects lung function and risk of lung cancer, tobacco-related cancer and death in the general population.  Methods: We genotyped 66,069 individuals from the Danish general population for two functional polymorphisms in the GSTP1 gene (Ile105Val and Ala114Val), and recorded lung function, lung cancer, tobacco-related cancer, and death as outcomes.  Results: Lung function was stepwise increased with Ile105Val genotype overall (P  Conclusion: The common GSTP1 Ile105Val variant was associated with elevated lung function and reduced risk of lung cancer, tobacco-related cancer, and death in the general population. The data support a role for GSTP1 in oxidant-mediated events influencing lung function, lung cancer, tobacco-related cancer and death, especially among smokers.
Impact of Preoperative Staging and Chemoradiation Versus Postoperative Chemoradiation on Outcome in Patients With Rectal Cancer: A Decision Analysis
Authors: J. J. Telford, J. R. Saltzman, K. M. Kuntz, S. Syngal
Journal: JNCI Journal of the National Cancer Institute (2004)

Although radical resection and postoperative chemoradiation have been the standard therapy for patients with rectal cancer, preoperative staging by local imaging and chemoradiation are widely used. We used a decision analysis to compare the two strategies for rectal cancer management.We developed a decision model to compare survival outcomes after postoperative chemoradiation versus preoperative staging and chemoradiation in patients aged 70 years with resectable rectal cancer. In the postoperative chemoradiation strategy, patients undergo radical resection and receive postoperative chemoradiation. In the preoperative staging and chemoradiation strategy, patients with locally advanced cancer receive preoperative chemoradiation and radical resection, whereas those with amenable localized tumors undergo local excision. The cohorts of patients were entered into a Markov model incorporating age-adjusted and disease-specific mortality. Outcomes were evaluated by modeling 5-year disease-specific survival for preoperative chemoradiation as less than, equal to, or greater than that of postoperative chemoradiation. Base-case probabilities were derived from published data; the Surveillance, Epidemiology, and End Results (SEER) Program database; and U.S. Life Tables. One-way and two-way sensitivity analyses were performed. The outcome measures were life expectancy and quality-adjusted life expectancy.Life expectancy and quality-adjusted life expectancy were 9.72 and 8.72 years, respectively, in the postoperative chemoradiation strategy. In the preoperative staging and chemoradiation strategy, life expectancy was 9.36, 9.72, and 10.09 years and quality-adjusted life expectancy was 8.71, 9.04, and 9.37 years when 5-year disease-specific survival was less than, equal to, or greater than that of postoperative chemoradiation, respectively. The decision model was sensitive to differences in the long-term toxicity of pre- and postoperative chemoradiation. When the 5-year disease-specific survival for patients after pre- or postoperative chemoradiation was equal, the decision model was sensitive to surgical mortality and to the probability of residual lymph node disease after local excision.If efficacy and toxicity after preoperative chemoradiation are equal to or better than that after postoperative chemoradiation in patients with locally advanced rectal cancer, then preoperative staging to select patients appropriate for preoperative chemoradiation is beneficial.
BMA's gold medal award to the president of the South African Medical Association
Authors: S. Lewin, J. de Gruchy, M. Armstrong
Journal: BMJ (1999)

Editor—We were surprised and disquieted to hear that the BMA awarded its highest honour—the gold medal for distinguished merit—to Bernard Mandell, president of the South African Medical Association, at its annual general meeting last year. Apparently the award was made for Mandell’s “distinguished contribution to the understanding of the relationship of medicine and human rights in the national and international spheres.”

Mandell was chairman of the Medical Association of South Africa’s federal council and board of trustees from 1987 to 1998, and from 1975 he was a member of the Federal Council, the highest decision making body of the organisation. For most of the time before 1990 the Medical Association of South Africa was notable in its slavish support of the apartheid government’s policies and was condemned both locally and internationally for failing to speak out against human rights abuses in the health sector and in the country in general.1–3

From 1990, after the unbanning of the African National Congress, the Medical Association of South Africa discovered human rights and repositioned itself within the new order to maintain its influence and power. At the health sector hearings of the Truth and Reconciliation Commission in June 1997, the association begrudgingly admitted its complicity in applying apartheid policies, but many people believe that it has yet to come entirely clean on its activities during that time.4 Furthermore, although Mandell may have played an important part in steering the association through its restructuring into the South African Medical Association, the new organisation has yet to show an active commitment to human rights in health.

The nature of Mandell’s “distinguished contribution” to human rights in health is not at all clear. Indeed, the award becomes a travesty when so many who fought against apartheid in health care, often at great personal cost, remain unrecognised. We call on the BMA to set the record straight on Mandell’s record at the helm of the Medical Association of South Africa and to bestow its award on someone more deserving.
Distinction between "high grade MALT" and diffuse large B cell lymphoma
Authors: S Ely
Journal: Gut (2002)

In order to communicate data about various lymphomas, it is necessary that we all speak the same language. To this end, many lymphoma classification schemes have been devised over the years. The most recent and current “official” lymphoma classification is that proposed by the World Health Organization (WHO).1,2 It differs very little from the previous “official” classification, the REAL (Revised European-American Lymphoma classification).3 Because the WHO classification is explicit, it is easy to follow and, if used correctly, studies using WHO terms should be reproducible and easy to interpret. However, when authors use language and classification schemes that are not widely accepted, they risk misinterpretation or that their data may be overlooked.

In the early 1980s, authors began referring to low grade B cell lymphomas that arise in mucosal locations as either “marginal zone” or mucosa associated lymphoid tissue (“MALT”) lymphomas.4,5 Being the catchier of the two terms “MALToma” became dominant in the common parlance. However, this led to some confusion because the “MALT” descriptor has the connotation that there is only one type of lymphoma that arises in mucosal …
Biomechanics of Microcirculatory Blood Perfusion
Authors: Geert W. Schmid-Schönbein
Journal: Annual Review of Biomedical Engineering (1999)

▪ Abstract The microcirculation represents a region of the circulation in which blood vessels are directly surrounded by the tissue and cells to which they supply nutrients and from which they collect metabolites. The cellular elements that make up the microcirculation have now been identified, and a large body of evidence has become available that provides molecular definitions of these elements. The blood flow is in a domain in which viscous stresses dominate, but the viscoelastic and active properties of cells lead to nonlinear problems. The ability of cells to actively control cytoplasmic mechanical properties and shape, as well as their membrane adhesion, leads to unique cell behavior in microvessels that has a direct influence on organ transport and function. There is also increasing evidence that the properties of the cells are in turn influenced by fluid shear stresses. These issues have greatly expanded the scope of microvascular analysis. The microcirculation is one of the sites in which diseases manifest themselves at an early stage. The application of biomechanical analysis of the microcirculation is starting to focus on diseases. The field is rich with problems of high significance.
Cost-effectiveness of interventions promoting physical activity
Authors: F Müller-Riemenschneider, T Reinhold, S N Willich
Journal: British Journal of Sports Medicine (2008)

Background: Sedentary and inactive lifestyle continues to increase and is associated with a substantial economic burden in most industrialised countries. To implement effective physical activity interventions on a broad population basis, their cost-effectiveness needs to be evaluated. Objective: To evaluate the cost-effectiveness of physical activity interventions targeted at healthy adults and to identify cost-effective intervention components. Design: Systematic review. Methods and data sources: The search strategy in electronic databases identified relevant literature published until June 2008. We included studies investigating the cost-effectiveness of interventions aiming to promote physical activity behaviour in healthy adults. Two researchers independently assessed publications according to predefined inclusion criteria and with regard to methodological quality. Study characteristics and predefined outcome measures were extracted and costs per participant to become sufficiently active were compared between interventions. Results: Out of 6543 identified publications, eight studies investigating 11 intervention strategies met the inclusion criteria. There was substantial heterogeneity in study quality, intervention strategies and intervention effects. Behavioural interventions were able to promote physical activity, with participants meeting recommended levels of physical activity, for about 800 Euros per year. Environmental interventions and interventions targeted at general practitioners seemed to have the potential to be substantially more cost-effective. Discussion: There was evidence that current physical activity intervention strategies can be a cost-effective means of resource allocation. But, despite the growing literature on physical activity promotion, appropriate cost-effectiveness analyses are rare and the generalisability of presented findings is limited. Further research is warranted to investigate the cost-effectiveness of behavioural and environmental intervention strategies.
Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments
Authors: Chau T. Dang, Andrew J. Dannenberg, Kotha Subbaramaiah, Maura N. Dickler, Mark M. Moasser, Andrew D. Seidman, Gabriella M. D’Andrea, Maria Theodoulou, Katherine S. Panageas, Larry Norton, Clifford A. Hudis
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Preclinical studies demonstrate a link between overexpression of HER-2/neu and cyclooxygenase-2 (COX-2) activity. To explore the possibility that COX-2 is a therapeutic target, we conducted a phase II study of celecoxib, a selective COX-2 inhibitor, and trastuzumab in patients with HER-2/neu-overexpressing metastatic breast cancer that had progressed while receiving trastuzumab. Experimental Design: Eligible patients had bi-dimensionally measurable or evaluable HER-2/neu-overexpressing metastatic breast cancer. HER-2/neu overexpression, defined as 2+ or 3+ by the HercepTest, was required. Patients had to have progressed despite prior trastuzumab-based therapy. Treatment consisted of celecoxib (400 mg twice daily) and trastuzumab. Results: Twelve patients were enrolled (42% status post 1 regimen for metastatic disease 58% status post &amp;gt; 2 prior regimens (range of 2–6). Eleven patients were evaluable. There were no responses. Median duration of treatment was 9 weeks. One patient had stable disease at 3 months but progressed at 6 months. A second patient stopped treatment at 3 months because of unresolved grade 2 rash, felt to be related to celecoxib. Toxicities were generally grade 1 or 2. One patient (8%) experienced grade 3 toxicity (abdominal pain). Conclusions: Celecoxib combined with trastuzumab is well tolerated. However, this combination in patients with HER2/neu-overexpressing, trastuzumab-refractory disease, was not active.
Impairment of Both Apoptotic and Cytoprotective Signalings in Glioma Cells Resistant to the Combined Use of Cisplatin and Tumor Necrosis Factor α
Authors: Lian Duan, Masaru Aoyagi, Masashi Tamaki, Yoshikazu Yoshino, Takashi Morimoto, Hiroaki Wakimoto, Yasuhiko Nagasaka, Kimiyoshi Hirakawa, Kikuo Ohno, Kiyotaka Yamamoto
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Tumor necrosis factor (TNF)-α elicits two opposing effects, the induction of apoptosis and the transcription of antiapoptotic genes. We have recently shown that cisplatin sensitizes glioma cells to TNF-induced apoptosis, but only in some cell lines. To understand the mechanism involved in the different susceptibilities, we examined both the activation of caspases and cytoprotective signaling by TNF-α. Experimental Design: Caspase activation was examined by estimating the cleavage of substrate peptides and by immunoblot to identify the cleavage of procaspases. Peptide inhibitors of caspases were used to reverse the cytotoxicity. The binding of TNF-α to the receptor was analyzed by flow cytometry. Nuclear factor (NF)-κB activation was assayed by the binding of NF-κB to oligonucleotides containing the consensus binding site. Interleukin (IL)-1β, IL-6, IL-8, and manganous superoxide dismutase (MnSOD) were measured by enzyme-linked immunoassays. Results: T98G and U87MG underwent apoptosis on treatment with cisplatin and TNF-α, but U373MG and A172 were resistant. Caspases 2, 3, and 6–10, but not caspases 1, 4, and 5, were activated in sensitive cells, and none were activated in resistant cells. The binding of TNF-α to the receptor was the same in all four of the cell lines. In the sensitive cells, NF-κB activation and the production of IL-1β, IL-6, IL-8, and MnSOD were significantly elevated by TNF-α. However, in the resistant cells, the production of IL-1β and IL-6 were specifically impaired in response to TNF-α. Conclusions: Our results indicate that both apoptotic and cytoprotective pathways are impaired in glioma cells that are resistant to treatment with cisplatin and TNF-α.
Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.
Authors: Boris Kubuschok, Frank Neumann, Rainer Breit, Martina Sester, Claudia Schormann, Claudia Wagner, Urban Sester, Frank Hartmann, Mathias Wagner, Klaus Remberger, Martin Schilling, Michael Pfreundschuh
Journal: Clinical Cancer Research (2006)

Abstract Mutated p21 ras proteins (muRas) are present in approximately 90% of pancreatic adenocarcinomas and express mutants which can function as cancer-specific antigens. To evaluate the frequency and magnitude of the natural T-cell response against muRas in 19 HLA-A2-positive patients with muRas-positive pancreatic carcinomas, antigen-experienced T lymphocytes in fresh peripheral blood mononuclear cells were shown by IFN-gamma enzyme-linked immunospot using muRas peptides (5-21) that encompass both HLA class I (HLA-A2)- and class II-restricted (HLA-DRB1) epitopes. Six of 19 patients (32%) were found to have a specific T-cell response against individual mutation-specific ras(5-21) but not against other ras mutations or wild-type ras. In contrast, none of 19 healthy subjects had T cells specifically secreting IFN-gamma (P = 0.004). The T-cell response consisted of both CD8(+) and CD4(+) T cells but was dominated by CD8 T cells in three of four patients. MuRas(5-14) and muRas(6-14) were shown to specifically induce CD8(+) T-cell mediated cytotoxicity against HLA-A2-positive, muRas-bearing pancreatic carcinoma cells. The T-cell response was not correlated with prognostic or clinical variables such as tumor-node-metastasis status, stage, or survival. In conclusion, a natural T-cell response against muRas proteins that could be exploited for immunostimulatory therapeutic approaches has been shown in a significant proportion of patients with pancreatic cancer.
Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors
Authors: Eddy J. Chen, Adam G. Sowalsky, Shuai Gao, Changmeng Cai, Olga Voznesensky, Rachel Schaefer, Massimo Loda, Lawrence D. True, Huihui Ye, Patricia Troncoso, Rosina L. Lis, Philip W. Kantoff, Robert B. Montgomery, Peter S. Nelson, Glenn J. Bubley, Steven P. Balk, Mary-Ellen Taplin
Journal: Clinical Cancer Research (2014)

Abstract Purpose: The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs. Experimental Design: AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone. Results: The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR. Conclusions: These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. Clin Cancer Res; 21(6); 1273–80. ©2014 AACR. See related commentary by Sharifi, p. 1240
PD07-08: The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy: NSABP Protocol B-40.
Authors: HD Bear, G Tang, P Rastogi, CE Geyer, R André, JN Atkins, L Baez-Diaz, AM Brufsky, RS Mehta, L Fehrenbacher, ER Pajon, FM Senecal, R Gaur, RG Margolese, PT Adams, HM Gross, JP Costantino, SM Swain, EP Mamounas, N Wolmark
Journal: Cancer Research (2011)

Abstract The NSABP trial B-40 was designed to determine whether adding capecitabine or gemcitabine to docetaxel followed by AC would increase the pathologic complete response (pCR) rates in patients with operable HER2−negative breast cancer and to determine whether the addition of bevacizumab to three docetaxel-based regimens followed by AC would increase pCR rates. Secondary endpoints include the percentage of surgical complications after mastectomy, lumpectomy, and axillary staging procedures in the patients who received chemotherapy versus those who received chemotherapy and bevacizumab. Methods: Women with HER2−negative operable breast cancer received one of the following docetaxel-based regimens with or without bevacizumab (15mg/kg) every 3 weeks for four cycles: docetaxel 100 mg/m2 IV; docetaxel 75 mg/m2 and capecitabine 825 mg/m2 po BID days 1–14; and docetaxel 75 mg/m2 day 1 and gemcitabine 1000 mg/m2 IV days 1 and 8. These regimens were followed by preoperative standard AC on day 1 every 21 days for four cycles with or without bevacizumab 15 mg/kg given with the initial 2 cycles of AC. Treatment groups randomized to receive bevacizumab resumed postoperative bevacizumab 15 mg/kg IV every 3 weeks for an additional 10 doses. Assessment of surgical complications was performed from the date of surgery through 24 months following study entry. Results: Planned analysis for surgical complications will be conducted in October 2011 and will be presented along with breast reconstruction data. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-52667, with additional support from F. Hoffmann La-Roche, Ltd., Genentech, USA, and Eli Lilly and Company. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-08.
The Interaction between Two Radiosensitizers: 5-Iododeoxyuridine and Caffeine
Authors: Yuji Seo, Tao Yan, Jane E. Schupp, Kazuhiko Yamane, Tomas Radivoyevitch, Timothy J. Kinsella
Journal: Cancer Research (2006)

Abstract 5-Iododeoxyuridine (IUdR) and caffeine are recognized as potential radiosensitizers with different mechanisms of interaction with ionizing radiation (IR). To assess the interaction of these two types of radiosensitizers, we compared treatment responses to these drugs alone and in combination with IR in two p53-proficient and p53-deficient pairs of human colon cancer cell lines (HCT116 versus HCT116 p53−/− and RKO versus RKO E6). Based on clonogenic survival, the three single agents (IR, IUdR, and caffeine) as well as IUdR or caffeine combined with IR are less or equally effective in p53-deficient human tumor cells compared with p53-proficient tumor cells. However, using both radiosensitizers, a significantly greater radiosensitization was found in p53-deficient human tumor cells. To better understand the interaction of these two radiosensitizers, additional studies on DNA repair and cell cycle regulation were done. We found that caffeine enhanced IUdR-DNA incorporation and IUdR-mediated radiosensitization by partially inhibiting repair (removal) of IUdR in DNA. The repair of IR-induced DNA double-strand breaks was also inhibited by caffeine. However, these effects of caffeine on IUdR-mediated radiosensitization were not found in p53-proficient cells. Cell cycle analyses also showed a greater abrogation of IR-induced S- and G2-phase arrests by caffeine in p53-deficient cells, particularly when combined with IUdR. Collectively, these data provide the mechanistic bases for combining these two radiosensitizers to enhance tumor cytotoxicity. This differential dual mode of radiosensitization by combining IUdR and caffeine-like drugs (e.g., UCN-01) in p53-deficient human tumors may lead to a greater therapeutic gain. (Cancer Res 2006; 66(1): 490-8)
Precise diagnosis of airflow obstruction - does it matter for treatment? An international questionnaire survey and its implications
Authors: P Vermeire
Journal: European Respiratory Journal (1990)

As emphasised by the recent international questionnaire survey, the absence of an agreed terminology in chronic non-specific lung diseases leads to much confusion and undoubtedly impairs communication between physicians. In each patient within the scope of CNSLD, the presence and combination of a number of basic features should be identified. The term bronchial asthma should be used when a number of features are present which are sufficiently characteristic to differentiate it from other forms of permanent airway obstruction. In non-asthmatic obstructive disease the term 'COLD' (or COPD), followed by some qualifying labels, seems preferable. Use of the term 'chronic bronchitis' should be restricted to refer as 'chronic mucus hypersecretion' or be abandoned.