tbuckley/cabot-search huggingface dataset:
Antibiotic-treated versus germ-free rodents for microbiota transplantation studies
Authors: Randi Lundberg, Martin F. Toft, Benjamin August, Axel K. Hansen, Camilla H. F. Hansen
Journal: Gut Microbes (2016)

We recently investigated the applicability of antibiotic-treated recipient mice for transfer of different gut microbiota profiles. With this addendum we elaborate on perspectives and limitations of using antibiotics as an alternative to germ-free (GF) technology in microbial transplantation studies, and we speculate on the housing effect. It is possible to transfer host phenotypes via fecal transplantation to antibiotic-treated animals, but problems with reproducibility, baseline values, and antibiotic resistance genes should be considered. GF animals maintained in isolators still seem to be the best controlled models for long-term microbial transplantation, but antibiotic-treated recipients are also commonly utilized. We identify a need for systematic experiments investigating the stability of microbial transplantations by addressing 1) the recipient status as either GF, antibiotic-treated or specific pathogen free and 2) different levels of protected housing systems. In addition, the developmental effect of microbes on host physiological functions should be evaluated in the different scenarios.
Tuberculosis and tumor necrosis factor alpha antagonist: Our experience
Authors: Nuria Maria Reina Marfil, Ezequiel Ortega Sáenz de Tejada, Lidia López López, Ana Milena Franco Torres, José Luis Velasco Garrido, Carmen Fernández Aguirre, María Victoria Hidalgo Sanjuán
Journal: European Respiratory Journal (2012)

Tumor necrosis factor alpha (TNF-alpha) antagonist are used for the treatment of chronic inflammatory disoders when they are refractory to standard therapy. Among its side effects are tuberculosis infection. OBJETIVE: To evaluate the tuberculosis in patients treated with TNF-alpha antagonist. METHOD: A retrospective review of patients treated with infliximab, etanercept and/or adalimumab in our hospital. We obtained 633 potential cases. We included patients with a positive cultivation or histologic findings suggestives of Mycobacterium tuberculosis infection. Data collected: sex, age, underlying disease, prior inmunosuppressive therapy, tuberculosis screnning and prophylaxis, TNF-alpha antagonist used and location of the infection. RESULTS: Of the 633 patients, three developed active tuberculosis. Two men recived chemoprophylaxis with isoniacid and they were affected by psoriatic arthropathy treated with infliximab (previously with methotrexate). One of them, a 39 year old man, developed pulmonary tuberculosis and the another one, a 53 year old man, a genitourinary disease with a resistant germ to isoniacid. And a 58-year old woman with rheumatoid artritis treated with infliximab (and previously with sulfasalazine, penicillamine, chloroquine and methotrexate), with unknown screening and prophylaxis, who developed pulmonary tuberculosis. CONCLUSIONS: Screnning and prophylactic measures can not eliminate the risk totally. All the patient that developed tuberculosis disease were undergoing infliximab treatment and all of them suffered rheumatic disease. At least two of them developed tuberculosis disease despite chemoprophylaxis. Two developed pulmonary tuberculosis disease and another one genitourinary disease.
A novel distant metastasis-related marker in colorectal cancer
Authors: R. Yoshikawa, T. Hashimoto-Tamaoki, H. Yanagi, M. Noda, Y. Fujiwara, M. Gega, T. Oshima, T. Yamamura
Journal: Journal of Clinical Oncology (2005)

9684 Background: Distant metastasis is one of the major problems in treatment for advanced colorectal cancer. There is growing evidence that Polysaccharide-K (PSK), or Krestin (Sankyo Co., Tokyo, Japan), a mushroom ingredient, prevents distant metastases and improves survival rates by 10 to 20% in colorectal, gastric, esophageal, nasopharynx, lung, and breast cancers. We set out to investigate the possible role of PSK-related markers in predicting distant metastasis and clinical outcome in colorectal cancer (CRC) patients. Methods: To screen PSK-related markers, we analyzed expression profiles using protein microarrays in human colorectal adenocarcinoma cell lines, SW480 with a mutant p53gene and HCT116 with a wild-type p53 gene, and their clinical implication on the prognosis of CRC patients (n=35). Results: We screened ECA39 protein, a direct target for c-Myc regulation, as a candidate relating to anti-metastatic effects of PSK. In immunohistochemistry, ECA39 was significantly expressed in the tumor tissues with distant metastases compared to the ones without metastases (p<0.00001). Positive ECA39 expression showed high reliability for prediction of distant metastases (sensitivity: 86.7%, specificity: 90%, positive predictive value: 86.7%, and negative predictive value 90%). Conclusions: Our results suggest that ECA39 is a dominant predictor of distant metastasis in patients with advanced CRC and may be useful for the application of immunotherapy by integrated medicine. No significant financial relationships to disclose.
A novel Bayesian dose-escalation phase Ib design investigating safety of combination of RAD001 with chemotherapy plus trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab
Authors: L. Di Scala, I. Pylvänäinen, B. Molloy, C. Manlius, L. Vittori, T. Sahmoud, D. Lebwohl, E. P. Zuber
Journal: Journal of Clinical Oncology (2008)

1130 Background: RAD001 (everolimus) is an oral inhibitor of the mTOR serine-threonine kinase, implicated in regulation of protein synthesis and ultimately cell growth, proliferation, and angiogenesis. Preclinical results have shown that RAD001 enhances the efficacy of several chemotherapy agents. It is being developed in combination with different agents across various indications, including breast cancer. Primary objective of this phase 1b methodology is to determine feasibility of combining different regimens (doses/schedules) of RAD001 with trastuzumab (T) plus a chemotherapy agent, in patients with metastatic breast cancer with documented resistance to trastuzumab. Methods: Design is tailored towards optimizing regimen selection in combination setting using an adaptive Bayesian dose-escalation scheme. Model is based on occurrence of dose-limiting toxicities (DLT) at any time during study. Primary endpoint is rate of DLT in cycle 1, i.e. estimate of risk that a patient experiences a DLT in cycle 1. As design actually models time-to-DLT, also rate of late-onset toxicities, e.g. rate of cycle 2 DLT, can be estimated. Design thus allows to monitor feasibility of therapy throughout treatment by quantifying the chance that DLT rate lies within targeted toxicity levels. Results: Adaptive nature of the Bayesian methodology allows DLT rate to be re-evaluated at any time during study, with quick reaction-time to DLT events and no fixed-size cohort constraints. Decision-making formally incorporates all DLT information from all patients recruited in identifying optimal phase 2 regimen. Conclusions: This novel statistical design improves on the traditional phase I designs. Its operating characteristics are investigated under realistic toxicity scenarios. Risk of choosing too high (toxic) or too low (sub-optimal) a dose is estimated and discussed comparatively. The use of the model will be illustrated using data from two phase Ib trials of RAD001 in combination with vinorelbine and T and RAD001 in combination with paclitaxel and T, complete results of which will be reported separately. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharma AG Novartis Pharma AG
Relationship of <i>HLA-DQA1*0201</i> and lapatinib-induced hepatotoxicity in women with advanced breast cancer.
Authors: C. F. Spraggs, L. R. Budde, L. P. Briley, N. Bing, A. J. Preston, V. E. Mooser, L. R. Cardon, S. H. Stein
Journal: Journal of Clinical Oncology (2010)

3100 Background: Lapatinib is a dual HER2/EGFR tyrosine kinase inhibitor approved for the treatment of advanced/metastatic breast cancer (AMBC). Serious hepatobiliary adverse events have been observed in a small proportion (<1.6%) of lapatinib treated patients. A pharmacogenetic investigation of lapatinib induced alanine aminotransferase (ALT) elevations was conducted in AMBC clinical trial patients who received lapatinib as mono- or combination therapy. Methods: Genetic marker associations were determined by on-treatment ALT elevation case (>3x ULN) and control (<1x ULN) analysis. Classical HLA genotyping and polymorphisms from approximately 300 candidate genes and genome wide screening (1M SNPs) were evaluated in the exploratory dataset of up to 37 ALT cases and 285 controls, derived from 12 lapatinib treatment AMBC trials. Markers that achieved prespecified association p-value thresholds were progressed to an independent confirmation dataset of 24 ALT cases and 154 controls from a single lapatinib plus letrozole AMBC trial. Results: Four out of 61 significant variants from the exploratory dataset maintained associations (p<0.01) in the confirmation dataset. These variants resided in the same MHC genomic locus and included HLA- DQA1*0201. In the confirmation study, DQA1*0201 allele carriage was present in 71% of ALT cases compared to 21% of controls, with an odds ratio for ALT cases of 9.3 (3.3-28.3) and negative and positive predictive values of 0.97 (0.95-0.99) and 0.18 (0.11-0.27), respectively. Conclusions: The class II MHC HLA-DQA1*0201 allele is associated with lapatinib induced ALT elevation. The study suggests that a test based on HLA-DQA1*0201 allele carriage may have clinical utility to support patient management of liver safety risk during lapatinib treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GE Healthcare, GlaxoSmithKline
Rituximab maintenenance therapy in CD20+ B-cell non-Hodgkin lymphoma - Interim results of a multicenter prospective randomised phase II study
Authors: M. Witzens-Harig, M. Hensel, J. W. Schmier, K. Neben, A. Benner, P. Dreger, I. G. Schmidt-Wolf, A. Krämer, A. D. Ho
Journal: Journal of Clinical Oncology (2006)

17524 Background: Clinical and pharmacokinetic data suggest that the effect of rituximab could be improved by prolonged exposure to the drug. Methods: To test for this hypothesis we performed a prospective randomized trial of rituximab maintenance therapy in patients with CD20+ B-cell Non-Hodgkins-Lymphoma. After completion of standard treatment patients were randomized to either observation or maintenance therapy with rituximab (375 mg/m 2 ) every 3 months for 2 years. Patients after first line therapy as well as relapse patients were included in the study. Patients with aggressive lymphoma were enrolled if they had achieved a complete response (CR) after initial treatment. Patients with aggressive lymphoma with residual tumor mass were examined with positrone emission tomography (PET) and qualified for randomization if PET showed no signs of tumor activity. Patients with indolent lymphoma qualified for the study if at least a partial response (PR) was achieved. Results: So far 124 patients (pts) with CD20+ B-cell Non-Hodgkins-Lymphoma were enrolled in this trial. Histological subtypes included diffuse large cell lymphoma (55 pts), follicular lymphoma (24 pts), mantle cell lymphoma (16 pts), primary mediastinal lymphoma (12 pts), marginal zone lymphoma (8 pt), Burkitt’s lymphoma (3 pt), immunocytoma (2 pt), primary intestinal lymphoma (1 pt), hairy cell leukemia (1 pt), chronic lymphocytic leukemia (1 pt) and unclassified B-cell lymphoma (1 pt). No severe adverse events were observed during rituximab maintenance therapy. Results from an interim analysis including event free survival and overall survival for the observation group and for the maintenance therapy group will be presented. Conclusions: We conclude that rituximab maintenance therapy is feasable, effective, safe and well tolerated in patients with CD20+ B-cell Non-Hodgkins-Lymphoma. No significant financial relationships to disclose.
Cardiopulmonary Resuscitation: A Survey of Standards among Junior Hospital Doctors
Authors: William F Casey
Journal: Journal of the Royal Society of Medicine (1984)

The theoretical knowledge of cardiopulmonary resuscitation of 50 junior hospital doctors was examined, and an attempt made to assess their practical ability to manage a collapsed patient. Major defects were found in both the doctors' theoretical knowledge and their practical abilities. Only 8% were able to manage a cardiopulmonary arrest adequately. Suggestions are made as to how standards might be improved.
Phase I trial of Seneca Valley Virus (NTX-010), a newly discovered systemically deliverable oncolytic picornavirus, in patients with solid tumors with neuroendocrine features
Authors: C. M. Rudin, D. Lansey, K. D. Burroughs, L. M. Hales, J. R. Neefe, P. S. Reddy, P. L. Hallenbeck
Journal: Journal of Clinical Oncology (2007)

18014 Background: NTX-010 is a replication-competent cytolytic picornavirus with selective tropism for cancers with neuroendocrine features. NTX-010 mediates high selective cytotoxicity for tumor cells with neuroendocrine properties and has no cytotoxicity on any human adult cell type tested. Antitumor efficacy has been demonstrated in 11/11 xenograft models, including metastatic, orthotopic, and syngeneic models. Intravenous (IV) administration of doses as low as 10 7 vp/kg are effective in xenograft models of small cell lung cancer. No significant toxicity in animals is seen at doses up to 10 13 vp/kg. Methods: We initiated a single dose administration phase I dose-escalation study in patients with advanced solid tumors with neuroendocrine markers (CD56+, synaptophysin+, or chromogranin A+), starting at 10 7 vp/kg IV over 1h. Planned dose escalation is in log increments. Results: The first dose cohort has been completed, with no dose-limiting toxicities observed. Low grade fever, chills, arthralgias and myalgias starting 3 - 4 days after virus administration and lasting less than a week have been noted. The first study subject, with a widely metastatic small cell cancer with bladder invasion, demonstrated viral replication in vivo peaking d4 with &gt;10,000-fold amplification of the input dose. This subject had complete clearance of infectious virus by day 17, but persistence of viral RNA detectable by RT-PCR in blood and urine until the time of her death from metastatic cancer on day 28. Autopsy demonstrated extensive intratumoral necrosis, and immunohistochemistry confirmed the presence of NTX-010 capsid protein in liver metastases but not adjacent normal liver. Conclusions: NTX-010 is a novel first-in-class anticancer virus with selective tropism for tumors with neuroendocrine features. This is the first anticancer virus given intravenously with documented selective intratumoral infection and replication. Administration was well tolerated. Safety data and viral kinetics will be presented. No significant financial relationships to disclose.
Abstract 8396: A Novel Lamin Interactor (MLIP) is Critical for Cardiac Development and its Potential Role in DCM
Authors: Patrick G Burgon, Julia Lockwood, Glenn Wells, Elmira Ahmady, Alexandre Blais, Alexandre F Stewart
Journal: Circulation (2011)

A-type lamins have been implicated in the maintenance of cellular commitment and differentiation. Mutations in the LMNA gene are associated with cardiac conduction disease and dilated cardiomyopathy (DCM) in humans. The molecular mechanisms that relate mutations in LMNA with different human diseases are poorly understood and its interactions become of prominence. Using protein:protein interaction assays against Lamin A/C we discovered a novel muscle enriched lamin interacting protein (MLIP) from human heart. MLIP (C6orf142 &amp; 2310046A06rik) is a unique single copy gene that is an innovation of amniotes (reptiles, birds and mammals). The MLIP gene encodes alternatively spliced protein variants (23 to 57kDa) that possess several novel structural motifs not found in other proteins. Like Lamin A/C, MLIP is ubiquitously expressed with tissue specific isoforms found most abundantly in heart, skeletal and smooth muscle. MLIP interacts directly and co-localizes with Lamin A and C in the nuclear envelope. Down-regulation of Lamin A/C expression by shRNA results in the up-regulation and mis-localization of MLIP. In the developing mouse heart MLIP is differentially expressed from E9 to adulthood. Conditional MLIP homozygous null mice die in utero , while hemizygous MLIP null mice develop DCM by 8 weeks of age (Table 1). Ongoing longitudinal studies combining echo with microSPECT-CT will further define the DCM phenotype. In addition to interacting with Lamin, MLIP also binds to genomic DNA within close proximity of genes encoding transcription factors (including Foxc1/c2, Foxa2, Gata4, Mef2c, Pitx2, Rxra and Tbx2) as determined by chromatin immmunoprecipitation and gel mobility shift assays. In conclusion, MLIP is a newly discovered lamin interacting protein that may serve as a tanscriptional regulator that impact genes involved in cardiac development and provides a new direction to study.
Changes in chemotherapy uptake and wait times in early-stage non-small cell lung cancer (NSCLC).
Authors: S. L. Gray, J. Bu, N. Saint-Jacques, D. Rayson, T. Younis
Journal: Journal of Clinical Oncology (2010)

6049 Background: Wait times along the care path for non-small cell lung cancer (NSCLC) may be influenced by changes in adjuvant chemotherapy (AdjC) uptake. The aims of this study were to examine changes in; (1) AdjC uptake in patients with early-stage NSCLC, and (2) wait times along their continuum of care at various care interval resolutions. Methods: All patients who underwent curative-intent surgery for stage I-III NSCLC in 2005 and 2007 in Nova Scotia, Canada were identified through the provincial cancer registry. Patient characteristics, medical oncology (MO) referral and/or AdjC uptake, and timelines from cancer detection to start of AdjC were abstracted via a retrospective charts review. AdjC uptake and wait times at different resolutions of care intervals were analyzed using logistic regression and general linear model. Results: A total of 223 patients were identified (108 in 2005; 115 in 2007). In 2005, 44% (47/108) of patients were referred and 27% (29/108) received AdjC. In 2007, 38% (44/115) were referred and 16% (18/115) received AdjC. Fewer patients with stage IB were referred in 2007 vs. 2005 (52% vs. 29%, p = 0.03). Lower referral rates were associated with earlier-stage disease (p < 0.001), treatment centre (p < 0.001) and surgery type (p = 0.015). Lower AdjC uptake was associated with older age (p = 0.004), treatment centre (p = 0.025) and cohort year (2007 vs. 2005; OR = 0.35; 95% CI 0.13-0.92, p = 0.034). A number of variables, including cohort year (2007 vs. 2005), influenced wait times at different resolutions of care intervals. Wait times for the ‘MO referral receipt– MO consult’ interval did not differ significantly between 2005 and 2007 (23 vs. 19 days, p = 0.719) while those for the ‘MO consult – start AdjC’ interval increased significantly (10 vs. 22 days, p = 0.014), despite the lower referral rate/chemo uptake observed in the later year. Conclusions: Significant differences were observed in referral rate and AdjC uptake between the 2005 and 2007 patient cohorts. However, these did not appear to influence wait times along the care path possibly suggesting inherent compensatory mechanisms within the health care system and/or impact of other factors affecting wait times in NSCLC management. No significant financial relationships to disclose.
Cell Growth Inhibition of Her2 Positive Trastuzumab Resistant Gastric Cancer Cell Lines By Combined Inhibition of Pi3K/Akt/Mtor and Mapk
Authors: A. Capasso, V. Gambardella, E. Martinelli, T. Troiani, A. Nappi, V. Sforza, A. Manzo, G. Martini, C.M. Della Corte, S. Napolitano, M.M. Laterza, F. Morgillo, D. Vitagliano, M. Orditura, F. De Vita, F. Ciardiello
Journal: Annals of Oncology (2014)
Margaret McCartney: The conflict of choice
Authors: Margaret McCartney
Journal: BMJ (2015)

Shared decision making is the pivot on which modern medical ethics rest. Doctor appraises patient of the choices available. Doctor supplies evidence and lays out the pros and cons. Patient has the intervention of choice. We are all happy.

Except we’re not. Doctors deny patients treatments all the time. A patient may want 40 mg temazepam nightly as the only effective long term treatment for insomnia. Evidence may show ineffectiveness, dependence, and associated risks of falls and dementia; the patient may want it anyway, understanding the evidence and fully accepting the risks. I might prescribe if my patient had metastatic cancer and was at the end of life. I wouldn’t, however, if my patient was otherwise fit and well, with a history of drug misuse. Similarly, I would not prescribe antibiotics for a simple sore throat, even if I heard that it would spoil the holiday booked for …
Abstract P284: Exploring Differences in Self-Reported Moderate and Vigorous Physical Activity Among Hispanic Subgroups, Non-Hispanic Black, and Non-Hispanic White: National Health Interview Survey (NHIS), 1997-2012
Authors: Bertha Hidalgo, Pravleen Bajwa, Renee Gennarelli, Cassandra Arroyo Johnson
Journal: Circulation (2015)

Background:  Epidemiologic studies to date have typically categorized all Hispanic subgroups into one group. To better understand moderate and physical activity trends among subgroups of Hispanic adults in the US, we assessed self-reported physical activity by race/ethnicity over 15 years (1997-2012) NHIS.   Methods:  Data from 452,845 Mexican/Mexican American, Puerto Rican, Cuban/Cuban American, Other Hispanic, non-Hispanic Black, and non-Hispanic White participants over the age of 18 years were used. Annual age-adjusted moderate physical activity and vigorous physical activity prevalence were estimated by race/ethnicity and analyses of trends in average annual age-adjusted physical activity prevalence were conducted by education and race/ethnicity.   Results:  Out of the 452,845 individuals included in this analysis, 48.7% were male, with an overall mean age of 45.9 years for both men and women. Fifty-four percent of the total population had greater than a high school education. There were statistically significant differences for all demographic variables by gender and by race/ethnicity (P   Conclusions:  These results suggest that further consideration should be given to subgroup analyses in studies of Hispanics, particularly as they pertain to self-reported levels of physical activity.