tbuckley/cabot-search huggingface dataset:
Monomeric annexin A2 is an oxygen-regulated toll-like receptor 2 ligand and adjuvant
Authors: Brian M. Andersen, Junzhe Xia, Alan L. Epstein, John R. Ohlfest, Wei Chen, Bruce R. Blazar, Christopher A. Pennell, Michael R. Olin
Journal: Journal for ImmunoTherapy of Cancer (2016)

Annexin A2 (ANXA2) is a pleiotropic, calcium-dependent, phospholipid-binding protein with a broad tissue distribution. It can be intracellular, membrane-bound, or secreted, and it exists as a monomer or heterotetramer. The secreted ANXA2 heterotetramer signals human and murine macrophages to produce IL-1, IL-6, and TNF-α through TLR4/MyD88- and TRIF-dependent pathways. GL261 glioma cells were cultured in 5 % or 20 % O2. Monomeric ANXA2 (ANXA2m) was identified as a TLR2-binding protein enriched in 5 % O2 by mass spectrometry. Purified ANXA2m and ANXA2-derived peptides were added to TLR2-expressing reporter cells and immature dendritic cells (DCs) cells in vitro. ANXA2m was then mixed with chicken ovalbumin (OVA) for vaccination of TLR2 (+/+) and TLR2 (-/-) mice for subsequent quantification of antigen-specific CD8(+) T cell responses. The TLR2-binding region of ANXA2m was determined using various peptides derived from the ANXA2 amino terminus on TLR2 reporter cells and in vaccinated mice. ANXA2m is overexpressed by murine glioblastoma GL261 cells grown under 5 % O2, but not atmospheric 20 % O2, and acts as an adjuvant by inducing murine and human DC maturation through TLR2. ANXA2m upregulates CD80 and CD86 expression, enhances antigen cross-presentation, and induces the secretion of IL-12p70, TNF-α, and IFN-γ. The amino-terminal 15 amino acids of ANXA2m are necessary and sufficient for TLR2 binding and DC activation. This novel finding adds to the known functions of ANXA2 and suggests ways to exploit it as a vaccine adjuvant. ANXA2-antigen fusion peptides could be developed for patients as "off-the-shelf" agents containing common tumor antigens. Alternatively, they could be "personalized" and synthesized after tumor sequencing to identify immunogenic tumor-specific neo-antigens. As the amino terminal 15 amino acids of ANXA2 are required to stimulate TLR2 activity, a fusion peptide could be as short as 30 amino acids if one or two CD8 T cell epitopes are fused to the ANXA2 amino terminal portion. Future work will address the efficacy of ANXA2 peptide fusions alone and in combination with established TLR agonists to induce synergy in preclinical models of glioma as observed in other vaccines.
Abstract 18105: National Utilization Rates of Fractional Flow Reserve in Guiding Coronary Revascularization
Authors: Vladimir Lakhter, Chad J Zack, Alfred A Bove, Riyaz Bashir
Journal: Circulation (2012)

Background: Fractional flow reserve (FFR) is a well-validated and cost effective method for guiding coronary revascularization, however, the national utilization rates of FFR in United States are u...
Evaluation of the Impact of the Presence of Neutralizing L-Asparaginase Antibodies on the Efficacy and Safety of Graspa in Phase 3 Randomized Trial Versus Native L-Asparaginase in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)
Authors: Yves Bertrand, Andre Baruchel, Xavier Thomas, Nicolas Blin, Emmanuelle Tavernier, Stephane Ducassou, Norbert Vey, Virginie Gandemer, Victoria Cacheux, Francoise Mazingue, Emmanuel Raffoux, Genevieve Plat, Jose Fernandes, Maryline Poiree, Luc Fornecker, Jean-Louis Stephan, Mathilde Hunault, Anne Auvrignon, Thibault Leguay, Dominique Plantaz, Stephane Lepretre, Alina Ferster, Isabelle Pellier, Emmanuel Plouvier, Claudine Schmitt, Cecile Bonin, Yann Godfrin, Iman El Hariry
Journal: Blood (2015)
A population pharmacokinetic analysis of ixabepilone in patients with cancer
Authors: M. Cohen, D. Mould, A. Roy, M. Mandava, M. Pfister
Journal: Journal of Clinical Oncology (2008)

2521 Background: Ixabepilone, the first in a new class of antimicrotubule agents: the epothilones, is indicated in the US for the treatment of resistant/refractory metastatic breast cancer (MBC). Mass balance studies found metabolism is the major elimination mechanism. A population pharmacokinetic (PK) analysis was performed to characterize the extent and variability of ixabepilone exposure in cancer patients and to evaluate the influence of selected categorical and continuous covariates on exposure. Methods: Data were collected from 12 monotherapy studies (2 phase I; 10 disease-specific phase II [MBC, localized breast cancer, non-small-cell lung cancer, colorectal cancer, gastric adenocarcinoma, melanoma, and small-cell lung cancer]). The dataset included 4540 observations from 674 patients (128 from phase I; and 546 from phase II) who were given intravenous ixabepilone doses ranging between 1 and 65 mg/m2. Ixabepilone PK was characterized by a compartmental nonlinear mixed-effects model. Results: Ixabepilone concentration-time data were well-described by a linear 2-compartment model with zero-order infusion. The model estimated geometric mean (%CV) of total clearance (CLT) in previously treated cancer patients was 36.8 L/h (48.8%). Age, gender, renal function, body weight, body surface area and race were not statistically significant predictors of CLT. However, the CLT in breast cancer patients who received ixabepilone as neoadjuvant treatment was estimated to be 25% higher than the CLT in patients with advanced cancer. Conclusions: The pharmacokinetics of ixabepilone are linear and time-invariant. Patients with early-stage breast disease appear to clear ixabepilone faster than those with more advanced disease. Exposure to ixabepilone was not affected by any of the other patient characteristics examined. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Canonical NF‐κB signaling in hepatocytes acts as a tumor‐suppressor in hepatitis B virus surface antigen‐driven hepatocellular carcinoma by controlling the unfolded protein response
Authors: Yoshiaki Sunami, Marc Ringelhan, Enikö Kokai, Miao Lu, Tracy O'Connor, Anna Lorentzen, Achim Weber, Ann‐Katrin Rodewald, Beat Müllhaupt, Luigi Terracciano, Sarah Gul, Sebastian Wissel, Frank Leithäuser, Daniel Krappmann, Petra Riedl, Daniel Hartmann, Reinhold Schirmbeck, Pavel Strnad, Norbert Hüser, Jörg Kleeff, Helmut Friess, Roland M Schmid, Fabian Geisler, Thomas Wirth, Mathias Heikenwalder
Journal: Hepatology (2016)

Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC). Efficient suppression of HBV viremia and necroinflammation as a result of nucleos(t)ide analogue treatment is able to reduce HCC incidence; nevertheless, hepatocarcinogenesis can occur in the absence of active hepatitis, correlating with high HBV surface antigen (HBsAg) levels. Nuclear factor κB (NF‐κB) is a central player in chronic inflammation and HCC development. However, in the absence of severe chronic inflammation, the role of NF‐κB signaling in HCC development remains elusive. As a model of hepatocarcinogenesis driven by accumulation of HBV envelope polypeptides, HBsAg transgenic mice, which show no HBV‐specific immune response, were crossed to animals with hepatocyte‐specific inhibition of canonical NF‐κB signaling. We detected prolonged, severe endoplasmic reticulum stress already at 20 weeks of age in NF‐κB‐deficient hepatocytes of HBsAg‐expressing mice. The unfolded protein response regulator binding immunoglobulin protein/78‐kDa glucose‐regulated protein was down‐regulated, activating transcription factor 6, and eIF2α were activated with subsequent overexpression of CCAAT/enhancer binding protein homologous protein. Notably, immune cell infiltrates and liver transaminases were unchanged. However, as a result of this increased cellular stress, insufficient hepatocyte proliferation due to G 1 /S‐phase cell cycle arrest with overexpression of p27 and emergence of ductular reactions was detected. This culminated in increased DNA damage already at 20 weeks of age and finally led to 100% HCC incidence due to NF‐κB inhibition. Conclusion: The role of canonical NF‐κB signaling in HCC development depends on the mode of liver damage; in the case of HBsAg‐driven hepatocarcinogenesis, NF‐κB in hepatocytes acts as a critical tumor suppressor by augmenting the endoplasmic reticulum stress response. (H epatology 2016;63:1592‐1607)
Prevalence of food sensitization and probable food allergy among adults in India: the EuroPrevall INCO study
Authors: P. A. Mahesh, Gary W. K. Wong, L. Ogorodova, J. Potts, T. F. Leung, O. Fedorova, Amrutha D. Holla, M. Fernandez‐Rivas, E. N. Clare Mills, I. Kummeling, S. A. Versteeg, R. van Ree, M. Yazdanbakhsh, P. Burney
Journal: Allergy (2016)

Abstract Background Data are lacking regarding the prevalence of food sensitization and probable food allergy among general population in India. We report the prevalence of sensitization and probable food allergy to 24 common foods among adults from general population in Karnataka, South India. Methodology The study was conducted in two stages: a screening study and a case–control study. A total of 11 791 adults in age group 20–54 were randomly sampled from general population in South India and answered a screening questionnaire. A total of 588 subjects (236 cases and 352 controls) participated in the case–control study involving a detailed questionnaire and specific IgE estimation for 24 common foods. Results A high level of sensitization (26.5%) was observed for most of the foods in the general population, higher than that observed among adults in Europe, except for those foods that cross‐react with birch pollen. Most of the sensitization was observed in subjects who had total IgE above the median IgE level. A high level of cross‐reactivity was observed among different pollens and foods and among foods. The prevalence of probable food allergy (self‐reports of adverse symptoms after the consumption of food and specific IgE to the same food) was 1.2%, which was mainly accounted for cow's milk (0.5%) and apple (0.5%). Conclusion Very high levels of sensitization were observed for most foods, including those not commonly consumed in the general population. For the levels of sensitization, the prevalence of probable food allergy was low. This disassociation needs to be further explored in future studies.
Fish oil for OA? Don't give up yet
Authors: Joel M Kremer
Journal: Annals of the Rheumatic Diseases (2016)

I read with interest the article by Hill et al ,1 with the accompanying editorial by Felson and Bischoff-Ferrari.2 The point made by the editorialists was that the absence of a difference in osteoarthritis outcomes could have been due to the comparator group, which was high in oleic acid. Hill et al chose sunola oil for the comparator with fish oil as they believed that the absence of polyphenols would make it less likely that there would be a therapeutic effect from the sunola oil.

We published a trial of the effects of supplementation with what we termed low- …
Abstract 298: Low-dose Interleukin-18 is Necessary to Adapt to Pressure Overload in Mice
Authors: Iwasaku Toshihiro, Hirotani Shinichi, Eguchi Akiyo, Suminatni Naoki, Okuhara Yoshitaka, Morisawa Daisuke, Sawada Hisashi, Naito Yoshiro, Masuyama Tohru
Journal: Circulation Research (2014)

Background: We previously reported that circulatory Interleukin-18 (IL-18) level elevates in heart failure (HF) patients. However, the roles of circulatory IL-18 in HF have not been fully elucidated. Continuous infusion of IL-18 induces cardiomyocyte hypertrophy and fibrosis, whereas IL-18 null mice were fragile to pressure overload. We hypothesized that systemic (circulatory) and local (cardiac) IL-18 have distinct effects on HF and cardiac remodeling. Purpose: The purpose of this study was to elucidate the role of circulatory IL-18 in adaptation to pressure overload in IL-18 null mice. Methods: Wild type (WT) mice and IL-18 null (IL-18-/-) were subjected to transaortic constriction (TAC). Sequential serum IL-18 levels myocardial IL-18 mRNA expressions were determined by ELISA and qRT-PCR in WT mice. After two week of TAC, IL-18 null mice were administered either (IP) saline or recombinant IL-18 intraperitoneally (10ng/20g every other day). Cardiac function was assessed by transthoracic echocardiography. Two weeks after TAC, myocardial samples were obtained. Haematoxylin and eosin stained sections and Masson’s trichrome staining sections were prepared. Results: IL-18 concentration in serum and IL-18 expression in myocardial tissue increased gradually after TAC in WT mice. Forty-seven % (7/15) of TAC-operated IL-18-/- mice and 12% (2/17) of TAC-operated WT mice died of heart failure by 14days. TAC-operated IL-18-/- mice exhibited more severe left ventricular (LV) remodeling, characterized by cardiomyocyte hypertrophy, extensive interstitial fibrosis and elevation of fetal gene expressions compared with TAC-WT mice. Recombinant IL-18 given intraperitoneally improved the survival rate to 100% (10/10) following TAC operation in IL-18-/- mice. Furthermore, exogenous IL-18 administration suppressed ventricular ANP mRNA expression and myocardial cross-sectional area enlargement to non-TAC-operated level, whereas LV enlargement and contractile dysfunction were only partially suppressed in IL-18-/- mice following TAC. Conclusions: Circulatory IL-18 exerts opposing effects on cardiac hypertrophy under pressure-overload. IL-18 produced in the heart may have an effect such as preserving contractile function.
Australian doctor challenges government over child detention “torture”
Authors: Michael Woodhead
Journal: BMJ (2016)

One of Australia’s leading paediatricians has invited the government to arrest and prosecute him for defying a new law that gags healthcare workers from speaking about conditions in detention centres for asylum seekers.

David Isaacs, clinical professor in paediatric infectious diseases at the University of Sydney, said that he witnessed appalling and inhumane conditions for children while working in Australia’s offshore immigration detention centre on the Pacific island of Nauru.

He also claimed that the Australian government was maintaining a media blackout and a culture of secrecy around the conditions in detention centres.

In a recent paper published in the Journal of Medical Ethics ,1 Isaacs said that keeping children in long term and indefinite detention met the definition of …
Chemoattractant Properties of Corynebacterium parvum and Pyran Copolymer for Human Monocytes and Neutrophils
Authors: J. A. Majeski, J. D. Stinnett
Journal: JNCI Journal of the National Cancer Institute (1977)

Both pyran copolymer and the Burroughs-Wellcome vaccine of Corynebacterium parvum were able to elicit a migratory response by human neutrophils or monocytes when incubated with serum. However, in the absence of serum, neither agent elicited such a response. The generation of the chemotactic factor by pyran was dependent on heat-labile components in the serum, while suggested involvement of the complement sequence. Conversely, the migratory response of C. parvum in heated serum was equivalent to that in normal serum. No specificity for either monocytes or neutrophils was observed.
Diethylcarbamazine Control of Bancroftian Filariasis
Authors: I. A. McGregor, H. M. Gilles
Journal: BMJ (1956)

In February, 1951, the available population of Keneba, a village in the West Kiang District of the Gambia Protectorate, were examined and those infected with Wuchereria bancrofti recorded.As many as possible of these carriers were treated in the same month with diethylcarbamazine (" hetrazan "), each person who com- pleted the prescribed course receiving 25 mg. of hetrazan base per kg. of body weight.Nine months later, in December, 1951, the population were again examined to determine the results of treatment.These results have already been described (McGregor et al., 1952).This paper records the results of a third survey of Keneba, November, 1954, conducted three years and nine months after administration of the drug.Methods.-Techniques identical to those of the earlier surveys were employed.Blood for the enumeration of microfilariae was taken by finger-prick between the hours of 9 p.m. and midnight.This blood, estimated by pre- vious measurement to be approximately 20 c.mm., was spread uniformly over a measured area of slide marked by grease pencil.It is to this volume of approximately 20 c.mm. that all microfilaria counts in this paper are referred.The thick films were dehaemoglobinized, fixed in methyl alcohol, and stained with haemalum. ResultsIn 1954, 390 villagers who had been examined in the $urveys of 1951 were again examined.Table I gives the breakdown of this number into groups pertinent to this paper.TABLE I A. Persons found infected in 1951 and treated with diethvlcarbamazine base (25 mg./kg.)... 122 B. Persons found infected in 1951 but not treated 46 C. Persons found uninfected in 1951 .
Changing patterns of prognosticators during long-term follow-up of gastric cancer after D2–3 resection and adjuvant chemotherapy: 15-year follow-up at one Korean institution
Authors: H. C. Jeung, Y. W. Moon, S. Y. Rha, S. H. Noh, G. E. Kim, B. S. Kim, H. C. Chung
Journal: Journal of Clinical Oncology (2006)

4050 Background: Clinical outcome of long-term follow-up after 5 years of gastrectomy, such as recurrence or survival rate, recurrence patterns, and prognosticators, have not been studied well. We evaluated long-term natural history of gastric cancer with a median follow up duration of 15 years after D2–3 resection and adjuvant chemotherapy at a single institution. Especially in survived patients after 5 years of surgery, we analyzed risk factors for recurrence or survival. Methods: A total of 525 patients with stage IB to IVM0 (AJCC 2002) were accrued between 1984 and 1996. As a standard surgery, radical gastrectomy with D2–3 lymphadenectomy was performed. All the patients had adjuvant 5-FU plus adriamycin chemotherapy and 160 of them had also immunotherapy with poly A:U. Results: The median follow-up duration was 191 months. 15 patients (2.9%) were lost to follow-up with median follow-up of 45 months. 15-year disease-free and overall survival rates were 49.5% and 42.9%, respectively. In survivors after 5 years, recurrence rate was 16.0% (11.3% between 5 and 10 years; 4.7% after 10 years). The dominant recurrence patterns were distant metastasis (29.0%) between 5 and 10 years and secondary cancer (53.9%) after 10 years of surgery. Stage (IB vs II vs IIIA vs IIIB vs IVM0) was a clear-cut prognosticator during 5 years of gastrectomy, but its significance was lost between 5 to 10 years. At this time, only stage IVM0 was a significant poor prognosticator for gastric cancer-specific recurrence (HR = 6.61; P = 0.000) and cancer-specific death (HR = 7.04, P = 0.000). However, stage did not represent any significance after 10 years of surgery. Conclusions: In gastric carcinoma with D2–3 resection and adjuvant treatment, late recurrences after 5 years of surgery were not rare. Prognosticators were different in survivors after 5-years, 5–10 years and more than 10 years of surgery. No significant financial relationships to disclose.
Preeclampsia and Congenital Heart Defects—Reply
Authors: Nathalie Auger, William D. Fraser, Laura Arbour
Journal: JAMA (2016)

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Persistent tachypnoea in an infant with cystic lung lucencies on CT scan
Authors: Vijayasekharan Kalasekhar, Selvam Nithiya, Venkatesh Chandrasekaran, Reena Gulati, Sajini Elizabeth Jacob, Biswajit Dubashi
Journal: Thorax (2016)

A 1 year and 8 months old boy, with mild motor developmental delay and right hemiparesis following a perinatal brain injury, was brought with a history of fast breathing and cough for 2 months and low-grade fever of 10 days duration. He was second born to non-consanguineously wed parents by spontaneous vaginal delivery with delayed cry at birth and neonatal intensive care unit stay for 10 days. There was no exposure to cigarette smoke. On examination there was mild central cyanosis with pan digital clubbing; pulse rate was 102 per minute; respiratory rate was 44 per minute; oxygen saturation of 89% which improved to 95% with 2 L/min of oxygen. On systemic examination, cardiovascular status was found to be normal; respiratory examination revealed coarse crepitations bilaterally in the entire lung …
QoL and resource use analysis of tegafur-uracil/LV or 5-FU/LV in first-line metastatic colorectal cancer (mCRC): Final results of a multicenter phase II study
Authors: B. Sizer, A. Makris, C. Barone, P. Mainwaring, P. Eggleton
Journal: Journal of Clinical Oncology (2006)

3631 Background: Tegafur-uracil (UFT) is an effective oral fluoropyrimidine for patients with mCRC. Aims of this prospective phase II study were to evaluate quality of life (QoL), patient preference and healthcare resource use in patients receiving oral UFT/LV or i.v. 5-FU/LV as first-line therapy for mCRC. Safety and efficacy were also assessed. Methods: 243 patients in 3 countries (Austria, Italy and UK) were randomized in a 2:1 ratio to receive either UFT 300mg/m 2 /d + LV 90mg/d for 28d q5w, or i.v. 5-FU 425mg/m 2 /d + LV 20mg/m 2 /d for 5d q4w. Patients were assessed at baseline and every cycle for symptoms, adverse events (AEs), and overall response rate (ORR). QoL was evaluated using EORTC QLQ-C30, and patients completed a preference questionnaire at baseline, end of cycle 1, and end of study. Data on hospital attendances (in- and out-patient), physician visits, concomitant medication use and other healthcare resources were collected for every cycle and during study follow up. Results: 162 patients received UFT/LV (median 3 cycles) and 81 i.v. bolus 5-FU/LV (median 4 cycles). Patient demographics were similar in both groups: median age was 70y (range 39–83) for UFT/LV and 69y (41–80) for 5-FU/LV; 92% of patients were ECOG PS ≤1. QoL was maintained in the UFT/LV group with little variation across time whereas QoL deteriorated with 5-FU/LV. Most patients in the UFT/LV (85–95%) and 5-FU/LV (49–66%) groups stated a preference for oral treatment with the most common reason being ‘taken at home’ (83%). Fewer UFT/LV patients had one or more hospitalizations for AEs (21% vs. 36%). Clinical benefit (ORR+SD) was 32% with UFT/LV (41% evaluable for response) and 32% with 5-FU/LV (45% evaluable). Median time to disease progression was 173d (95% CI 140–199) for UFT/LV and 168d (95% CI 133–205) for 5-FU/LV. Median overall survival was 385d (95% CI 296–472) for UFT/LV and 330d (95% CI 252–484) for 5-FU/LV. Conclusions: UFT with LV has comparable efficacy to i.v. 5-FU/LV in first-line mCRC, with the advantages of favorable QoL, patient preference for oral treatment, and fewer hospitalizations for managing AEs. [Table: see text]