tbuckley/cabot-search huggingface dataset:
Thiazolidinedione (TZD) exposure and overall survival (OS) in squamous cell carcinoma of the head and neck (SCCHN)
Authors: R. Govindarajan, E. R. Siegel, D. L. Simmons, N. P. Lang
Journal: Journal of Clinical Oncology (2008)

6079 Background: TZD are synthetic ligands for peroxisome proliferator-activated receptor γ (PPARγ), a nucleic acid receptor. A decreased incidence of lung cancer and SCCHN among those exposed to TZD has been demonstrated in the past. We hypothesized that TZD may also impact survival of subjects with SCCHN, and conducted a retrospective cohort study of subjects with a diagnosis of SCCHN among male veterans with diabetes mellitus (DM). Methods: Data were obtained from the VISN 16 (VA) patient database for males age>40 with DM who developed SCCHN between 10/01/96 and 12/31/05. Diagnoses were identified by ICD9 codes. They were followed till 12/31/06. Subjects were analyzed for effect on OS via Cox regression with time-dependent covariates to model exposures to TZDs, insulin, and other anti-DM agents. Results: Out of 130,406 diabetic subjects in the database, 911 subjects developed SCCHN. Median (quartiles) age at SCCHN diagnosis was 67 (59–74). There were 21% African-American, 69% Caucasian, and 10% other/unknown. 360 deaths were observed during 2552.1 person-years on study. The table shows hazard ratios for death and confidence limits for subjects exposed to TZDs, other oral agents, and insulin after adjusting for age, race, HgbA1C, and years of DM prior to SCCHN diagnosis. Conclusions: A 37% reduction in the risk of death was observed in SCCHN subjects exposed to TZDs versus those not exposed (P=0.038). Exposure to TZD may prolong overall survival in diabetics who are diagnosed with SCCHN. The exact mechanism of action needs further evaluation. Anti-DM Agent Subjects Exposed: Numbers (Person-years) Hazard Ratio 95% Confidence Limits P-value Diet Only 205 (563.9) 1.000 – – TZDs 127 (265.3) 0.628 0.404-0.975 0.0382 Other Oral 612 (1713.4) 1.023 0.814-1.285 0.8464 Insulin 318 (851.6) 1.742 1.375-2.208 <0.0001 Drug-drug interactions: not significant (χ2=1.48, DF=3, P=0.69). No significant financial relationships to disclose.
Volatile Anesthetics. Is a New Player Emerging in Critical Care Sedation?
Authors: Angela Jerath, Matteo Parotto, Marcin Wasowicz, Niall D. Ferguson
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Volatile anesthetic agent use in the intensive care unit, aided by technological advances, has become more accessible to critical care physicians. With increasing concern over adverse patient consequences associated with our current sedation practice, there is growing interest to find non-benzodiazepine-based alternative sedatives. Research has demonstrated that volatile-based sedation may provide superior awakening and extubation times in comparison with current intravenous sedation agents (propofol and benzodiazepines). Volatile agents may possess important end-organ protective properties mediated via cytoprotective and antiinflammatory mechanisms. However, like all sedatives, volatile agents are capable of deeply sedating patients, which can have respiratory depressant effects and reduce patient mobility. This review seeks to critically appraise current volatile use in critical care medicine including current research, technical consideration of their use, contraindications, areas of controversy, and proposed future research topics.
Risk Factors for Developing Skeletal-Related Events Associated with Metastatic Breast Cancer Patients Receiving Bone-Modifying Agents
Authors: R. Tanaka, K. Yonemori, A. Hirakawa, J. Hashimoto, M. Kodaira, H. Yamamoto, M. Yunokawa, C. Shimizu, M. Fujimoto, Y. Fujiwara, K. Tamura
Journal: Annals of Oncology (2014)
Impact of Early Weight Loss During Concurrent Chemoradiotherapy (Ccrt) on Survival in Advanced Stage Non-Small Cell Lung Cancer (Nsclc) Patients
Authors: L. Hendriks, A.M. Schols, C.M. Op den Kamp, R.A. van Kollenburg, E. Troost, A.C. Dingemans
Journal: Annals of Oncology (2014)
Abstract 19386: Adaptive Upregulation of MicroRNA-146b Following Surgical Ischemia-Reperfusion Attenuates Myocardial Inflammation
Authors: Kevin A Friede, Qing Ma, Kyle K Phua, Zhiquan Zhang, Michael P Smith, Kam W Leong, Mircea Ivan, Mihai V Podgoreanu
Journal: Circulation (2012)

Introduction: Using a comparative biology approach we prioritized microRNAs (miRs) deregulated by surgical myocardial I/R. We hypothesized that in vitro overexpression of miR-146b is cardioprotective following simulated I/R through attenuation of NF-kB mediated inflammation. Finally, we compared two delivery methods of miR modulators - chemical transfection versus nanoparticle-bound. Methods: 1) miR expression analysis - microarray of myocardium from 2 models of I/R: a) rats - cardioplegic arrest (CA) or deep hypothermic circulatory arrest (DHCA) and 24h reperfusion, or sham; 2 rat strains with different susceptibilities to myocardial I/R used - Brown Norway (BN) and Dahl Salt Sensitive (DSS); b) pigs - CA or DHCA and 6h reperfusion, or sham (N=4/group). Deregulated miRs (FDR &lt;0.1) validated by qPCR. 2) miR-146b functional analysis- ARVCs transfected with miR-146b mimics or inhibitors, subjected to 2h OGD - 6h reoxygenation; target gene expression IRAK1 and TRAF6 qPCR and Western; necrosis and apoptosis assays. 3) Nanoparticle delivery - chemical or nanoparticle-mediated ARVC transfection monitored as above plus Cy3-miR. Nanoparticle-bound Cy3-miR administered to rats in cardioplegia; biodistribution by fluorescence microscopy. Results: Robust post I/R miR-146b upregulation conserved across species, experimental conditions, and reperfusion timepoints (Fig, A). Different miR-146b expression between rat strains (BN vs DSS) corresponded to severity of myocardial injury. miR-146b overexpression attenuated IRAK 1, TRAF6 and NF-kB p65 upregulation following simulated I/R (Fig, B), resulting in improved cardiomyocyte viability (Fig, C). Nanoparticles show superior transfection efficiency to chemical methods in vitro, and early extravascular myocardial distribution. Conclusion: miR-146b may exert inhibitory feedback on NF-kB activation through effects on key regulatory elements IRAK1 and TRAF6 with potential cardioprotective roles.
Dysregulated bioenergetics: a key regulator of joint inflammation
Authors: M Biniecka, M Canavan, T McGarry, W Gao, J McCormick, S Cregan, L Gallagher, T Smith, J J Phelan, J Ryan, J O'Sullivan, C T Ng, D J Veale, U Fearon
Journal: Annals of the Rheumatic Diseases (2016)

This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation.Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions.Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.
High School Contact Among Persons With Leukemia and Lymphoma2
Authors: Matthew M. Zack, Clark W. Heath, M. DeWayne Andrews, A. Scott Grivas, Barbara W. Christine
Journal: JNCI Journal of the National Cancer Institute (1977)

We studied frequency of contact among Connecticut high school students and teachers with leukemia and lymphoma diagnosed during or after high school from 1960 through 1971. Risk of having attended the same grade at the same school during the same year was greater among students with Hodgkin's disease (HD) than among simulated controls drawn in proportion to school enrollment (relative risk = 1.44; approximate 95% lower confidence limit = 1.05). Risk of developing HD was also greater among students enrolled simultaneously at the same school as students already diagnosed with HD than among students not so enrolled (relative risk = 2.05; 95% lower confidence limit = 1.39). However, fewer HD cases (16) were diagnosed from 1965 through 1970 at schools that formerly had patients enrolled (1959-64) than at matched schools without such patients (24). We found no evidence of Increased contact among persons with non-HD lymphomas or leukemias, except between HD and non-HD lymphomas (relative risk = 1.41; approximate 95% lower confidence limit = 1.11
Synergy in Proliferative and Cytotoxic Responses of WF Rats to Syngeneic Gross Virus-Induced Lymphoma Cells In Vitro23
Authors: Peter W. Wright, Stephen M. Loop, Irwin D. Bernstein
Journal: JNCI Journal of the National Cancer Institute (1980)

A synergistic interaction between rat lymphoid cell subsets was found for the in vitro immune response to the syngeneic Gross virus-induced lymphoma (C58NT)D. Mixtures of thymocytes and lymph node cells from inbred WF rats primed in vivo to the lymphoma demonstrated significantly greater proliferative and cytotoxic reactivities in vitro than would be expected from the sum of the reactivities of the two cell types tested separately. A soluble extract of nonimmune syngeneic thymocytes, shown in previous studies to amplify the in vitro responses to alloantigen, was also demonstrated to increase significantly proliferative and cytotoxic responses in vitro to syngeneic lymphoma cells. Preliminary evidence indicated that this soluble thymus amplifier factor differed from previously described thymus factors.
Phase I trial of the targeted alpha-particle nano-generator actinium-225 (<sup>225</sup>Ac-lintuzumab) (anti-CD33; HuM195) in acute myeloid leukemia (AML).
Authors: J. G. Jurcic, T. L. Rosenblat, M. R. McDevitt, N. Pandit-Taskar, J. A. Carrasquillo, S. M. Chanel, C. Ryan, M. G. Frattini, D. Cicic, S. M. Larson, D. A. Scheinberg
Journal: Journal of Clinical Oncology (2011)

6516 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers. Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Twelve patients (median age, 65 yrs; range, 45-80 yrs) with relapsed/refractory AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5, 1, 2, 3, or 4 μCi/kg (total dose, 23-390 μCi). No acute toxicities were seen. DLT (myelosuppression lasting >35 days; death due to sepsis) occurred in one patient treated with 3 μCi/kg and in both patients receiving 4 μCi/kg. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities. With a median follow-up of 5 mos (range, 1-24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, 221Fr and 213Bi. Two-phase elimination kinetics was seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived isotopes. Peripheral blood blasts were eliminated in 7 of 11evaluable patients. BM blast reductions of >33% were seen in 6 of 10 evaluable patients at 4 weeks, including 2 patients with <5% blasts. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab is tolerable at doses <4 μCi/kg and has antileukemic activity. Accrual to this trial continues.
David Antony Long
Authors: S Charles Gallannaugh
Journal: BMJ (2015)

The death of David Antony Long at the age of 98 severs one of the last direct links with the era that followed the discovery of penicillin by Alexander Fleming in 1928, an event that was to change the course of medical practice in the 20th century. Long’s long and distinguished career in microbiology and molecular science began shortly after he qualified, with a series of papers on the clinical effects of penicillin in humans.

Long was born on 27 February 1917 in London after his father, who had been a professor of Classics in Dublin, had moved to England. He was educated at Eastbourne College and St Bartholomew’s Hospital, where he qualified with honours and distinction in medicine, pharmacology, and therapeutics. He won the Brackenbury scholarship in medicine at St Bartholomew’s and the Mathews Duncan prize and gold medal.

On qualifying he was appointed house physician to the medical unit at St Bartholomew’s, and the following year he became lecturer in bacteriology there. Bart’s had played a major part in evaluating penicillin from the earliest days. Long’s work on the effect of penicillin in the treatment of diphtheria stimulated an early research interest in methods of assaying antigens and antibodies and led to several early papers. Later, at the National Institute for Medical Research, which he joined in 1948, he showed that diphtheria antitoxin as used in humans failed to neutralise toxin injected into …
Carcinogenic Properties of Nuts From &lt;italic&gt;Cycas Circinalis&lt;/italic&gt; L. Indigenous to Guam&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: G L LAQUEUR, O MICKELSEN, M G WHITING, L T KURLAND
Journal: JNCI Journal of the National Cancer Institute (1963)

Neoplastic disease in rats developed after chronic ingestion of cycad nut meal as a part of the diet. The nuts, obtained from the plant Cycas circinalis L. indigenous to Guam, originally were suspected of possessing a neurotoxin. Although the experiments failed to demonstrate this effect, benign and malignant tumors developed, mainly in the liver and kidneys, with 1 in the lung and 2 in the intestine. The tumors in the liver were hepatocellular carcinomas and reticuloendothelial neoplasms, occurring simultaneously but independently. The tumors in the kidney were adenomas and undifferentiated tumors, bilateral and simultaneous. The tubular adenomas grew expansively. The undifferentiated tumors were thought to have originated from cells between tubules and capillaries in the inner cortex and grew infiltratively between pre-existing renal structures. Peculiar vascular changes characterized by subintimal hyalinosis of capillaries and limited to the undifferentiated tumors were described and thought to represent a secondary phenomenon. The similarities in pathologic changes between rats fed toxic cycad nut meal and those, reported in the literature, given dimethylnitrosamine were emphasized, and the possibility was suggested that a glycoside isolated from cycads, namely cycasin, may yield in its metabolic breakdown a compound carcinogenic for rats and similar to the one suggested as the carcinogenic agent in dimethylnitrosamine. This possibility is currently being investigated.
A randomized controlled trial evaluating a topical treatment for chemotherapy-induced neuropathy: NCCTG trial N06CA
Authors: D. L. Barton, E. Wos, R. Qin, B. Mattar, N. Green, K. Lanier, J. Bearden, J. Kugler, K. Rowland, C. Loprinzi
Journal: Journal of Clinical Oncology (2009)

9531 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a prevalent dose limiting toxicity for several important cancer treatment agents. CIPN can impair function and cause distress. There are no proven pharmacologic treatments for established CIPN currently. This double blind randomized placebo controlled trial evaluated a compounded topical gel for this problem. The novelty of this treatment is that it might incorporate several agents with different mechanisms of action to provide relief locally without negative systemic effects. Methods: Patients with CIPN (rated ≥4 out of 10) for at least one month, related to previous and/or concurrent exposure to neurotoxic agents, were randomized to baclofen 10 mg, amitriptyline HCL 40 mg and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) vs placebo (PLO) to determine its effect on numbness, tingling, pain, and motor function. Exclusion criteria included other causes and/or current treatment for peripheral neuropathy. The primary endpoint was the baseline adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results: Between February and May 2008, 208 patients were enrolled onto this trial. Four week data are shown in the table below, higher numbers being better. The percentage of patients that had improvements of at least 10, on a 100 point scale, in the motor subscale was statistically significantly higher in the BAK-PLO arm, p=.04. There were no unwanted toxicities associated with the BAK-PLO that were significantly different from placebo and no evidence of CNS or systemic toxicity. Conclusions: Topical treatment with BAK-PLO appears to moderately improve symptoms of CIPN. This topical gel was well tolerated without systemic side effects. [Table: see text] No significant financial relationships to disclose.
Will endoscopic ultrasound-guided bile duct drainage replace ERCP?
Authors: Jong Moon, Hyun Choi, Yun Lee
Journal: Endoscopy (2016)

Endoscopic ultrasound (EUS)-guided transmural drainage has become an established endoscopic intervention for the drainage of peripancreatic and other fluids that collect adjacent to the gastrointestinal tract. During the past decade, the use of EUS-guided drainage has expanded to the biliary and pancreatic duct systems. Since Giovannini et al. [1] first reported EUS-guided bile duct drainage (EUS-BD) in 2001, it has been increasingly performed and has been shown to be a technically feasible procedure, with high success rates (75 % – 100 %) in clinical trials [2]. In selected cases, EUS-BD can replace traditional percutaneous intervention in patients with distal malignant biliary obstruction and failed endoscopic retrograde cholangiopancreatography (ERCP); EUS-BD can be performed during the same endoscopy session as ERCP and avoids the inconvenience of external drainage [3]. However, there is controversy over whether EUS-BD can replace percutaneous transhepatic biliary drainage as the primary modality for biliary obstruction and failed ERCP. Furthermore, some endoscopists suggest that EUS-BD may replace the standard transpapillary ERCP as the first-line drainage procedure for malignant biliary obstructions [4].
Epstein-Barr Virus Latent Gene Expression in Primary Effusion Lymphomas Containing Kaposi's Sarcoma–Associated Herpesvirus/Human Herpesvirus-8
Authors: Marcelo G. Horenstein, Roland G. Nador, Amy Chadburn, Elizabeth M. Hyjek, Giorgio Inghirami, Daniel M. Knowles, Ethel Cesarman
Journal: Blood (1997)
Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways
Authors: Shuang Peng, Nan Hang, Wen Liu, Wenjie Guo, Chunhong Jiang, Xiaoling Yang, Qiang Xu, Yang Sun
Journal: Acta Pharmaceutica Sinica B (2016)

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.