tbuckley/cabot-search huggingface dataset:
p16 expression as a human papillomavirus (HPV)-independent prognostic biomarker in non-oropharyngeal squamous cell carcinoma (non-OPSCC).
Authors: Christine H. Chung, Qiang Zhang, Christina Kong, Jonathan Harris, K. Kian Ang, Paul M. Harari, Dian Wang, Kevin P. Redmond, George Shenouda, Andy Trotti, David Raben, Maura L. Gillison, Richard Jordan, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2013)

6007 Background: p16 is an important tumor suppressor and cell cycle regulator that is commonly lost in HPV-negative (-) and upregulated in HPV-positive (+) OPSCC. While the role of p16 expression in OPSCC as a surrogate marker of HPV infection and its association with prognosis are well established, its significance has not been studied in non-OPSCC including oral cavity, hypopharynx and larynx, where HPV infection is rare. We hypothesize that p16 expression is a prognostic biomarker of favorable outcome (progression-free and overall survival) in non-OPSCC. Methods: p16 expression in non-OPSCC from RTOG 0129, 0234 and 0522 was determined by immunohistochemistry (p16 mouse monoclonal antibody, prediluted, MTM-CINtech, 9518) and considered positive if &gt;70% of the tumor cells demonstrated diffuse staining. The high risk HPV status in non-OPSCC from RTOG 0129 and 0522 was determined by in situ hybridization using a cocktail probe including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66. Hazard ratios from Cox models were expressed as positive/negative, stratified by trial, and adjusted for age, gender, T, and N stage. Results: p16 expression was positive in 14.1% (12/85), 24.2% (23/95) and 19.0% (27/142) of non-OPSCC from RTOG 0129, RTOG 0234, and RTOG 0522, respectively. HPV ISH was positive in 6.5% (6/93) and 6.9% (7/101) of non-OPSCC from RTOG 0129 and RTOG 0522, respectively. There was moderate agreement between p16 and HPV status (kappa=0.53). The hazard ratios for p16 expression are 0.63 (p=0.03) and 0.56 (p=0.01) for PFS and OS, respectively. In 0522, there was no interaction between p16 status and two treatment arms (RT+cisplatin+/-cetuximab). In comparison of OPSCC and non-OPSCC, patients with p16(+) OPSCC have better PFS and OS than patients with p16(+) non-OPSCC, but patients with p16(-) OPSCC and non-OPSCC have similar outcomes. Conclusions: Similar to results in patients with OPSCC, patients with p16(+) non-OPSCC have better outcomes than patients with p16(-); however, the differential appears smaller than has been observed in HPV(+) OPSCC. Further studies are warranted to delineate the role of p16 expression as a prognostic biomarker in non-OPSCC and OPSCC. Clinical trial information: NCT00265941, NCT00047008, NCT00084318.
Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing
Authors: Adrien Decque, Olivier Joffre, Joao G Magalhaes, Jack-Christophe Cossec, Ronnie Blecher-Gonen, Pierre Lapaquette, Aymeric Silvin, Nicolas Manel, Pierre-Emmanuel Joubert, Jacob-Sebastian Seeler, Matthew L Albert, Ido Amit, Sebastian Amigorena, Anne Dejean
Journal: Nature Immunology (2015)
MEP1A contributes to tumor progression and predicts poor clinical outcome in human hepatocellular carcinoma
Authors: Han‐Yue OuYang, Jing Xu, Jun Luo, Ru‐Hai Zou, Keng Chen, Yong Le, Yong‐Fa Zhang, Wei Wei, Rong‐Ping Guo, Ming Shi
Journal: Hepatology (2015)

Although many staging classifications have been proposed for hepatocellular carcinoma (HCC), determining a patient's prognosis in clinical practice is a challenge due to the molecular diversity of HCC. We investigated the relationship between MEP1A, a candidate oncogene, and clinical outcomes of HCC patients; furthermore, we explored the role of MEP1A in HCC. In this report, it was demonstrated by quantitative real‐time polymerase chain reaction that MEP1A messenger RNA levels were significantly elevated in HCC tumor tissues compared with matched adjacent nonneoplastic tissues and nonmalignant liver disease tissues. Immunohistochemical analyses of tissue samples from two independent groups of 394 HCC patients showed that positive expression of MEP1A in tumor cells was an independent and significant risk factor affecting survival after curative resection in both cohort 1 (hazard ratio = 2.05, 95% confidence interval 1.427‐2.946; P &lt; 0.001) and cohort 2 (hazard ratio = 1.89, 95% confidence interval 1.260‐2.833; P = 0.002). Analysis of Barcelona Clinic Liver Cancer stage 0‐A subgroup further showed that patients with positive MEP1A expression in tumor cells had poorer surgical prognoses than those with negative MEP1A expression in tumor cells (cohort 1 P = 0.001, cohort 2 P &lt; 0.001). Both in vitro and in vivo assays showed that MEP1A promoted HCC cell proliferation, migration, and invasion. Further analyses found that MEP1A played an important role in regulating cytoskeletal events and induced epithelial‐mesenchymal transition in HCC cells. Conclusion : MEP1A is a novel prognostic predictor in HCC and plays an important role in the development and progression of HCC. (H epatology 2016;63:1227‐1239)
Abstract 15509: Genomwide-Association Identifies a Novel Locus for Anthracycline Cardiotoxicity
Authors: Quinn S Wells, Jonathan D Mosley, Sara L Van Driest, Peter Weeke, Jason H Karnes, Christian M Shaffer, Erica Bowton, Joshua C Denny, Dan M Roden
Journal: Circulation (2013)

Anthracyclines are important chemotherapeutic agents, but use can be limited by cardiotoxicity. Prior candidate gene studies have identified loci linked to toxicity. Here we used genome-wide associ...
High-stretch, but not atelectasis, causes systemic cytokine release by lung-marginated monocytes
Authors: Kenji Wakabayashi, Michael Wilson, Kate Tatham, Kieran O'Dea, Masao Takata
Journal: European Respiratory Journal (2013)

Introduction  The proposed pathophysiology of ventilator-induced lung injury (VILI) includes overdistension (volutrauma) and repetitive collapse and reopening (atelectrauma) of lung units. Using an isolated perfused mouse lung, we investigated the physiological and inflammatory consequences of these two mechanisms of VILI.  Methods  Isolated buffer-perfused lungs were ventilated with one of three protocols for 3 hours (n=5 each): ‘Control’ (7ml/kg tidal volume (VT), PEEP (5cmH2O) and regular sustained inflation (SI)); ‘Atelectasis’ (7ml/kg VT, zero PEEP without SI; ‘High-stretch’ (30-32ml/kg VT, PEEP (3cmH2O) with SI).  Results  Both injurious ventilation protocols led to increased peak inspiratory pressure (PIP; p  Conclusion  These results strongly suggest that volutrauma, but not atelectrauma, activates lung-marginated monocytes leading to systemic cytokine release, which is a critical factor for multiple organ failure in ventilated critically-ill patients. Our findings may provide a novel explanation why open lung strategy seemingly has limited mortality benefits.
Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche
Authors: Yoku Hayakawa, Hiroshi Ariyama, Jitka Stancikova, Kosuke Sakitani, Samuel Asfaha, Bernhard W. Renz, Zinaida A. Dubeykovskaya, Wataru Shibata, Hongshan Wang, Christoph B. Westphalen, Xiaowei Chen, Yoshihiro Takemoto, Woosook Kim, Shradha S. Khurana, Yagnesh Tailor, Karan Nagar, Hiroyuki Tomita, Akira Hara, Antonia R. Sepulveda, Wanda Setlik, Michael D. Gershon, Subhrajit Saha, Lei Ding, Zeli Shen, James G. Fox, Richard A. Friedman, Stephen F. Konieczny, Daniel L. Worthley, Vladimir Korinek, Timothy C. Wang
Journal: Cancer Cell (2015)
Estrogenic Properties of 3,9-Dihydroxybenz[ a ]anthracene, a Potential Metabolite of Benz[ a ]anthracene 2
Authors: Sara L. Schneider, Vitauts Alks, Charles E. Morreal, Oilip K. Sinha, Thomas L. Dao
Journal: JNCI Journal of the National Cancer Institute (1976)

The estrogen receptor binding properties of 3,9-dihydroxybenz[a]anthracene (3,9-diOHBA) were determined in uterine cytosol of immature Sprague-Dawley rats by competitive binding experiments with (3H]estradiol and sucrose density centrifugation. 3,9-DiOHBA inhibited estradiol binding to the 8S binding protein at a concentration (1.2×10−5M) approximately equal to that of nafoxidine-HCI (3×10−5M) required to inhibit estradiolspecific binding, and bioassay for estrogenic activity substantiated this finding.
Fatal Aeromonas bacteraemia in West Africa
Authors: Hong Zhang, Xiaohui Zou, Xiang Zhao, Liang Cai, Wenbing Chen, Lei Yang, Fuqiang Liu, Di Qin, Ge Zeng, Tian Bai, Wenfei Zhu, Dayan Wang, Yuelong Shu, Lidong Gao
Journal: Journal of Infection (2015)
Abstract 17936: Endotoxin Disrupts Circadian Rhythms in Macrophages via Reactive Oxygen Species
Authors: Yusi Wang, Paramita Pati, Feng Chen, David Stepp, Daniel Rudic, David Fulton
Journal: Circulation (2014)

Introduction:  The circadian clock helps to regulate the expression of a subset of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses is strongly regulated by a macrophage-intrinsic circadian clock.   Hypothesis:  We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in inflammatory cells can predispose to cardiovascular disease.   Methods and Results:  To investigate circadian rhythms in inflammatory cells, peritoneal macrophage were isolated from Per2-luciferase transgenic mice. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from Per2-luc mice while real-time PCR data suggested that the pattern of expression of the core circadian genes (Bmal1 and Per2) was disrupted. The ability of LPS to disrupt circadian rhythms was reduced by inhibitors of TLR4. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with TEMPOL or PEG-SOD mitigated LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of Nox5, a source of ROS, could significant disrupt circadian function in U2OS cells whereas iNOS, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration.   Conclusions:  These results suggest that pro-inflammatory stimuli can disrupt circadian rhythms in macrophages and that impaired circadian rhythms may contribute to cardiovascular diseases by altering macrophage behavior.
Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors.
Authors: I Rafi, A V Boddy, J A Calvete, G A Taylor, D R Newell, N P Bailey, M J Lind, M Green, J Hines, A Johnstone, N Clendeninn, A H Calvert
Journal: Journal of Clinical Oncology (1998)

PURPOSE A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects. METHODS In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition. RESULTS The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colorectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/ m2/d for 5 days. The half-life (t1/2) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose. CONCLUSION Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.
Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis
Authors: Giuliana Giardino, Vera Gallo, Domenico Somma, Emily G. Farrow, Isabelle Thiffault, Roberta D'Assante, Vittoria Donofrio, Mariateresa Paciolla, Matilde Valeria Ursini, Antonio Leonardi, Carol J. Saunders, Claudio Pignata
Journal: Journal of Allergy and Clinical Immunology (2015)
Public Health England denies conspiracy over obesity report’s timing
Authors: Adrian O’Dowd
Journal: BMJ (2015)

The head of Public Health England has flatly denied any “conspiracy” between his independent organisation and the government over the publication of a much anticipated report expected to help tackle the epidemic of obesity.

In an angry session of the parliamentary health committee held on Monday 19 October, MPs repeatedly took chief executive Duncan Selbie to task over Public Health England’s decision not to publish its review of evidence on how best to reduce the population’s sugar intake.

The television chef Jamie Oliver, also appearing before the committee, called on the government to be “big and bold” by introducing a tax on sugar sweetened drinks.

The committee was holding the session as part of its inquiry into the government’s imminent strategy on tackling childhood obesity.

Last week Sarah Wollaston, chair of the committee and Conservative MP for …
Merging alcohol giants threaten global health
Authors: J. Collin, S. E. Hill, K. E. Smith
Journal: BMJ (2015)

Alcohol has comparable health risks to tobacco but none of its pariah status

The world’s two largest beer manufacturers, Anheuser-Busch InBev (AB InBev) and SABMiller, have agreed in principle to merge. AB InBev, the Belgium based producer of global brands such as Budweiser, Corona, and Stella Artois will acquire London based SABMiller, brewer of Peroni, Miller, and Grolsch. At £70bn (€100bn; $106bn) this would be the third largest deal in corporate history, establishing a dominant position in the global beer market.1 Its completion depends on navigating the regulatory demands of competition policy in multiple jurisdictions. Yet the real importance of the deal is what it symbolises for the future of the global alcohol industry. Here we focus on its implications for the growing epidemic of alcohol related harm across low and middle income countries.

The health interest of this business story lies partly in the sheer scale of the merger. The new company will produce an estimated one third of all beer sold worldwide and will be market leader in 24 of the …
Threonine-145/Methionine-145 variants of baculovirus produced recombinant ligand binding domain of GPIbα express HPA-2 epitopes and show equal binding of von Willebrand factor
Authors: Chester Q. Li, Stephen F. Garner, Julian Davies, Peter A. Smethurst, Mark R. Wardell, Willem H. Ouwehand
Journal: Blood (2000)
Value-Based Cancer Care
Authors: Robert C. Young
Journal: New England Journal of Medicine (2015)

Interview with Dr. Peter Neumann on the use of various new value-based frameworks for assessing drugs and drug prices. (08:22)Download In the face of the growing cost of cancer care, the American Society of Clinical Oncology has published a proposed framework for assessing the value of cancer treatments, aiming to help physicians evaluate regimens on the basis of clinical benefit, toxicity, and cost.
Abstract 11935: Molecular and Cellular Mechanisms of Right Ventricular Remodeling in Pulmonary Hypertension
Authors: Suvd Nergui, Yoshihiro Fukumoto, Zhulanqiqige Do.e, Md. Elias-Al-Mamun, Hiroaki Shimokawa
Journal: Circulation (2013)

Background: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the roles of endothelial nitric oxide (NO) ...
Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice
Authors: Berno Dankbar, Michelle Fennen, Daniela Brunert, Silvia Hayer, Svetlana Frank, Corinna Wehmeyer, Denise Beckmann, Peter Paruzel, Jessica Bertrand, Kurt Redlich, Christina Koers-Wunrau, Athanasios Stratis, Adelheid Korb-Pap, Thomas Pap
Journal: Nature Medicine (2015)
Interstitial high dose rate (HDR) brachytherapy under local anesthesia for early stage prostate cancer
Authors: D. White, R. Mark, P. J. Anderson, T. Neumann, M. Nair
Journal: Journal of Clinical Oncology (2006)

14639 Background: Transrectal Ultrasound (TRUS) guided interstitial implant for prostate cancer using Low Dose Rate (LDR) and High Dose Rate (HDR) techniques has been reported with results comparing very favorably to external beam radiation therapy. TRUS interstitial implant of the prostate has been traditionally performed under general or spinal anesthetic in an operating room. We report our results with a technique performed under local anesthesia in a Department procedure room. Methods: Patients with T1 and T2 localized prostate cancer were judged to be candidates for TRUS guided interstitial implant. Results: Between 2002 and 2006, 248 TRUS guided prostate implants were performed under local anesthesia. Conscious sedation consisted of intravenous Morphine (12–22 mg) and Versed (6–14 mg), or intravenous Demerol (50–175 mg) and Versed (3–12 mg). Local anesthetic was given with a mixture of 1% Lidocaine, 0.25% Marcaine, 1:100,000 Epinephrine, and 4% Sodium Bicarbonate neutralizing solution (20–120 cc). Local anesthesia was given to a 5 × 5 cm perineal area to a depth of 10 cm under TRUS guidance. The implants were placed under mobile multi-plane prostate template (Radiation Therapy Products Prostate Template) guidance using from 3 to 4 planes, and 12 to 22 needles. Needle spacing was 1.0 cm. The implant procedure included sigmoidoscopy and cystoscopy. Median implant time was 45 minutes (range: 30 to 150 minutes). HDR treatment was given using the Nucletron afterloading system. The implant volume received 2,250 cGy in 3 fractions prescribed to the 100% Isodose line, given over 24 hours. Urethral dose points (12–16) were followed, and limited to ≤ 105% of the prescription dose. The procedure was well tolerated, with all patients having completed the procedure. One patient developed respiratory suppression, and required reversal with Narcan. He recovered uneventfully. Otherwise, there have been no acute complications to date. Conclusions: TRUS interstitial implant of the prostate under local anesthesia is feasible. Implant time and complications compare favorably to general or spinal anesthetic technique. No significant financial relationships to disclose.
PDGF regulation of Mcl-1 expression in bone-metastatic human prostate cancer cells
Authors: Shareen Iqbal, Daqing Wu, Nicole Johnson, Zhi-Ren Lui, S Edwards, Leland Chung
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3583 

Previous studies have shown that aberrant expression of platelet derived growth factor (PDGF) is correlated with human cancer progression. Overexpression of PDGF receptor (PDGFR) is implicated in the progression of prostate cancer (PCa) bone metastases. However, the role of PDGF signaling in prostate cancer cell growth and survival has not been well characterized. We studied the implication of PDGF signaling in an ARCaP human PCa progression model, which demonstrates epithelial to mesenchymal transition (EMT), and closely mimicking the clinical pathophysiology of human PCa bone metastasis. Treatment of metastatic ARCaPM cells with PDGFBB, an isoform of PDGF family, rapidly induced mRNA expression of myeloid cell leukemia-1 (Mcl-1), an antiapoptoic factor that has been correlated to higher Gleason grades and metastasis in clinical PCa specimens. Western blotting and reporter analyses confirmed PDGFBB as a novel regulator of Mcl-1 expression in PCa cells. Mechanistic study indicated that PDGF induction of Mcl-1 is mediated by a beta-catenin-dependent pathway. PDGFBB treatment induced rapid nuclear translocation of beta-catenin in ARCaPM cells. Further analyses suggested that beta-catenin signaling may be coupled with other transcriptional factors, i.e., cAMP-responsive element-binding protein (CREB) and T-cell factor 4 (TCF-4), to coordinately regulate Mcl-1 expression. Transient transfection of wild-type beta-catenin expression cDNA resulted in increased Mcl-1 expression, whereas a TCF-4 dominant negative cDNA effectively abrogated PDGFBB induction of Mcl-1 expression. In conclusion, these data demonstrate that activation of the PDGF-beta-catenin-Mcl-1 signaling may contribute to human PCa bone metastasis. Interruption of the Mcl-1 survival signal in addition to blocking the PDGF pathway may provide a novel target for the treatment of human PCa bone metastasis.
Disease-Specific Induced Pluripotent Stem Cells Recapitulate The Pathophysiology Of Familial Platelet Disorder With Predisposition To Acute Myelogenous Leukemia
Authors: Shunya Arai, Hiromitsu Iiduka, Naoya Takayama, Miyauchi Masashi, Kazuki Taoka, Keisuke Kataoka, Masataka Hosoi, Keiki Kumano, Koji Eto, Mineo Kurokawa
Journal: Blood (2013)
A statistical test that supports a human/chimpanzee clade based on noncoding DNA sequence data.
Authors: S A Williams, M Goodman
Journal: Molecular Biology and Evolution (1989)

Using the aligned DNA sequence data of Miyamoto et al. and Maeda et al., all noncoding genetic material, and a simple statistical test, we show that a Homo/Pan clade is supported at approximately the 3% level of significance. The method accommodates polymorphism and different evolutionary rates for different sites. All assumptions on which the statistical study is based are made explicit. (See the Note added in proof, which--adding recently published data--improves the significance level to about 1%.
Polymorphisms of Genes Involved in Glucose and Energy Metabolic Pathways and Prostate Cancer: Interplay with Metformin
Authors: Teemu J. Murtola, Tiina Wahlfors, Antti Haring, Kimmo Taari, Ulf-Håkan Stenman, Teuvo L.J. Tammela, Johanna Schleutker, Anssi Auvinen
Journal: European Urology (2015)
10-minute consultation: Gastro-oesophageal reflux disease
Authors: J. Jankowski
Journal: BMJ (2002)

This is part of a series of occasional articles on common problems in primary care A 45 year old man complains of heartburn (retrosternal burning) and regurgitation, usually after food but also at night, for six months. Symptoms are particularly bad after a heavy, fatty meal. Physical straining, bending, stooping, or lying flat also worsen the symptoms.