tbuckley/cabot-search huggingface dataset:
ET-63 * TARGETING THE EGFR-STAT-NF- B AXIS IN GLIOBLASTOMA
Authors: W. Weiss, Q.-W. Fan, A. Baldwin, R. Wong, K. Shokat
Journal: Neuro-Oncology (2014)

Amplification of the epidermal growth factor receptor (EGFR) is observed in ∼50% of glioblastoma tumors. Half of EGFR-amplified tumors in-turn harbor the EGFRvIII mutant, a tumor-associated allele of EGFR which signals constitutively in the absence of ligand. We have previously shown that EGFR and EGFRvIII are co-expressed in rare cells in co-amplified glioblastoma, and that co-expression drives progression through activated STAT signaling. Others have shown that EGFRvIII-expressing cells signal though NF-κB to activate adjacent EGFR-expressing cells, and that GBM without amplified EGFR activates NF-κB through monoallelic inactivation of IκBα, a negative regulator. Thus, NF-κB is likely critical for gliomagenesis. We and others have shown that STAT3 is important for glioma, and that STAT3 and NF-κB can cooperate to promote progression. We propose that the axis linking EGFR, NF-κB, and STAT is a critical driver of stemness and aggression in glioblastoma, and that targeting this axis using available and emerging clinical agents will improve survival. We demonstrate that co-expression of EGFR and EGFRvIII activates NF-κB in addition to STAT signaling. Blockade of STAT3 activates both EGFR and NF-κB. Inhibition of NF-κB blocks STAT3 but activates EGFR, and cooperates with EGFR inhibitors to shut down EGFR-NF-κB-STAT signaling. Thus, the EGFR-STAT3-NF-κB axis represents a critical axis for GBM, with complex feedback regulation thwarting attempts to block any single node. We hypothesize that targeting this axis using combinatorial, translatable approaches will suppress EGFR-STAT-NF-κB signaling, leading to improved outcome in patients. We will present data testing combination therapies, prioritizing existing and emerging clinical agents, to determine effects on signaling and on malignant progression, in tumors expressing EGFR or co-expressing EGFR with EGFRvIII.
Associations between peripheral neuropathy and nausea/vomiting in survivors of ovarian cancer: Evidence of persistent vagal neuropathies?
Authors: Heidi AS Donovan, Charles Horn, Grace Campbell, Teresa Hagan, Dana H. Bovbjerg
Journal: Journal of Clinical Oncology (2016)

165 Background: Persistent numbness and tingling in extremities are reported by many ovarian cancer survivors and are widely recognized symptoms of chemotherapy-induced peripheral neuropathy. Minimal research has addressed the possibility that chemotherapy may also result in vagal neuropathy, with associated adverse effects on somatosensory input to the brain. We hypothesize that ovarian cancer survivors with persistent numbness and tingling, hallmark symptoms of peripheral neuropathy, will report higher levels of nausea and vomiting, consistent with vagal neuropathy. Methods: A secondary analysis was conducted with data from 713 respondents to a survey of randomly selected members of the National Ovarian Cancer Coalition with a history of ovarian cancer. A validated questionnaire was used to assess symptom severity (0-10) at it worst over the past week for 22 commonly reported symptoms. For the present study, analyses were limited to women reporting no evidence of disease following chemotherapy (n = 362) at a mean of 50.3 months post-treatment. The mean age of the sample was 53.1y; 71.7% were married; 54.5% were college graduates. The symptom experiences of women with persistent numbness and tingling , N/T, (n = 206) were statistically compared to those without numbness and tingling (n = 156) with age and time since treatment included as covariates. Results: Ovarian cancer survivors with N/T had significantly higher levels of nausea (p &lt; 0.001) and vomiting (p &lt; 0.001), as well as several other symptoms consistent with vagal neuropathy, compared to women without N/T. Sensitivity analysis indicated that among women with the highest N/T severity (7-10), nausea severity was nearly three times higher than among women with the lowest levels of N/T severity (1-3), p &lt; 0.002. Conclusions: Consistent with the study hypothesis, ovarian cancer survivors with persistent numbness and tingling also reported higher levels of nausea and vomiting. These results suggest the importance of new research efforts to examine vagal neuropathy in ovarian cancer survivors.
Flexibility in trial enrolment decisions
Authors: Janet T Powell, Pinar Ulug
Journal: BMJ (2015)

We read the debate about patient consent in acute myocardial infarction trials with interest. 1 We randomly allocated critically ill patients with an admission diagnosis of ruptured abdominal aortic aneurysm to endovascular repair or open surgical repair. 2 Of the 652 patients approached for initial brief consent, 42 (6.4%)refused because they had a preference for no treatment or for a specific treatment.Six hundred and thirteen patients were randomised, 509 (83%) of whom provided brief witnessed verbal or written consent.A relative or carer provided consent for 44 (7%), and 60 (10%) were randomised using the Mental Capacity Act, with a clinician from outside the immediate management team confirming that this route was appropriate.For patients who survived until discharge, further full consent was obtained, and at this point 6/384 (2%) patients refused consent.It seems important to allow patients the option of immediate consent whenever possible (in our experience nearly all agree to participate) and to allow them to reconsider this decision when their health has improved.This type of flexible arrangement could also be used in acute myocardial infarction trials.
Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation
Authors: Hung D. Nguyen, Shilpak Chatterjee, Kelley M.K. Haarberg, Yongxia Wu, David Bastian, Jessica Heinrichs, Jianing Fu, Anusara Daenthanasanmak, Steven Schutt, Sharad Shrestha, Chen Liu, Honglin Wang, Hongbo Chi, Shikhar Mehrotra, Xue-Zhong Yu
Journal: Journal of Clinical Investigation (2016)

Alloreactive donor T cells are the driving force in the induction of graft-versus-host disease (GVHD), yet little is known about T cell metabolism in response to alloantigens after hematopoietic cell transplantation (HCT). Here, we have demonstrated that donor T cells undergo metabolic reprograming after allogeneic HCT. Specifically, we employed a murine allogeneic BM transplant model and determined that T cells switch from fatty acid β-oxidation (FAO) and pyruvate oxidation via the tricarboxylic (TCA) cycle to aerobic glycolysis, thereby increasing dependence upon glutaminolysis and the pentose phosphate pathway. Glycolysis was required for optimal function of alloantigen-activated T cells and induction of GVHD, as inhibition of glycolysis by targeting mTORC1 or 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) ameliorated GVHD mortality and morbidity. Together, our results indicate that donor T cells use glycolysis as the predominant metabolic process after allogeneic HCT and suggest that glycolysis has potential as a therapeutic target for the control of GVHD.
Endoscopic repair of complex pyloroduodenal stenosis resulting from post-transplant lymphoproliferative disorder
Authors: Alvaro Martínez-Alcalá, Juan Gutierrez, Klaus Mönkemüller
Journal: Endoscopy (2016)

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ or allogeneic hematopoietic stem cell transplantation with an incidence rate up to 11 % [1].
Carcinogenicity of Epoxides, Lactones, and Peroxy Compounds. V. Subcutaneous Injection in Rats&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: B. L. Van Duuren, L. Langseth, L. Orris, M. Baden, M. Kuschner
Journal: JNCI Journal of the National Cancer Institute (1967)

Twelve epoxides, lactones, and peroxy compounds were tested for carcinogenic activity by subcutaneous injection in rats. Three of these compounds induced sarcomas at the injection site. They are, in order of decreasing activity, glycidaldehyde, β-butyrolactone, and 2,2,4-trimethyl-3-hydroxy-3-pentenoic acid-β-lactone.
Oxygen demand and collateral vessels of the heart: Factors influencing the severity of myocardial ischaemic injury after experimental coronary artery occlusion
Authors: K. STEPHAN, W. MEESMANN, V. SADONY
Journal: Cardiovascular Research (1975)

Epicardial electrocardiographic maps were used to assess the effect of heart rate, myocardial contractility, and oxygen need on the severity of myocardial ischaemic injury after acute coronary artery occlusion in dogs. The experimental data indicate statistically significant dependence of the severity of ischaemia on heart rate, contractility, and oxygen need of the heart. These dependences are highly influenced by the spontaneous collateral vessels of the heart.
Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis
Authors: Darren Plant, Amy Webster, Nisha Nair, James Oliver, Samantha L. Smith, Steven Eyre, Kimme L. Hyrich, Anthony G. Wilson, Ann W. Morgan, John D. Isaacs, Jane Worthington, Anne Barton
Journal: Arthritis & Rheumatology (2016)

Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA.An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients.Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10(-8) and cg26401028, P = 1.69 × 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10(-7) and P = 1.05 × 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204).We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.
Utilization review of treatment for suicide attempters
Authors: L Kirstein, B Prusoff, M Weissman, D M Dressler
Journal: American Journal of Psychiatry (1975)

The authors describe an effort to develop criteria for utilization review of treatment for suicide attempters. Explicit criteria proposed by a panel of experts as essential determinants for hospitalization of these patients were compared with actual clinical practice. It was found that according to the experts' criteria (which were operationalized into rating assessments), over half of the outpatient sample should have been hospitalized. After multiple regression analysis was carried out on the criteria, however, four predictors showed that only 20 percent of the outpatients should have been hospitalized. The authors discuss the issues these findings raise about the criteria of the experts, their utility for research, their validity, and their implications for utilization review.
Dementia plan for England is unveiled
Authors: Jacqui Wise
Journal: BMJ (2016)

People as young as 40 will be given information about dementia at their NHS Health Check, as part of a pilot scheme announced by the government.

The scheme is contained in the implementation plan for the Prime Minister’s Challenge on Dementia 2020 , which aims to make England the best country in the world for dementia care and research.1 The plan builds on progress made since the first challenge document was issued in 2012.

Under the plan, clinical commissioning groups will publish Ofsted-style ratings on the diagnosis and quality of dementia care in their area, and the Care Quality Commission will include standards of dementia care in its inspections. The plan recommends …
Successful Immunotherapy against a Transplantable Mouse Squamous Lung Carcinoma with Anti–PD-1 and Anti-CD137 Monoclonal Antibodies
Authors: Arantza Azpilikueta, Jackeline Agorreta, Sara Labiano, José Luis Pérez-Gracia, Alfonso R. Sánchez-Paulete, M. Angela Aznar, Daniel Ajona, Ignacio Gil-Bazo, Marta Larrayoz, Alvaro Teijeira, María E. Rodriguez-Ruiz, Ruben Pio, Luis M. Montuenga, Ignacio Melero
Journal: Journal of Thoracic Oncology (2016)
Response to Letter Regarding Article, “Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate”
Authors: Jeffrey J. Goldberger, Rishi Arora, David Green, Philip Greenland, Daniel C. Lee, Donald M. Lloyd-Jones, Michael Markl, Jason Ng, Sanjiv J. Shah
Journal: Circulation (2016)
Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination
Authors: Anne-Sophie Thomas-Claudepierre, Isabelle Robert, Pedro P. Rocha, Ramya Raviram, Ebe Schiavo, Vincent Heyer, Richard Bonneau, Vincent M. Luo, Janardan K. Reddy, Tilman Borggrefe, Jane A. Skok, Bernardo Reina-San-Martin
Journal: The Journal of Experimental Medicine (2016)

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to Ig switch regions (S regions). During CSR, the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers, and S regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. In this study, we show that Med1 and Med12, two subunits of the mediator complex implicated in transcription initiation and long-range enhancer/promoter loop formation, are dynamically recruited to the IgH locus enhancers and the acceptor regions during CSR and that their knockdown in CH12 cells results in impaired CSR. Furthermore, we show that conditional inactivation of Med1 in B cells results in defective CSR and reduced acceptor S region transcription. Finally, we show that in B cells undergoing CSR, the dynamic long-range contacts between the IgH enhancers and the acceptor regions correlate with Med1 and Med12 binding and that they happen at a reduced frequency in Med1-deficient B cells. Our results implicate the mediator complex in the mechanism of CSR and are consistent with a model in which mediator facilitates the long-range contacts between S regions and the IgH locus enhancers during CSR and their transcriptional activation.
Uridine triacetate for prevention of 5FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency.
Authors: M. K. Bamat, R. Tremmel, S. F. Eberwine, R. Garcia, J. A. Saydoff, R. von Borstel
Journal: Journal of Clinical Oncology (2011)

e19560 Background: Dihydropyrimidine dehydrogenase (DPD) catalyzes degradation of 5-fluorouracil (5FU). Patients with complete or partial DPD deficiency (0.1 and 3% of the population, respectively) can experience severe or lethal toxicities to 5FU, and impaired clearance may underlie many of the 1300 US 5FU toxicity deaths each year. Uridine triacetate prevents or diminishes toxicities when orally administered after 5FU overexposure, and has been used successfully as an investigational antidote in >50 patients following accidental overdoses. Methods: A colorectal cancer patient experienced Grade 3 and 4 GI and hematologic toxicities after a 96 hour infusion of 1000 mg/m2 5FU and was found to be DPD deficient (double mutation). The patient subsequently tolerated 50 and 100 mg 5FU bolus treatments in a modified FOLFOX regimen. However, during the second cycle, this DPD-deficient patient inadvertently received 1000 mg 5FU in 1 minute. Life-threatening toxicity was expected. Treatment with uridine triacetate (10 g q6h for 20 total doses) began within 8 hours. Results: In marked contrast to his first exposure to 5FU, the patient experienced no mucositis or additional cytopenia. Preclinical and mechanistic data predicted and support this observation. In a mouse model of DPD deficiency using ethynyluracil (2 mg/kg i.p.), a standard therapeutic 5FU dose of 100 mg/kg i.p. was lethal. Treatment with oral uridine triacetate (2 g/kg t.i.d. x 5 d) starting 2, 24 or 72 hours after 5FU resulted in 100%, 80% or 70% survival, respectively. Conclusions: Timely treatment with uridine triacetate appeared to prevent severe 5FU toxicity in a DPD-deficient patient and reduced mortality in DPD-inhibited mice receiving 5FU. Uridine triacetate has been shown previously to protect patients (and mice) from 5FU toxicities following 5FU overdose. Therefore, DPD-deficient patients who have received 5FU should also benefit from uridine triacetate treatment if the overexposure is identified soon enough after 5FU dosing. Therapeutic monitoring of 5FU during or after infusions would permit rapid detection of 5FU overexposure due to DPD-deficiency or other clearance defects, enabling the use of uridine triacetate as a potential antidote.
Culture of bullying at Birmingham hospital prevented staff from reporting high cardiac death rates
Authors: Gareth Iacobucci
Journal: BMJ (2016)

An NHS hospital under investigation for its high mortality rates from cardiac surgery saw a culture of bullying develop that prevented staff from speaking out against poor care, a damning report has found.

The report, from the Care Quality Commission (CQC),1 detailed the findings of an inspection at University Hospitals Birmingham NHS Foundation Trust, which was ordered after more patients died from cardiac surgery at the Queen Elizabeth Hospital than would have been expected.

As The BMJ reported last week,2 the hospital was told to submit weekly returns on its cardiac surgery mortality after the inspection in December 2015.

In the final report published on 8 March, the CQC said …
A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects
Authors: Saswata Talukdar, Yingjiang Zhou, Dongmei Li, Michelle Rossulek, Jennifer Dong, Veena Somayaji, Yan Weng, Ronald Clark, Adhiraj Lanba, Bryn M. Owen, Martin B. Brenner, Jeffrey K. Trimmer, Kathryn E. Gropp, Jeffrey R. Chabot, Derek M. Erion, Timothy P. Rolph, Bryan Goodwin, Roberto A. Calle
Journal: Cell Metabolism (2016)
Platelet Storage Pool Deficiency: Establishment Of Reference Ranges For Platelet Dense Granule Count By Transmission Electron Microscopy
Authors: Cindy B. Uhl, Ryan L. Barness, Mary C. Olson, Susan C. Gossman, Sibel Erdogan, Scott I. Gamb, Jon E. Charlesworth, Ravi Lingineni, Sandra C. Bryant, Randall S. Miller, Jeffery L. Salisbury, William L. Nichols, James G. White, Dong Chen
Journal: Blood (2013)
Abstract P150: Aldosterone Dysregulation Increases Cardiovascular Risk in African-American Youth
Authors: Gregory A Harshfield, Evan Mulloy, Melinda Beavers
Journal: Circulation (2012)

Background: The prevalence of hypertension and blood pressure-related target organ damage in African-Americans is among the highest in the world. We hypothesize that this is in part due to aldosterone dysregulation among African-Americans beginning in youth and leading to the early development of cardiovascular disease in this population. To begin to test this hypothesis, we examined ethnic differences in aldosterone regulation in normal, healthy adolescents. Methods: The subjects in this study were 145 (60 Caucasian, 85 African-American) healthy, normotensive youth aged 15–19 years. Testing was performed following 72 hours on a controlled sodium diet. Testing consisted of the collection of aldosterone, systolic blood pressure (SBP), and urinary sodium excretion (U Na V) during continuous water intake (400 ml total) over a 2 hour period. An echocardiogram was also performed to measure target organ changes. Log transformations were performed on aldosterone levels prior to analyses. Results: African-American compared to Caucasian subjects had higher casual SBP (109±10 v 104±10; p=.006) and relative wall thickness (0.32±.03 v 0.34±.04; p=.003). During the testing procedure African-Americans also had lower levels of aldosterone (4.78±.6 v 4.35±.6 pg/ml; p =.001). In the Caucasian subjects only, aldosterone was inversely correlated with U Na V (r=−0.427; p=.001) and U Na V was positively correlated with SBP (r=0.356; p=.001). The subjects were divided into those in the upper and lower quartiles of salt intake for further analysis. The interaction between race and salt intake was significant for aldosterone (F=7.173; p=.008). Caucasian subjects with high salt intake had lower aldosterone (4.56±.59 v 5.02±0.59 pg/ml). However, aldosterone levels did not differ by salt intake in African-Americans. Summary and Conclusion: African-American subjects did not show the expected associations between aldosterone and the pressure natriuresis relation. Furthermore, African-Americans on the high salt intake failed to suppress aldosterone. These findings are consistent with our hypothesis that aldosterone dysregulation in youth may lead to the early development of cardiovascular disease in Africans-Americans.
A new eosinophilic esophagitis (EoE)-like disease without tissue eosinophilia found in EoE families
Authors: A. Straumann, C. Blanchard, S. Radonjic-Hoesli, Ch. Bussmann, P. Hruz, E. Safroneeva, D. Simon, A. M. Schoepfer, H.-U. Simon
Journal: Allergy (2016)

Background Eosinophilic esophagitis (EoE) is a rapidly emerging, chronic inflammatory, genetically impacted disease of the esophagus, defined clinically by symptoms of esophageal dysfunction and, pathologically, by an eosinophil-predominant tissue infiltration. However, in four EoE families, we have identified patients presenting with EoE-typical and corticosteroid-responsive symptoms, but without tissue eosinophilia. The aim of this study was to clinically and immunologically characterize these patients with EoE-like disease. Methods Five patients suffering from an EoE-like disease were evaluated with endoscopic, histologic, functional, and quantitative immunohistological examinations, and mRNA expression determination. Results The frequency of first-generation offspring of patients affected by EoE or EoE-like disease was 40%. Immunofluorescence analysis confirmed an almost complete absence of eosinophils in the esophageal tissues of patients with EoE-like disease, but revealed a considerable T-cell infiltration, comparable to EoE. In contrast to EoE, eotaxin-3 mRNA and protein were markedly reduced in EoE-like disease (P < 0.05). The mRNA expression levels of three selected EoE genes (eotaxin-3, MUC4, and CDH26) allowed to discriminate between EoE-like disease, EoE, and normal epithelium. Conclusions Patients suffering from 'EoE without eosinophilia' do not fulfill formally the diagnostic criteria for EoE. However, their clinical manifestation, immunohistology, and gene expression pattern, plus the fact that they bequeath EoE to their offspring, suggest a uniform underlying pathogenesis. Conventional EoE, with its prominent eosinophilia, therefore appears to be only one phenotype of a broader 'inflammatory dysphagia syndrome' spectrum. In this light, the role of the eosinophils, the definition of EoE, and its diagnostic criteria must likely be reconsidered.