tbuckley/cabot-search huggingface dataset:
Dysfunctional activity of macrophages from tumor-bearing mice is reflected in a deficient production and decreased nuclear translocation of transcription factors NFκB and C/EBP
Authors: Marta Torroella-Kouri, Giselle Perry, Diana M. Lopez
Journal: Cancer Research (2005)

5309   Tumor progression is associated with the development of a profound state of immunosuppression in the host. In patients and animals bearing advanced tumors, both the innate and the adaptive immune defenses are impaired. Innate immunity represents the first line of protection against the development of tumors, and its actions are exerted through effector cells such as macrophages, polymorphonuclear (PMN) leukocytes, and NK cells. Earlier work from our laboratory has shown that BALB/c mice bearing large D1-DMBA-3 mammary tumors exhibit decreased expressions of nitric oxide (NO) and IL-12, two relevant inflammatory molecules produced by macrophages that are involved in anti-tumor responses. We have previously shown that NO is a major mediator of macrophages’ tumoricidal function. On the other hand, IL-12 is the main inducer of IFN-γ production by T and NK cells, and the most important factor in Th1 development in CD4 +  T cells, which, together with its anti-tumor properties, make this cytokine a crucial element in anti-tumor defenses. We have demonstrated a decreased expression of both iNOS and IL-12p40 genes in macrophages from tumor bearers. Two major transcription factors involved in the functions of the innate immune system and the inflammatory response, NFκB and C/EBP, show a decreased expression and binding activity to their respective promoter sites on the iNOS and IL-12p40 genes in macrophages from tumor-bearing mice. Importantly, a diminished nuclear translocation of these two transcription factors was observed, providing a molecular explanation for the dysfunctional production of iNOS and IL-12 in macrophages of tumor hosts in comparison to those from normal mice.
Abstract 14647: Stress Echocardiography Predicts Heart Failure Progression and Alters Management Strategies in Patients with Hypertrophic Cardiomyopathy
Authors: Ethan J Rowin, Barry J Maron, Iacopo Olivotto, Susan A Casey, Anna Arretini, Benedetta Tomberli, Ross Garberich, John R Lesser, Martin S Maron
Journal: Circulation (2014)

Background: One-third of HCM patients without left ventricular outflow tract obstruction under resting conditions have the propensity to develop an outflow gradient with physiologic exercise. However, the natural history and management implications of exercise-induced (i.e., provocable) obstruction is unresolved. Methods: We prospectively studied 533 consecutive HCM patients without outflow obstruction at rest (&lt;30mmHg) who underwent a symptom limiting stress (exercise) echocardiogram to assess development of outflow obstruction following physiologic provocation and followed for 6.5 ± 2.0 years. Of the 533 patients, obstruction ≥ 30 mmHg was present following exercise in 262 patients (49%; provocable obstruction), and was absent both at rest and with exercise in 271 (51%; nonobstructive). Results: Over the follow-up period, 43 out of 220 (20%) HCM patients with provocable obstruction and baseline NYHA class I/II symptoms developed progressive limiting heart failure symptoms to class III/IV, compared to 24 of 249 (10%) nonobstructive patients. Rate of heart failure progression was significantly greater in patients with provocable obstruction vs. nonobstructive patients (3.1%/year vs. 1.5%/year; RR=2.0, 95% CI of 1.3-3.2; p=0.003). However, the vast majority of patients with provocable obstruction who developed advanced heart failure symptoms achieved substantial improvement in symptoms to class I / II following relief of obstruction with invasive septal reduction therapy (n=30/32; 94%). In comparison, the majority of nonobstructive patients who developed advanced heart failure remained in class III/IV (16/24;67%), including 10 (42%) currently listed for heart transplant. Conclusions: Stress (exercise) echocardiogram identifies physiological provocable outflow tract obstruction in HCM, and is a predictor of future risk for progressive heart failure (3.1%/year), in patients who become candidates for invasive septal reduction therapy. Therefore, exercise echocardiography should be considered in all HCM patients without obstruction under resting conditions.
Methanol-based fixation is superior to buffered formalin for next-generation sequencing of DNA from clinical cancer samples
Authors: A.M. Piskorz, D. Ennis, G. Macintyre, T.E. Goranova, M. Eldridge, N. Segui-Gracia, M. Valganon, A. Hoyle, C. Orange, L. Moore, M. Jimenez-Linan, D. Millan, I.A. McNeish, J.D. Brenton
Journal: Annals of Oncology (2015)
Analgesic drug delivery via recombinant tissue plasminogen activator and microRNA-183-triggered opening of the blood-nerve barrier
Authors: Shaobing Yang, Susanne M. Krug, Johanna Heitmann, Liu Hu, Ann Kristin Reinhold, Solange Sauer, Judith Bosten, Claudia Sommer, Michael Fromm, Alexander Brack, Heike L. Rittner
Journal: Biomaterials (2015)
Cystic Fibrosis, Basic and Clinical Research
Journal: Thorax (1993)

Zanen, Rietveld of administration of oxygen and, if needed, corticosteroids.9'°R eports about health hazards of microwave ovens are few."PTFE is also used in non- stick plastic coated frying pans, which are reported to give the same toxic symptoms to both humans and birds after overheating.2Birds should preferably not therefore be kept in the kitchen.1 Wahrheit DB.Interspecies comparisons of lung responses to inhaled particles and gasses.
Downregulation of JAK3 Protein Levels in T Lymphocytes by Prostaglandin E2 and Other Cyclic Adenosine Monophosphate-Elevating Agents: Impact on Interleukin-2 Receptor Signaling Pathway
Authors: Vladimir Kolenko, Patricia Rayman, Biswajit Roy, Martha K. Cathcart, John O’Shea, Raymond Tubbs, Lisa Rybicki, Ronald Bukowski, James Finke
Journal: Blood (1999)
USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance
Authors: Jin-Ku Lee, Nakho Chang, Yeup Yoon, Heekyoung Yang, Heejin Cho, Eunhee Kim, Yongjae Shin, Wonyoung Kang, Young Taek Oh, Gyeong In Mun, Kyeung Min Joo, Do-Hyun Nam, Jeongwu Lee
Journal: Neuro-Oncology (2015)

Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.
Lymphatic and proinflammatory candidate gene variations and lymphedema.
Authors: Mei R. Fu, Deborah M. Axelrod, Amber Guth, Judith D. Goldberg, Xiaochun Li, Francis Cartwright, Judith Haber, Yvette Conley
Journal: Journal of Clinical Oncology (2013)

9 Background: Traditionally, breast cancer-related lymphedema is considered to be mainly due to the mechanical injury from cancer surgery. Recent research identified that inflammation-infection may be one of the important predictors for lymphedema. This pilot study aimed to explore the associations between lymphatic and pro-inflammatory candidate gene variations and lymphedema. Methods: A prospective, longitudinal, repeated-measure, and comparative design was used to recruit 178 breast cancer survivors. To ensure the accuracy of lymphedema phenotype, lymphedema was classified into lymphedema of arm and breast. Arm lymphedema must have been validated by infra-red perometer and a bioimpedance device. Breast lymphedema was validated by an observational scale since no objective measure is available. Saliva samples were collected for DNA extraction. Candidate Gene Association Research Method was used to examine the eight genes known for inflammation and lymphatic specific growth factors: cytokines (IL1A, IL6, IL8, IL10, IL13) and PTGS2 (COX2), and lymphatic specific growth factors [VEGF-C and D]. Descriptive statistics, Chi-Squared tests for contingency tables and one-way analysis of variance for continuous variables were used to compare the genotypes for each of these genes in patients with and without lymphedema. Odds ratios of developing lymphedema are estimated. Results: Among 178 survivors, 39 women were confirmed to have arm lymphedema and 43 women had breast lymphedema. Five genes were significantly associated with breast cancer-related lymphedema. Specific single nucleic polymorphisms (SNPs) for lymphatic specific growth factors VEGF-C (rs4604006) and cytokine IL13 (rs1800925) were related to arm lymphedema. Specific SNPs of cytokine IL1A (rs1800587) and PTGS2 (COX2) (rs20417) were associated with breast lymphedema. Conclusions: Our findings provided preliminary data on genetic susceptibility as a risk factor for breast cancer-related lymphedema. Findings of our study may serve as a preliminary foundation for a priori recognition of genetic risk that may facilitate lymphedema risk prediction prior to surgery and raises the potential for early intervention for a high-risk group.
Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells
Authors: Michele Cea, Antonia Cagnetta, Sophia Adamia, Chirag Acharya, Yu-Tzu Tai, Mariateresa Fulciniti, Hiroto Ohguchi, Aditya Munshi, Prakrati Acharya, Manoj K. Bhasin, Lei Zhong, Ruben Carrasco, Fiammetta Monacelli, Alberto Ballestrero, Paul Richardson, Marco Gobbi, Roberto M. Lemoli, Nikhil Munshi, Teru Hideshima, Alessio Nencioni, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2015)
Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients
Authors: Sean E. Collins, Philip M. Grant, Robert W. Shafer
Journal: Drugs (2015)

HIV-1-infected patients with suppressed plasma viral loads often require changes to their antiretroviral (ARV) therapy to manage drug toxicity and intolerance, to improve adherence, and to avoid drug interactions. In patients who have never experienced virologic failure while receiving ARV therapy and who have no evidence of drug resistance, switching to any of the acceptable US Department of Health and Human Services first-line therapies is expected to maintain virologic suppression. However, in virologically suppressed patients with a history of virologic failure or drug resistance, it can be more challenging to change therapy while still maintaining virologic suppression. In these patients, it may be difficult to know whether the discontinuation of one of the ARVs in a suppressive regimen constitutes the removal of a key regimen component that will not be adequately supplanted by one or more substituted ARVs. In this article, we review many of the clinical scenarios requiring ARV therapy modification in patients with stable virologic suppression and outline the strategies for modifying therapy while maintaining long-term virologic suppression.
Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066
Authors: E. L. Kwak, D. R. Camidge, J. Clark, G. I. Shapiro, R. G. Maki, M. J. Ratain, B. Solomon, Y. Bang, S. Ou, R. Salgia
Journal: Journal of Clinical Oncology (2009)

3509 Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule oral inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases that has not previously been tested in humans. A Phase 1 dose-escalation trial evaluating PF as an oral single agent was conducted to investigate safety, PK and PD in patients (pts) with advanced cancer (excluding leukemias). Methods: PF was administered under fasting conditions QD or BID on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 50 mg QD to 300 mg BID. Pts with advanced cancer were enrolled in the study. Results: Thirty-seven pts were enrolled into the dose escalation part of the study. Tumor types included colorectal, pancreatic, sarcoma, ALCL and NSCLC. The MTD was 250 mg BID. Three DLTs were observed: grade 3 increase in ALT (1 pt at 200 mg QD) and grade 3 fatigue (2 pts at 300 mg BID). The most common AEs were nausea, emesis, fatigue and diarrhea. Nausea and emesis were independent of dose or duration of treatment. Mean AUC (30–57% CV) and Cmax (36–69% CV) increased proportionally with dose from 100 mg QD to 300 mg BID. The median terminal half-life was 46 hours. A 2- to 4-fold increase in the oral midazolam (MDZ) AUC was observed following 28-days of PF dosing at 100 mg QD (n = 3) and 300 mg BID (n = 2), respectively, suggesting PF to be an inhibitor of CYP3A. Ten pts have entered an enriched RP2D cohort of pts with tumors harboring c-Met amplification/gene mutation or ALK fusion genes. There has been 1 confirmed PR in a sarcoma pt with ALK rearrangement (inflammatory myofibroblastic tumor). Among 10 NSCLC pts whose tumors harbor EML4-ALK rearrangement, 1 pt has had a PR, 2 pts have achieved unconfirmed PR and 4 pts have had SD (3 have experienced reduction in tumor burden by ∼20% in measurable lesions and 1 has been treated for 28 weeks). Conclusions: The MTD of PF is 250 mg BID. The major AEs were fatigue or GI-related, and all AEs were manageable and reversible. There was no evidence of non-linear PK at PF doses &gt;100 QD. Treatment with PF-02341066 resulted in promising clinical activity against tumors carrying activating ALK gene rearrangements. Further study of PF in pts with ALK-dependent tumors is warranted. [Table: see text]
Inhaled corticosteroid/long-acting beta-2 agonist (ICS/LABA) combination can decrease mortality of COPD patients, a nationwide population-based cohort study in Taiwan
Authors: Ming-Cheng Chan, Gin-Hen Lin
Journal: European Respiratory Journal (2012)

Background: Chronic Obstructive Pulmonary Disease (COPD) remains a major public health problem. Current treatments, including pharmacological and non-pharmalogical, can only alleviate symptoms, prevent exacerbation and improve quality of life. Previous large-scale studies failed to demonstrate benefit of mortality reduction which is also important for a chronic illness.  Objective: The aim of this study is to determine whether ICS/LABA combination can reduce mortality of COPD by using Taiwan National Health Insurance Database.  Method: This was a nationwide population-based cohort study. A total of 1989 COPD patients were identified from one million sampling cohort dataset between January to December in 2005. Patients with diagnosed in 2005 as COPD were grouped as non-controller use (n=1638), ICS/LABA (n=265) and LAMA (n=86). Cox regression model was used to evaluate the incidence of mortality and pneumonia in the following 3 years to December 2008.  Result: The incidence of pneumonia was not different among three groups. However, COPD patients with older age (H.R. 1.398 for every increase of 10 years, p   Conclusion: In the selected Taiwanese population, COPD mortality was lower among patients who used ICS/LABA. Incidence of pneumonia was not increased with ICS/LABA, but significantly related increased age and male gender.
Ordinary soap is as effective as antibacterial soap for handwashing, study finds
Authors: Jacqui Wise
Journal: BMJ (2015)

Antibacterial soap is no more effective than plain soap at reducing bacterial contamination when used in real life situations, a study published in the Journal of Antimicrobial Chemotherapy has found.1

Korean scientists examined the bactericidal effects of triclosan, the most commonly used ingredient in antibacterial soap, in two experiments. In the first laboratory experiment 20 bacterial strains …
A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation
Authors: Dirk S. Paul, Allison Jones, Rob S. Sellar, Neema P. Mayor, Andrew Feber, Amy P. Webster, Neuza Afonso, Ruhena Sergeant, Richard M. Szydlo, Jane F. Apperley, Martin Widschwendter, Stephen Mackinnon, Steven G. E. Marsh, J. Alejandro Madrigal, Vardhman K. Rakyan, Karl S. Peggs, Stephan Beck
Journal: Genome Medicine (2015)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95% CI = 0.96-0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.
Differential Inhibition of Human Atherosclerotic Plaque–Induced Platelet Activation by Dimeric GPVI-Fc and Anti-GPVI Antibodies
Authors: Janina Jamasbi, Remco T.A. Megens, Mariaelvy Bianchini, Götz Münch, Martin Ungerer, Alexander Faussner, Shachar Sherman, Adam Walker, Pankaj Goyal, Stephanie Jung, Richard Brandl, Christian Weber, Reinhard Lorenz, Richard Farndale, Natalie Elia, Wolfgang Siess
Journal: Journal of the American College of Cardiology (2015)

Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this receptor has selective antithrombotic potential. This study sought to compare compounds interfering with platelet GPVI–atherosclerotic plaque interaction to improve current antiatherothrombotic therapy. Human atherosclerotic plaque–induced platelet aggregation was measured in anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s, and 1,500/s). Inhibition by dimeric GPVI fragment crystallizable region of IgG (Fc) masking GPVI binding sites on collagen was compared with that of 3 anti-GPVI antibodies: BLO8-1, a human domain antibody; 5C4, a fragment antigen-binding (Fab fragment) of monoclonal rat immunoglobulin G; and m-Fab-F, a human recombinant sFab against GPVI dimers. GPVI-Fc reduced plaque-triggered platelet aggregation in static blood by 51%, BLO8-1 by 88%, and 5C4 by 93%. Under arterial flow conditions, BLO8-1 and 5C4 almost completely inhibited platelet aggregation while preserving platelet adhesion on plaque. Inhibition by GPVI-Fc, even at high concentrations, was less marked but increased with shear rate. Advanced optical imaging revealed rapid persistent GPVI-Fc binding to collagen under low and high shear flow, upstream and downstream of plaque fragments. At low shear particularly, platelets adhered in plaque flow niches to GPVI-Fc–free segments of collagen fibers and recruited other platelets onto aggregates via ADP and TxA2 release. Anti-GPVI antibodies inhibit atherosclerotic plaque-induced platelet aggregation under static and flow conditions more effectively than GPVI-Fc. However, potent platelet inhibition by GPVI-Fc at a higher shear rate (1,500/s) suggests localized antithrombotic efficacy at denuded or fissured stenotic high-risk lesions without systemic bleeding. The compound-specific differences have relevance for clinical trials targeting GPVI-collagen interaction combined with established antiplatelet therapies in patients with spontaneous plaque rupture or intervention-associated plaque injury.
The use of ADA liquid level in diagnosis of tuberculous pleurisy in countries with low incidence of tuberculosis
Authors: Perlat Kapisyzi, Dhimitraq Argjiri, Anila Aliko, Jeta Beli, Ylli Vakeflliu, Roland Kore, Elenka Shehu, Regina Hasa, Holta Tafa
Journal: European Respiratory Journal (2011)

The aim:  To study the use of cut off values of fluid ADA level in differential diagnosis of tuberculous pleurisy.   Materials and methods:  121 consecutive patients with pleural effusion were prospectively studied. The study included 82 males, 39 females with a mean age of 59.3±17 years. Exudative effusions were classified: malignant pleural effusions, 39 (39.8%), TB pleural effusions, 39 (39.8%), parapneumonic pleural effusions, 20 (20.4%).The photometric method was used.   Results:  In tuberculous group the mean of ADA level was 122.4±53.3UI/L, malignant effusion it was 59.7±31.7 UI/L (p= 0.0001) parapneumonic effusions 96±48UI/L.  Fluid ADA in 24/39 of malignant effusions and 18/20 parapneumonic effusions was above diagnostic cut-off 40 UI/L; in four of 39 tuberculous pleurisy ADA was under 40 UI/L. Mean ADA level was greater in patients   The sensitivity of ADA in TB effusions at cut-off > 40 U/L was 89.7%, specificity 28.8%, PPV 54.5%.  The cut-off value at 95 UI/L had the greatest YOUDEN index (0.488), best Lahr+ (3.4), the highest specificity, PPV 79.6%, and 69.2% respectively,sensibility 69.2%.   Conclusions:  In countries with low incidence of TB the diagnostic cut off value of ADA level have to be different from countries with high incidence.  The best cut off value of pleural fluid ADA level in diagnosis of TB was 95UI/L.In many cases ADA levels in non-tuberculous exudative pleural effusions exceeded the cut off values of tubercular disease (40 UI/L). Adenosine deaminase level of less than 40 U/L in patients
M17-02: Immunotherapy of extensive stage small cell lung cancer with dendritic cell based p53 vaccine
Authors: Scott Antonia, Noweeda Mirza, Alberto Chiappori, Ingo Fricke, Gerold Bepler, George Simon, William Janssen, Ji-hyun Lee, Kerstin Menander, Sunil Chada, Dmitry I. Gabrilovich
Journal: Journal of Thoracic Oncology (2007)