tbuckley/cabot-search huggingface dataset:
Tobacco smoking and arsenic exposure are associated with tumor suppressor gene hypermethylation in bladder cancer
Authors: Carmen J. Marsit, Margaret Karagas, Hadi Danaee, Mei Liu, Angeline Andrew, Alan Schned, Karl T. Kelsey
Journal: Cancer Research (2005)

2215  Over 60,000 new cases of bladder cancer will be diagnosed this year in the United States. Tobacco use, occupational exposures (particularly to aromatic amines), and exposure to arsenic are all etiologically related to bladder cancer, although the pattern of somatic alterations attributable to these exposures remains unclear. Our lab and others have observed associations between tobacco-smoke exposure and epigenetic silencing of specific tumor suppressors, through promoter hypermethylation, in lung cancer. Associations between carcinogenic exposures and epigenetic silencing of tumor suppressor genes may yield critical understanding of the mechanistic roles of these exposures in carcinogenesis. To identify the relationship of promoter hypermethylation of specific tumor suppressor genes to known etiologic risk factors of the disease, we investigated a series study of bladder cancer derived from a case-control study of bladder cancer in New Hampshire. This study is unique due to its population-based approach, thereby reducing bias in the sampling of tumors. In 360 cases, promoter hypermethylation of CDKN2A, DAPK, RARB, RASSF1A, CDH1, and CDH13 were determined utilizing methylation-specific PCR. The prevalence of hypermethylation for each gene was: RASSF1A 33%, CDKN2A 31%, CDH13 18%, RARB 15%, DAPK 9%, and CDH1 3%. Controlling for age and sex, hypermethylation of CDKN2A occurred more than twice as often in ever-smokers compared to non-smokers (O.R. 2.55 95% C.I. 1.19-5.47) and was associated with invasive tumors (O.R.1.69, 95% C.I. 1.03-2.78). Hypermethylation of RASSF1A, controlling for age and sex, was positively associated with invasive tumors (O.R. 2.86, 95% C.I. 1.54-5.31), TP53 alterations (O.R 2.03, 95% C.I. 1.06-3.87), and arsenic exposure, measured by toenail arsenic (O.R. 3.30, 95% C.I. 1.14-9.54). Both RASSF1A and CDKN2A strongly related to bladder cancer invasiveness making these candidates for determining patient prognosis. The relationship between smoking and CDKN2A methylation provides additional evidence that tobacco carcinogens induce epigenetic silencing or act to select silenced cells which produce altered clonal fields. Finally, the association between RASSF1A methylation and high level arsenic exposure suggests a novel mechanism of carcinogenicity for this non-mutagenic metal. Additional analyses will define relationships between these various epigenetic alterations. Specifically, we will investigate if there is evidence, in bladder cancer, for a CpG island methylator phenotype, similar to that described in other tumor types.
Reply
Authors: Anna S. Lok, William G. Powderly
Journal: Hepatology (2019)

Potential conflict of interest: Dr. Lok advises and received grants from Gilead. She received grants from Bristol‐Myers Squibb. Dr. Powderly consults for and received grants from Merck. He consults for Gilead. We are disappointed that the Cochrane group remains unconvinced that sustained virologic response (SVR) is a validated surrogate outcome and that direct‐acting antiviral agents (DAAs) have been demonstrated to improve clinical as well as patient‐reported outcomes in patients with chronic hepatitis C. Since our commentary in 2017, there have been many more studies supporting the benefits of SVR and DAA therapies, including a decline in patients added to the waiting list for liver transplantation for hepatitis C. We recognize that randomized controlled trial is the gold standard for showing the benefits of treatments, but given the robust evidence from clinical trials and observational studies all over the world, we do not believe that it is ethical to contemplate withholding clinically proven beneficial therapy. We stand by our associations' recommendations that all patients with chronic hepatitis C should be treated.
Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics
Authors: Zong Sheng Guo, Binfeng Lu, Zongbi Guo, Esther Giehl, Mathilde Feist, Enyong Dai, Weilin Liu, Walter J. Storkus, Yukai He, Zuqiang Liu, David L. Bartlett
Journal: Journal for ImmunoTherapy of Cancer (2019)

Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.
Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response
Authors: Yongjun Sui, George K. Lewis, Yichuan Wang, Kurt Berckmueller, Blake Frey, Amiran Dzutsev, Diego Vargas-Inchaustegui, Venkatramanan Mohanram, Thomas Musich, Xiaoying Shen, Anthony DeVico, Timothy Fouts, David Venzon, James Kirk, Robert C. Waters, James Talton, Dennis Klinman, John Clements, Georgia D. Tomaras, Genoveffa Franchini, Marjorie Robert-Guroff, Giorgio Trinchieri, Robert C. Gallo, Jay A. Berzofsky
Journal: Journal of Clinical Investigation (2019)

It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose. Surprisingly, vaccinated animals exhibited no anti-gp120 humoral responses above background and Gag- and Env-specific T cells were induced but failed to correlate with viral acquisition. Instead, vaccine-induced gut microbiome alteration and myeloid cell accumulation in colorectal mucosa correlated with protection. Ex vivo stimulation of the myeloid cell-enriched population with SHIV led to enhanced production of trained immunity markers TNF-α and IL-6, as well as viral coreceptor agonist MIP1α, which correlated with reduced viral Gag expression and in vivo viral acquisition. Overall, our results suggest mechanisms involving trained innate mucosal immunity together with antigen-specific T cells, and also indicate that vaccines can have critical effects on the gut microbiome, which in turn can affect resistance to infection. Strategies to elicit similar responses may be considered for vaccine designs to achieve optimal protective efficacy.
Mosaic DNMT3A Germline Mutation As a Model for Mutant DNMT3A Competitive Advantage in the Blood Lineage
Authors: Ayala Tovy, Hyun Jung Park, Jaime M. Reyes, Anna Guzman, Rachel E. Rau, Aaron Jeffries, Mill Jonnathan, Emma Baple, Andrew Crosby, Mia Petljak, Henry Lee-Six, Heng Wang, Xin Baozhong, Mathijs A. Sanders, Peter J. Campbell, Michael Stratton, Wei Li, Margaret Goodell
Journal: Blood (2018)
People with mental illness are most at risk of losing benefits, study shows
Authors: Gareth Iacobucci
Journal: BMJ (2019)

People who are mentally ill are more than twice as likely to lose their existing benefits than claimants with a physical condition, a study has shown.1

Researchers from the University of York analysed government data of around 320 000 claimants aged 16 to 64 with either a physical or mental health condition who had been reassessed from an existing Disability Living Allowance (DLA) entitlement for transfer to Personal Independence Payments (PIP) between April 2013 and October 2016.

The results, to be published in the British Journal of Psychiatry next month, show that claimants with …
Long-term Association of 13-Valent Pneumococcal Conjugate Vaccine Implementation With Rates of Community-Acquired Pneumonia in Children
Authors: Naïm Ouldali, Corinne Levy, Philippe Minodier, Laurence Morin, Sandra Biscardi, Marie Aurel, François Dubos, Marie Alliette Dommergues, Ellia Mezgueldi, Karine Levieux, Fouad Madhi, Laure Hees, Irina Craiu, Chrystèle Gras Le Guen, Elise Launay, Ferielle Zenkhri, Mathie Lorrot, Yves Gillet, Stéphane Béchet, Isabelle Hau, Alain Martinot, Emmanuelle Varon, François Angoulvant, Robert Cohen
Journal: JAMA Pediatrics (2019)

<h3>Importance</h3> In several countries, 5 years after 13-valent pneumococcal conjugate vaccine (PCV13) implementation, serotype replacement has been reported for invasive pneumococcal disease, which raises concerns about the long-term outcome of PCV13 implementation. The long-term effect of vaccination on community-acquired pneumonia (CAP) remains unknown. <h3>Objective</h3> To assess the long-term outcome of PCV13 implementation on CAP in children. <h3>Design, Setting, and Participants</h3> This quasi-experimental, population-based, interrupted time-series analysis was based on a prospective multicenter study conducted from June 2009 to May 2017 in 8 French pediatric emergency departments. All patients 15 years and younger with chest radiography–confirmed CAP were included. <h3>Exposures</h3> Community-acquired pneumonia. <h3>Main Outcomes and Measures</h3> The number of CAP cases per 1000 pediatric emergency department visits over time, analyzed usingasegmented regression model, adjusted for influenza-like illness syndromes. <h3>Results</h3> We enrolled 12 587 children with CAP, including 673 cases of CAP with pleural effusion (5.3%), 4273 cases of CAP requiring hospitalization (33.9%), 2379 cases of CAP with high inflammatory biomarkers (18.9%), and 221 cases of proven pneumococcal CAP (1.8%). The implementation of PCV13 in 2010 was followed by a sharp decrease in the frequency of CAP (−0.8% per month [95% CI, −1.0% to −0.5% per month]), from 6.3 to 3.5 cases of CAP per 1000 pediatric emergency department visits until May 2014, then a slight increase since June 2014 (0.9% per month [95% CI, 0.4%-1.4% per month]), until 3.8 cases of CAP per 1000 pediatric emergency department visits in May 2017. There were marked immediate decreases in cases of CAP with pleural effusion (−48% [95% CI, −84% to −12%]), CAP requiring hospitalization (−30% [95% CI, −56% to −5%]), and CAP with high inflammatory biomarkers (−30% [95% CI, −54% to −6%]), without any rebound thereafter. <h3>Conclusions and Relevance</h3> The changes associated with PCV13 use 7 years after implementation remain substantial, especially for CAP with pleural effusion, CAP requiring hospitalization, and CAP with high inflammatory biomarkers. Emerging non-PCV13 serotypes may be less likely involved in severe CAP than invasive pneumococcal disease.
A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis
Authors: Hila Doron, Tobias Pukrop, Neta Erez
Journal: Cancer Research (2019)

Brain metastases are more common than primary CNS tumors and confer grave prognosis on patients, as existing treatments have very limited efficacy. The tumor microenvironment has a central role in facilitating tumorigenesis and metastasis. In recent years, there has been much progress in our understanding of the functional role of the brain metastatic microenvironment. In this review, we discuss the latest advances in brain metastasis research, with special emphasis on the role of the brain microenvironment and neuroinflammation, integrating insights from comparable findings in neuropathologies and primary CNS tumors. In addition, we overview findings on the formation of a hospitable metastatic niche and point out the major gaps in knowledge toward developing new therapeutics that will cotarget the stromal compartment in an effort to improve the treatment and prevention of brain metastases.
698. Effective Depletion of Pre-Existing Anti-AAV Antibodies Requires Broad Immune Targeting
Authors: Haiyan Fu, Aaron S. Meadows, Victoria Velazquez, Marybeth Camboni, Ricardo Pineda, F. Jason Duncan, Christopher M. Walker, Douglas M. McCarty
Journal: Molecular Therapy (2016)

Pre-existing antibodies (Abs) poses a critical challenge for the translation of gene therapy approaches using viral vectors, especially AAV, which is widespread in humans. It is known that very complex anatomical niches, molecular signals and cellular components are required for the development, priming and survival of Ab producing plasma cells (PCs), and the maintenance of Ab production. We therefore hypothesize that overcoming pre-existing Abs requires broad immune targeting. In preliminary studies, we generated a mouse model of pre-existing AAV9-Abs by an IP injection of 1e10vg rAAV9 vector, and tested multiple immunosuppressants (IS), including proteasome inhibitor Bortezomib (Bort), m-TOR inhibitor rapamycin (Rap) and the classical broad IS agent prednisolone (Pred), individually or in combination at routine clinical doses for humans. As a result, we have identified an effective approach combining Rap and Pred, that led to significant reduction in serum AAV9-Abs, by 70-80% at 4wk and 85-93% at 8wk of treatment. Flow cytometry and ELISpot showed that Rap+Pred treatment led to significant decreases in bone marrow B cell and PC frequency, and in the frequency of IgG-secreting and AAV9-specific Ab-producing PCs. Splenocyte analyses of Rap+Pred treated mice showed significantly reduced frequencies of class-switched (IgD−IgG+) B cells, and of CD4+ T cells expressing the co-inhibitory receptor programmed death 1 (PD-1). While the mechanisms remain unclear, our data indicate that Rap+Pred may have selective inhibitory effects on both T helper type 2 support of B cell activation in the spleen, and on PC survival in the bone marrow, leading to effective depletion of pre-existing AAV9-Abs. This promising immunomodulation approach for depleting pre-existing Abs is highly translatable to clinical applications. Ongoing efforts are to identify the optimal Rap+Pred regimen for maximal effect and minimal risk of potential side effects.
Impact of Depression or Anxiety on Opioid and Benzodiazepine Use in Hospitalized Hematopoietic Stem Cell Transplantation (HSCT) Recipients
Authors: Madiha Iqbal, Aaron C. Spaulding, Chanel Wood, Salman Ahmed, Prachi Jani, Rami Manochakian, Aneel Paulus, Mohamed A Kharfan-Dabaja, Ernesto Ayala, Sikander Ailawadhi, Asher A. Chanan-Khan, Shehzad Niazi, Taimur Sher
Journal: Blood (2018)
PACE chronic fatigue trial was properly conducted, says UK research watchdog
Authors: Nigel Hawkes
Journal: BMJ (2019)

The PACE trial, which compared treatments for chronic fatigue syndrome, met all the regulatory requirements of its day and exceeded transparency requirements, the Health Research Authority has concluded.1

The judgment came in the form of a letter from Jonathan Montgomery, chair of the HRA, to Norman Lamb, chair of the House of Commons Science and Technology Committee. A member of the committee, Carol Monaghan, had raised the issue with Montgomery when he gave evidence on research integrity to its inquiry last year.

Although the HRA’s intervention will come as a comfort to the team that led the trial and to the Medical Research Council, which funded it, it is unlikely to put to bed a longstanding campaign by activists to discredit it.

PACE was a trial led by Peter White of Queen Mary University of London that compared four treatments for chronic fatigue syndrome. Its conclusions, published in the Lancet in 2011,2 found that cognitive behavioural therapy and graded exercise therapy worked better than adaptive …
Abstract P2-05-04: The WNT pathway gene, LBH, is critically required for breast carcinogenesis by promoting tumor initiation and survival
Authors: K Garikapati, P Chen, K Ashad-Bishop, K Briegel
Journal: Cancer Research (2019)

Abstract Background: Cancer stem cells (CSCs) are a small subset of tumor cells with stem cell properties that drive tumor initiation, treatment resistance, and metastasis, thereby leading to rapid disease relapse. However, no cancer stem cell specific treatments are currently available in the clinic. Thus, there is a need to identify novel cancer stem cell-specific molecular targets. LBH (Limb-Bud and Heart), is a poorly characterized transcription co-factor in the WNT pathway, a signaling network that is key to normal stem cell control and cancer stem cell transformation. We previously identified LBH as a basal mammary stem cell specific marker critically required for stem cell self-renewal and maintenance during normal mammary gland development. Significantly, LBH is also abnormally over-expressed specifically in worst prognosis basal-like breast cancers, a treatment-resistant breast cancer subtype that is enriched in cancer stem cells. Moreover, high inter-tumor LBH expression levels correlate with reduced metastasis-free patient survival and increased chemo-resistance. However, the role of LBH in breast carcinogenesis is not known. Results: To identify the potential role of LBH in breast carcinogenesis, we abrogated LBH expression in breast cancer cell lines with high CSC populations (HCC1395, MDA-MB-231) using shRNA and CRISPR/Cas technologies. Conversely, we stably introduced LBH into more differentiated breast cancer cell lines with low CSC populations (MCF7, BT549). We found that LBH depletion significantly reduced, while LBH overexpression increased in vitro tumor sphere formation and clonogenic ability, suggesting LBH promotes a CSC phenotype. Modulation of LBH expression did not change proliferation rates, indicating the CSC promoting effects of LBH were not due to increased cell proliferation. However, LBH reduced apoptosis rates and increased tumor cell survival. Importantly, loss of LBH markedly decreased in vivo tumor initiation and metastatic potential of triple negative breast cancer cells, which are important functions of CSC. The underlying mechanisms will be discussed. Conclusions: Collectively our results suggest that LBH is required for breast CSC self-renewal and maintenance. Thus, LBH inhibition may have value for future CSC-targeted anti-cancer therapy. Citation Format: Garikapati K, Chen P, Ashad-Bishop K, Briegel K. The WNT pathway gene, LBH, is critically required for breast carcinogenesis by promoting tumor initiation and survival [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-04.
TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism
Authors: Hirokazu Takahashi, Christiano R. R. Alves, Kristin I. Stanford, Roeland J. W. Middelbeek, Pasquale Nigro, Rebecca E. Ryan, Ruidan Xue, Masaji Sakaguchi, Matthew D. Lynes, Kawai So, Joram D. Mul, Min-Young Lee, Estelle Balan, Hui Pan, Jonathan M. Dreyfuss, Michael F. Hirshman, Mohamad Azhar, Jarna C. Hannukainen, Pirjo Nuutila, Kari K. Kalliokoski, Søren Nielsen, Bente K. Pedersen, C. Ronald Kahn, Yu-Hua Tseng, Laurie J. Goodyear
Journal: Nature Metabolism (2019)
Abstract 16653: Does Late Gadolinium Enhancement Identify the Patients at Risk in Childhood Hypertorophic Cardiomyopathy? A Multicenter Study
Authors: Seiko Ide, Lars Grosse-Wortmann, Lee Benson, Dariusz Mroczek, Raymond H Chan
Journal: Circulation (2017)

Background: Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in the young. Late gadolinium enhancement (LGE) seen on contrast-enhanced cardiovascular magneti...
Sphingosine-1-Phosphate Receptor 3 (S1PR3) Promotes Myeloid Commitment of Human Hematopoietic and Leukemic Stem Cells
Authors: Stephanie Zhi-Juan Xie, Kerstin Kaufmann, Olga I. Gan, Elisa Laurenti, Stanley W.K. Ng, Qiang Liu, Melissa Kleinau, Joseph Jargostf, Gareth Holmes, Chiara Luberto, Lina M Obeid, Yusuf A. Hannun, Jean C.Y. Wang, Mark D. Minden, John E. Dick
Journal: Blood (2018)
Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery system for antitumor application
Authors: Qing Xia, Yongtai Zhang, Zhe Li, Xuefeng Hou, Nianping Feng
Journal: Acta Pharmaceutica Sinica B (2019)

Erythrocytes (red blood cells, RBCs) are the most abundant circulating cells in the blood and have been widely used in drug delivery systems (DDS) because of their features of biocompatibility, biodegradability, and long circulating half-life. Accordingly, a "camouflage" comprised of erythrocyte membranes renders nanoparticles as a platform that combines the advantages of native erythrocyte membranes with those of nanomaterials. Following injection into the blood of animal models, the coated nanoparticles imitate RBCs and interact with the surroundings to achieve long-term circulation. In this review, the biomimetic platform of erythrocyte membrane-coated nano-cores is described with regard to various aspects, with particular focus placed on the coating mechanism, preparation methods, verification methods, and the latest anti-tumor applications. Finally, further functional modifications of the erythrocyte membranes and attempts to fuse the surface properties of multiple cell membranes are discussed, providing a foundation to stimulate extensive research into multifunctional nano-biomimetic systems.
Strong Dose-response Using a Conjunctival Provocation Test During a Phase II Allergen Immunotherapy Study With Subcutaneously Administered Tyrosine Adsorbed Modified Grass Allergen + MPL
Authors: Rachel Ballard, Stefan Zielen, Werner Aberer, Sabine Lassmann, Anette Wade, Karolin Kluehr, Jennifer Raab, Denise Lee, Chris Jones, Kulasari Gunawardena, Matthias Kramer, Murray A. Skinner, Tim Higenbottam
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 16627: Predicting Vascular Complications in Transcatheter Aortic Valve Replacement (TAVR) Using Computed Tomography Angiography (CTA)
Authors: Akhil Parashar, Shikhar Agarwal, Dhruv K Modi, Kanhayia L Poddar, William Stewart, Lars Svensson, Eric Roselli, Paul Schoenhagen, E Murat Tuzcu, Samir R Kapadia, Amar Krishnaswamy
Journal: Circulation (2013)

Background: Vascular complications are frequent during trans-femoral (TF)-TAVR. 3D CTA may provide a more thorough assessment of the vasculature than 2D angiography for patient selection. Methods: ...