tbuckley/cabot-search huggingface dataset:
Epstein−Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas
Authors: Eleni Anastasiadou, Dina Stroopinsky, Stella Alimperti, Alan L Jiao, Athalia R Pyzer, Claudia Cippitelli, Giuseppina Pepe, Martina Severa, Jacalyn Rosenblatt, Marilena P Etna, Simone Rieger, Bettina Kempkes, Eliana M Coccia, Shannan J Ho Sui, Christopher S Chen, Stefania Uccini, David Avigan, Alberto Faggioni, Pankaj Trivedi, Frank J Slack
Journal: Leukemia (2018)

Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein−Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.
Abstract 414: Broad range chromosomal abnormality detection through Bionano genome mapping
Authors: Alex R. Hastie
Journal: Cancer Research (2018)

Abstract Current methods for detection of balanced structural variation can be broken down into two categories: traditional cytogenetics and molecular methods. Cytogenetics may include chromosomal karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray and adaption of them. Molecular methods primarily include NGS sequencing based methods. Bionano genome mapping, an optical mapping approach in a NanoChannel array system, is a method that combines the advantages of different categories while solving many of the limitations. Compared to cytogenetics, Bionano mapping is high throughput and removes manual interpretation, it also has much higher resolution, detecting balanced events as small as about 30 kbp compared to multi-megabases needed for cytogenetic approaches, and unbalanced events starting at 1 kbp. NGS based methods often are limited by read lengths that cannot provide unambiguous information across repeat elements longer than individual reads. This limitation results in significantly reduced sensitivity for balanced variation and abnormalities as well as for insertions and even some categories of larger deletions. This is particularly true in highly medically relevant locations where segmental duplications mediate chromosomal abnormalities. Genome mapping using Bionano Genomics' Saphyr System offers high-throughput, genome-wide visualization of extremely long DNA molecules in their native form. It allows researchers to interrogate genomic structural variations (SVs) in the range of one kilobase pair and above. We present several in silico and biological validation experiments that demonstrate the sensitivity and specificity of Bionano mapping for the detection of insertions, deletions, inversions and translocations compared to benchmark studies using short read and long read sequencing. We also show a new direct labeling method that dramatically improves assembly contiguity such that chromosome arms can be assembled into single maps. Bionano mapping is a fast and cost effective method for the detection of a broad range of traditionally refractory SVs across the human genome. Citation Format: Alex R. Hastie. Broad range chromosomal abnormality detection through Bionano genome mapping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 414.
Abstract 1620: ATR inhibition for the treatment of ATM-deficient gastric cancer
Authors: Mu-Yan Cai, Hunter D. Reavis, Jie-Wei Chen, Chirag Ganesa, Bose Kochupurakkal, Geoffrey I. Shapiro, Alan D. D'Andrea
Journal: Cancer Research (2018)

Abstract ATM and ATR are central kinases in the cellular response to DNA damage and play a crucial role in maintaining genome integrity. Inactivation of ATM has been observed in multiple tumor types and pre-clinical studies suggest that inhibition of ATR is synthetic-lethal in ATM-deficient tumors. More than 10% of gastric cancers carry potentially deleterious mutations in ATM and patients with ATM-deficient gastric cancers could potentially benefit from ATR inhibitor-based therapy. This study focuses on establishing the critical parameters for clinical development of ATR inhibitors in treating gastric cancer. First, we tested the cytotoxic response to ATR inhibition of ATM-deficient and ATM-complemented derivative of human fibroblasts. Next, we utilized a panel of gastric cancer cell lines that represent the spectrum of ATM mutations and ATM expression levels to further confirm the correlation between reduced ATM activity and the cytotoxic effects of ATR inhibition. Third, we evaluated the effect of a series of missense and truncating mutations in ATM that were identified in The Cancer Genome Atlas (TCGA) project. Finally, we developed an immunohistochemistry (IHC) assay to assess the expression level of ATM in gastric tumor samples. Our results confirmed that ATM-deficient human fibroblasts were acutely sensitive to ATR inhibition compared to ATM-complemented cells. Acute sensitivity to ATR inhibition was also observed in gastric cancer cell lines that carry deleterious mutations in ATM and in those that express very low levels of ATM. Complementation experiments with mutant versions of the ATM ORF using ATM-deficient human fibroblasts identified deleterious mutations in ATM that sensitize to ATR inhibition. The IHC assay was applied to a cohort of 208 primary gastric cancers. ATM expression was undetectable in approximately 11% of the samples; an additional 26% expressed very low levels. Our findings suggest that ATR inhibition may elicit favorable responses in gastric cancer patients with tumors harboring deleterious ATM mutations or very low levels of ATM expression. Targeted exon-sequencing methods that are used widely combined with IHC for ATM may be useful for patient selection. Citation Format: Mu-Yan Cai, Hunter D. Reavis, Jie-Wei Chen, Chirag Ganesa, Bose Kochupurakkal, Geoffrey I. Shapiro, Alan D. D'Andrea. ATR inhibition for the treatment of ATM-deficient gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1620.
Reviving the FDA’s Authority to Publicly Explain Why New Drug Applications Are Approved or Rejected
Authors: Matthew Herder
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers
Authors: Muhammad Umair Mushtaq, Athanasios Papadas, Adam Pagenkopf, Evan Flietner, Zachary Morrow, Sibgha Gull Chaudhary, Fotis Asimakopoulos
Journal: Journal for ImmunoTherapy of Cancer (2018)

Recent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1). ICIs have been reported to have activity against a broad range of tumor types, in both solid organ and hematologic malignancy contexts. However, less than one-third of the patients achieve a durable and meaningful treatment response. Expression of immune checkpoint ligands (e.g., PD-L1), mutational burden and tumor-infiltrating lymphocytes are currently used as biomarkers for predicting response to ICIs. However, they do not reliably predict which patients will benefit from these therapies. There is dire need to discover novel biomarkers to predict treatment efficacy and to identify areas for development of combination strategies to improve response rates. Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating each step of the cancer-immunity cycle. Here we review tumor matrix dynamics and matrix remodeling in context of anti-tumor immune responses and immunotherapy and propose the exploration of matrix-based biomarkers to identify candidates for immune therapy.
Latest legal challenge to tobacco plain packaging is rejected by the World Trade Organization
Authors: Adrian O’Dowd
Journal: BMJ (2018)

Complaints by four countries that the introduction of plain packaging of tobacco products in Australia violated international trade have been rejected by the World Trade Organization (WTO).

On 28 June, a WTO panel said it was ruling against complaints brought by the tobacco producing countries of Cuba, Dominican Republic, Honduras, and Indonesia who had argued plain packaging was infringing on trademarks and intellectual property rights.

In 2012, Australia was the first country to fully implement plain tobacco packaging, also known as standardised packaging, which prohibits the use of logos, colours, brand images, and promotional information on tobacco …
Spatial Modeling to Identify Sociodemographic Predictors of Hydraulic Fracturing Wastewater Injection Wells in Ohio Census Block Groups
Authors: Genevieve S. Silva, Joshua L. Warren, Nicole C. Deziel
Journal: Environmental Health Perspectives (2018)

Background: Hydraulically fractured wells produce 2–14 million liters of wastewater, which may contain toxic and radioactive compounds. The wastewater is predominantly disposed of using Class II injection wells. Objective: Our objective was to evaluate the relationship between sociodemographic characteristics and injection well locations in Ohio. Methods: Using state and federal data sources, we classified Ohio census block groups by presence of injection wells, number of hydraulically fractured wells, sociodemographic factors (median household income, % white, population density, % ≥high school education, median age, voter turnout), and geographic information (land area, water area, situated over shale). We modeled the odds of having at least one injection well within a block group with respect to all covariates using three multivariable models incorporating different spatial components to account for similarities in neighboring block groups. Results: In bivariate analyses, block groups with injection wells (n=156) compared with those without (n=9,049) had lower population density (71 vs. 2,210 people/mi2 or 27 vs. 854 people/km2), larger median area (43.5 vs. 1.35 km2), higher median age (42.8 vs. 40.2 y), and higher % white (98.1% vs. 92.1%). After adjustment using a spatial logistic regression model, the odds of a block group containing an injection well were 16% lower per $10,000 increase in median income [odds ratio(OR)=0.837; 95% credible interval (CI): 0.719, 0.961] and 97% lower per 1,000 people/mi2 (or per 386 people/km2) increase (OR=0.030; 95% CI=0.008, 0.072). Block groups on shale and those containing fewer hydraulically fractured wells were more likely to include an injection well. Percentage white, median age, % ≥high school education, and % voter turnout were not significant predictors of injection well presence. Conclusion: In Ohio, injection wells were inversely associated with block groups' median incomes after adjusting for other sociodemographic and geographic variables. Research is needed to determine whether residents in census blocks with injection wells face increased risk of chemical exposures or adverse health outcomes. https://doi.org/10.1289/EHP2663
Factors Associated With Participation in Cardiac Episode Payments Included in Medicare’s Bundled Payments for Care Improvement Initiative
Authors: Andrew S. Oseran, Sydney E. Howard, Daniel M. Blumenthal
Journal: JAMA Cardiology (2018)

Medicare's Bundled Payments for Care Improvement (BPCI) is a voluntary pilot program evaluating bundled payments for several common cardiovascular conditions. Evaluating the external validity of this program is important for understanding the effects of bundled payments on cardiovascular care.To determine whether participants in BPCI cardiovascular bundles are representative of US acute care hospitals and identify factors associated with participation.Retrospective cross-sectional study of hospitals participating in BPCI model 2 bundles for acute myocardial infarction (AMI), congestive heart failure (CHF), coronary artery bypass graft, and percutaneous coronary intervention and nonparticipating control hospitals (October 2013 to January 2017). The BPCI participants were identified using data from the Centers for Medicare and Medicaid Services, and controls were identified using the 2013 American Hospital Association's Survey of US Hospitals. Hospital structural characteristics and clinical performance data were obtained from the American Heart Association survey and Centers for Medicare and Medicaid Services. One hundred fifty-nine hospitals participating in BPCI model 2 cardiac bundles and 1240 nonparticipating control hospitals were compared, and a multivariable logistic regression was estimated to identify predictors of BPCI participation.Bundled payments.Hospital-level structural characteristics and 30-day risk-adjusted readmission and mortality rates for AMI and CHF.Compared with nonparticipants, BPCI participants were larger, more likely to be privately owned or teaching hospitals, had lower Medicaid bed day ratios (ratio of Medicaid inpatient days to total inpatient days: 17.0 vs 19.3; P < .001), and were less likely to be safety net hospitals (2.5% vs 12.3%; P < .001). The BPCI participants had higher AMI and CHF discharge volumes, were more likely to have cardiac intensive care units and catheterization laboratories, and had lower risk-standardized 30-day mortality rates for AMI (13.7% vs 16.6%; P = .001) and CHF (11.3 vs 12.4; P = .005). In multivariable analysis, larger hospital size and access to a cardiac catheterization laboratory were positively associated with participation. Being a safety net hospital was negatively associated with participation (odds ratio, 0.3; 95% CI, 0.1-0.7; P = .001).Hospitals participating in BPCI model 2 cardiac bundles differed in significant ways from nonparticipating hospitals. The BPCI outcomes may therefore have limited external validity, particularly among small and safety net hospitals with limited clinical cardiac services.
Phase I clinical study of glypican-3 peptide vaccine in patients with advanced hepatocellular carcinoma
Authors: Tetsuya Nakatsura
Journal: Cancer Research (2008)

2834   We previously reported that Glypican-3 (GPC3) is uniquely overexpressed in human hepatocellular carcinoma and melanoma and that it is an ideal tumor antigen for immunotherapy in mouse models. We recently identified both HLA-A24  (A*2402)  and H-2K d  restricted GPC3 298-306  (EYILSLEEL) and HLA-A2  (A*0201)  -restricted GPC3 144-152  (FVGEFFTDV), both of which can induce GPC3-reactive cytotoxic T cells (CTLs).  Preclinical study in a mouse model:  BALB/c mice were intradermally vaccinated at the base of the tail with K d -restricted GPC3 298-306  peptide mixed with incomplete Freund9s adjuvant (IFA), CpG, αGalCer or aluminum, but only the peptide emulsified in IFA induced peptide-specific CD8 +  T cells. Furthermore proteomic analyses showed that IFA protected the peptide against degradation in the human serum. Peptide-reactive CTLs were induced by peptide vaccine in a dose-dependent manner. In addition, compared with the proportion of CTLs elicited by one to four vaccinations at 7-day intervals, and induction of GPC3 298-306 -specific CTLs required for at least two vaccinations with a single dose > 10 μg. Repeated vaccination with a lower dose of GPC3 298-306  did not induce peptide-specific CTLs. Similarly, induction of an Ag-specific immune response by HLA-A2 GPC3 144-152  depended on the dose administered.  The results of this study suggested that IFA is an indispensable adjuvant for peptide-based immunotherapy, and that the immunological effect of peptide vaccine depends on the dose of peptide injected. We devised a schedule based on these results.  Phase I clinical study:  After approval of IRB of National Cancer Center, we started the phase I clinical study of GPC3 peeptide vaccine for patients with advanced HCC. Patients were intradermally injected with an GPC3 peptide emulsified with Montanide ISA51 adjuvant at 0.3, 1.0, or 3.0 mg per body 3 times at 2-week intervals, with toxicity and immunological responses as the principal endopoints and clinical responses as the secondary endopoint. For the present, 8 patients received GPC3 vaccinations at 0.3 mg per body, and 6 of the 8 patients completed GPC3 vaccination protocol with three injections of GPC3 peptides. Toxicity only consisted of local erythema at the GPC3 vaccine injection sites. As for immunological response, we found the increase of the GPC3 peptide-specific CTLs in 10 6  PBMCs of all 8 patients by ELISPOT assay, and found DTH-positive in two of 8 patients. Furthermore, 3 of 6 cases ended evaluation showed stable disease (SD). Other 3 cases showed progressive disease. After this phase I study, we are planning phase II study of GPC3 peptide vaccine for patients with cured HCC, and prevention study for Chronic hepatitis and Liver Cirrhosis patients.
Cause‐specific mortality in patients with psoriasis and psoriatic arthritis
Authors: L. Skov, S.F. Thomsen, L.E. Kristensen, R. Dodge, M.S. Hedegaard, J. Kjellberg
Journal: British Journal of Dermatology (2018)

There are limited data regarding causes of mortality in patients with psoriasis or psoriatic arthritis (PsA).This retrospective cohort study evaluated the risk and leading causes of mortality in patients with psoriasis or PsA.Individuals with a hospital-based diagnosis of PsA or psoriasis were identified using the Danish National Patient Registry. Matched control individuals were identified from the general population. The main outcome measures were risk of death and cause-specific mortality in patients with psoriasis or PsA.Death rates per 1000 patient-years (with 95% confidence intervals) vs. controls were 22·3 (19·7-24·9) vs. 13·9 (11·8-16·0) for patients with psoriasis and 10·8 (8·9-12·8) vs. 11·6 (9·6-13·6) for patients with PsA. Survival, according to stratified hazard ratios (HRs), was significantly lower in patients with psoriasis than in controls (HR 1·74, P < 0·001), but not in patients with PsA (HR 1·06, P = 0·19). Significantly increased risk of death was observed in patients with psoriasis vs. controls due to a number of causes; the highest risks were observed for diseases of the digestive system; endocrine, nutritional and metabolic diseases; and certain infectious and parasitic diseases (HRs 3·61, 3·02 and 2·71, respectively). In patients with PsA, increased mortality was observed only for certain infectious and parasitic diseases (HR 2·80) and diseases of the respiratory system (HR 1·46). Patients with psoriasis died at a younger age than controls (mean age 71·0 vs. 74·5 years, P < 0·001).Patients with severe psoriasis have increased mortality risk compared with matched controls, due to a number of causes. Evidence to support an increased risk for patients with PsA was less convincing.
Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial
Authors: Abdenour Nabid, Nathalie Carrier, André-Guy Martin, Jean-Paul Bahary, Céline Lemaire, Sylvie Vass, Boris Bahoric, Robert Archambault, François Vincent, Redouane Bettahar, Marie Duclos, Marie-Pierre Garant, Luis Souhami
Journal: European Urology (2018)
Abstract 772: High MDC1 expression in cervical cancer cells can affect the chemo- and radiotherapeutic response as its depletion leads to increased cell death
Authors: Neeru Singh, Rashmi Bhakuni, Sivapriya Kirubakaran
Journal: Cancer Research (2018)

Abstract Cervical cancer is the third most frequent cancer and common cause of death in women worldwide. The work presented identifies mediator of DNA damage checkpoint 1 (MDC1) as an important molecular target to increase sensitivity of cervical cancer cells to chemo or radiotherapy. MDC1 functions as an adaptor protein for recruitment and retention of many other DNA damage repair proteins in ataxia telangiectasia mutated (ATM) pathway for double-stranded DNA damage repair. It is reported to be highly expressed in cervical cancer cells. Also, its expression tends to increase with increase in malignancy. We have studied in detail MDC1 mRNA expression in three cervical cancer cell lines, HeLa, SiHa and CasKi, in response to various genotoxic stresses including some known inhibitors, UV exposure or gamma irradiation through quantitative PCR. The cellular response to the DNA damage resulted in increase in MDC1 expression, which declined with increase in treatment time period. Protein expression and activation by Western blotting with anti-MDC1 and anti-phosphoMDC1 antibody indicated a higher level of phosphorylated as compared to unphosphorylated MDC1. The significance of this increase in MDC1 expression was studied by generating stable cell lines knocked down for MDC1 expression. The modified cell lines were assessed for apoptosis through various assays, including flow cytometry, and showed greater cell death in response to DNA damage. In summary, high MDC1 expression can significantly affect chemo or radiotherapeutic response and its inhibition can improve sensitivity to these treatments. Citation Format: Neeru Singh, Rashmi Bhakuni, Sivapriya Kirubakaran. High MDC1 expression in cervical cancer cells can affect the chemo- and radiotherapeutic response as its depletion leads to increased cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 772.