tbuckley/cabot-search huggingface dataset:
PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer
Authors: Constantia Pantelidou, Olmo Sonzogni, Mateus De Oliveria Taveira, Anita K. Mehta, Aditi Kothari, Dan Wang, Tanvi Visal, Michelle K. Li, Jocelin Pinto, Jessica A. Castrillon, Emily M. Cheney, Peter Bouwman, Jos Jonkers, Sven Rottenberg, Jennifer L. Guerriero, Gerburg M. Wulf, Geoffrey I. Shapiro
Journal: Cancer Discovery (2019)

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8+ T-cell infiltration and activation in vivo, and that CD8+ T-cell depletion severely compromises antitumor efficacy. Olaparib-induced T-cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-deficient compared with HR-proficient TNBC cells and in vivo models. CRISPR-mediated knockout of STING in cancer cells prevents proinflammatory signaling and is sufficient to abolish olaparib-induced T-cell infiltration in vivo. These findings elucidate an additional mechanism of action of PARP inhibitors and provide a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. SIGNIFICANCE: This work demonstrates cross-talk between PARP inhibition and the tumor microenvironment related to STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8+ T-cell recruitment and antitumor efficacy. The data provide insight into the mechanism of action of PARP inhibitors in BRCA-associated breast cancer.This article is highlighted in the In This Issue feature, p. 681.
Abstract P292: Re-evaluation of the Relations of Egg Consumption to Serum Total Cholesterol, Cause-specific and All-cause Mortality
Authors: Yasuyuki Nakamura, Tomonori Okamura, Yoshikuni Kita, Katsuyuki Miura, Akira Okayama, Hirotsugu Ueshima
Journal: Circulation (2017)

Background: We previously reported that egg consumption was related to age-adjusted serum total cholesterol (TCH), and all-cause mortality in the 1-2-eggs/wk group was significantly lower than that in the 1-egg/d group in women, whereas no such relations were noted in men, using 14 year follow-up of NIPPON DATA80. Re-evaluation of these relations in a different cohort is needed. Methods: We analyzed the relations of egg consumption to serum total cholesterol (TCH) and cause-specific and all-cause mortality by using the NIPPON DATA90 database with a 15-year follow-up. At the baseline in 1990, a nutritional survey was performed by using the food-frequency method, and data were collected on study participants, ages 30 years and over, from randomly selected areas in Japan. We followed 4,799 female participants without history of stroke or myocardial infarction (mean age 52.8 y) for 15 years. Results: The participants were categorized into 5 egg consumption groups on the basis of their responses to a questionnaire (seldom, 1-2/wk, 1/2 d, 1/d, and ≥2/d). There were 218, 1507, 1622, 1409, and 43 women in each of the 5 groups, respectively. Age-adjusted TCH was not related to egg consumption (206.4, 206.3, 207.0, 207.7, and 203.8 mg/dL in the 5 egg consumption categories, respectively, P=0.737, analysis of covariance). There were 199 cardiovascular disease (CVD), 221 cancer, and 642 all-cause mortality during follow-up. Cox analysis, adjusted for confounding factors, found that all-cause and cancer mortality in the ≥2/d group were significantly higher than that in the 1-egg/d group (HR in the ≥2/d vs the 1-egg/d group: all-cause, 1.88 [95%CI: 1.12-3.16]; cancer, 2.77 [1.32-5.80]), and that cancer mortality in the 1-2-eggs/wk group was significantly lower than that in the 1-egg/d group (0.70 [0.50-0.99]). Egg consumption was not associated with CVD mortality. Conclusions: Loss of the relation of egg consumption to TCH might be due to that hypercholesterolemic individuals avoided eating eggs. Positive association of egg consumption with cancer and all-cause mortality needs further evaluation, and it may indicate that limiting egg consumption has some health benefits, at least in women in Japan.
THER-35. TARGETED DUAL DRUG DELIVERY USING NON-TOXIC CARBON DOTS AS A NANOCARRIER FOR PEDIATRIC BRAIN TUMORS
Authors: Regina Graham, Sajini Hettiarachchi, Piumi Liyanage, Yiqun Zhou, Roger Leblanc, Steven Vanni
Journal: Neuro-Oncology (2019)

Notable obstacles to successful treatment of pediatric brain tumor patients include the presence of the blood brain barrier (BBB), tumor heterogeneity and the development of drug resistance. Nanotechnology-based drug delivery systems (DDS) have the potential to overcome these obstacles and improve outcomes by delivering chemotherapies through the BBB directly to brain tumor cells. To develop a brain tumor targeted dual DDS, we utilized non-toxic carbon dots (C-dots) as the nanocarriers. C-dots were functionalized transferrin as the targeting ligand and the chemotherapies epirubicin and temozolomide via the classical EDC/NHS coupling reaction. The cytotoxicity of the C-dot conjugates (targeted and non-targeted, single and dual drug) was evaluated in the pediatric brain tumor cell lines SJGBM2, CHLA200 (both GBM) and CHLA266 (ATRT). The non-targeted dual drug conjugated C-dots induced more cell death in all cell lines compared to either single drug conjugate. A concentration of 10uM reduced cell viability by 79–93% to depending on the cell line with SJGBM2 cells being the most sensitive. Furthermore, the increased cell death was more than additive suggestive of synergy. The addition of transferrin increased cytotoxicity of the dual drug conjugated C-dots by 100 to 1000 fold. The dual drug transferrin conjugate reduced viability by over 80% at concentrations ranging between 0.01uM to 0.1uM with again SJGBM2 cells being the most sensitive. To date most nanoparticle DDS deliver a single chemotherapy, this potentially can lead to treatment resistance and patient relapse. To address this issue, we have successfully developed brain tumor targeted dual drug delivery system. Our data indicates that non-toxic C-dots are an excellent platform in which multiple drugs and a targeting ligand(s) can be covalently conjugated and both the drugs and the ligand remain functional. Such C-dot DDS represents a promising therapeutic strategy for the treatment of pediatric brain tumors. PEDIATRIC BRAIN TUMOR MODELS
Injectable stem cell-laden supramolecular hydrogels enhance in situ osteochondral regeneration via the sustained co-delivery of hydrophilic and hydrophobic chondrogenic molecules
Authors: Jianbin Xu, Qian Feng, Sien Lin, Weihao Yuan, Rui Li, Jinming Li, Kongchang Wei, Xiaoyu Chen, Kunyu Zhang, Yanhua Yang, Tianyi Wu, Bin Wang, Meiling Zhu, Rui Guo, Gang Li, Liming Bian
Journal: Biomaterials (2019)
Prediction of lymph node metastatic status in superficial esophageal squamous cell carcinoma using an assessment model combining clinical characteristics and pathologic results: A retrospective cohort study
Authors: Yue Zhou, Junjie Du, Yiqiu Wang, Hai Li, Guoqiang Ping, Jinhua Luo, Liang Chen, Shijiang Zhang, Wei Wang
Journal: International Journal of Surgery (2019)
Impact of bronchial colonization with Candida spp. on the risk of bacterial ventilator-associated pneumonia in the ICU: the FUNGIBACT prospective cohort study
Authors: Jean-Francois Timsit, Carole Schwebel, Lenka Styfalova, Muriel Cornet, Philippe Poirier, Christiane Forrestier, Stéphane Ruckly, Marie-Christine Jacob, Bertrand Souweine
Journal: Intensive Care Medicine (2019)
Safety of guselkumab in patients with psoriasis treated through 100 weeks
Authors: K. Reich, K.A. Papp, A.W. Armstrong, Y. Wasfi, S. Li, Y.K. Shen, B. Randazzo, M. Song, A.B. Kimball
Journal: British Journal of Dermatology (2019)

Psoriasis is a long‐term skin condition that causes extra skin cells to form scaly red plaques that can be itchy and painful. Guselkumab is a biologic drug that blocks a molecule linked to psoriasis, interleukin‐23, and is approved for the treatment of psoriasis. Two large clinical trials (called VOYAGE 1 and VOYAGE 2) showed that guselkumab was more effective than adalimumab (another biologic treatment for psoriasis) and was safe to use for a year. Because psoriasis is a disease which reoccurs, understanding the safety of newer treatments over long periods of time is important. Therefore, VOYAGE 1 and VOYAGE 2 were extended to five years. The study designs were the same, with three treatment groups, guselkumab, placebo followed by guselkumab, or adalimumab, for the first six months. Then, depending on the study, patients were switched from one treatment to the other at different times during the next year and/or remained on the same treatment through two years. Rates of safety events, including common adverse events (unwanted side effects), serious adverse events, serious infections, malignancies (cancers), and major adverse cardiovascular events were calculated across studies to assess the safety of each treatment. Because of the complicated study design, data were compared in different ways: (1) one year versus two years of guselkumab treatment, and (2) before versus after transition from adalimumab to guselkumab. Results showed that cumulative safety event rates after two years of guselkumab treatment were generally consistent with those after one year. No safety concerns were found for adalimumab‐treated patients after they switched to guselkumab. In summary, guselkumab is safe for both longer‐term treatment for up to two years and after transition from adalimumab in patients with psoriasis.
Host-response-based gene signatures for tuberculosis diagnosis: A systematic comparison of 16 signatures
Authors: Hayley Warsinske, Rohit Vashisht, Purvesh Khatri
Journal: PLoS Medicine (2019)

The World Health Organization (WHO) and Foundation for Innovative New Diagnostics (FIND) have published target product profiles (TPPs) calling for non-sputum-based diagnostic tests for the diagnosis of active tuberculosis (ATB) disease and for predicting the progression from latent tuberculosis infection (LTBI) to ATB. A large number of host-derived blood-based gene-expression biomarkers for diagnosis of patients with ATB have been proposed to date, but none have been implemented in clinical settings. The focus of this study is to directly compare published gene signatures for diagnosis of patients with ATB across a large, diverse list of publicly available gene expression datasets, and evaluate their performance against the WHO/FIND TPPs.
RESULTS OF A COLORECTAL SCREENING PROGRAMME BELOW THE FIT THRESHOLD OF 100 NG/ML (20UG/G)
Authors: DJ Matias, L Rodríguez Martín, C Villar Lucas, R Quiñones Castro, R Pérez Fernández, R Diez Rodríguez, M Jiménez Palacios, F Jorquera Plaza, S Vivas Alegre
Journal: Endoscopy (2019)

The CRC screening programmes based on the immunological FOBT/FIT (faecal occult blood test) among asymptomatic subjects between 50 – 69 years old have proved its efficacy in the reduction of CRC incidence and mortality. The threshold to consider a FIT positive in the Spanish CRC screening programme and therefore be invited to undergo colonoscopy is 100 ng/ml. Considering that values above 50 ng/mL are considered positive out of the screening programme, there is a % of asymptomatic subjects with values between 50 – 99 ng/mL that could have undetected lesions.
Reform pension rules or doctors will reduce their hours, BMA warns chancellor
Authors: Zosia Kmietowicz
Journal: BMJ (2019)

The BMA has warned the chancellor of the exchequer, Philip Hammond, that doctors will reduce their NHS working hours unless tangible reforms are made to the NHS pension scheme.

Changes to rules on pension allowance that limit what staff can save into a pension each year before tax charges apply have landed some consultants with huge unexpected tax bills and have already prompted 3500 doctors to retire early since 2016, while many others are avoiding …
LGG-10. TUMOR-ASSOCIATED IMMUNE RESPONSE IN ANAPLASTIC PROGRESSION OF PXA
Authors: Anupam Kumar, Katharine Chen, Sonia Patel, Claudia Petritsch, Theodore Nicolaides, David A Solomon, Joanna J Phillips
Journal: Neuro-Oncology (2019)

Pleomorphic xantoastrocytoma (PXA) is a typically well circumscribed astrocytic neoplasm that can progress to anaplastic PXA with an aggressive biologic behavior and worse prognosis. Histological features of anaplastic progression include increased proliferation, necrosis, microvascular proliferation, loss of pericellular reticulin, and increased infiltrative growth. Genetically anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling, as observed in PXA, as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation (Phillips et al 2018). Common to both PXA and anaplastic PXA is the perivascular accumulation of lymphocytes. Given the potential importance of the immune response in brain tumors we asked whether the immune response in anaplastic PXA was different than that in PXA and in IDH-mutant diffuse glioma. To do this we used quantitative multiplex immunofluorescence of scanned slides and quantified the populations and phenotypes of T cells and microglia/macrophages in tumors identified from the UCSF Brain Tumor Center Biorepository and from the archives of the UCSF Neuropathology Division. All tumors were molecularly characterized by immunostaining and/or comprehensive genomic profiling. A total of 30 PXA, including 6 paired tumors before and after tumor progression, and 30 diffuse glioma were examined. Immunostaining for T cell subsets included CD3, CD8, and FOXP3 and for microglial/macrophages included Iba1, CD204, and CD163. Using quantitative multiplex immunostaining we assess immune cell subsets and their localization within the tissue highlighting the perivascular CD3+ lymphocytes. Our data suggest differences in the quantity and quality of immune cells in anaplastic PXA.
DIPG-12. CHARACTERIZING THE ROLE OF PPM1D MUTATIONS IN THE PATHOGENESIS OF DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)
Authors: Prasidda Khadka, Zachary J Reitman, Graham Buchan, Rachel Hartley, Heather Bear, Yohanna Georgis, Spandana Jarmale, Kathleen Schoolcraft, Peter Miller, Charles D Stiles, Dipanjan Chowdhury, Daphne Haas-Kogan, Cory Johannessen, Benjamin L Ebert, Keith L Ligon, Timothy Phoenix, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2019)

Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal. Effective treatments are desperately needed. DIPGs harbor histone K27M mutations (H3F3A or HIST1H3B) and also alterations that lead to growth factor receptor activation (such as PDGFRA amplification). We and others have found recurrent truncating PPM1D mutation (PPM1Dtr) in up to 20% of all DIPGs, and they are mutually exclusive with TP53 mutations. We hypothesized that PPM1D mutations are sufficient to induce oncogenesis and necessary for DIPG proliferation, and therefore represent a therapeutic target. To assess the ability of PPM1Dtr to cooperate with H3F3A K27M and PDGFRA activation to drive DIPG tumorigenesis, we overexpressed PPM1Dtr in mouse neural stem cells (mNSCs), along with the contextual H3F3A K27M and PDGFRA D842V activating mutations. Overexpression of PPM1Dtr conferred a significant proliferative advantage to mNSCs in the presence of H3F3A K27M and PDGFRA D842V overexpression. PPM1Dtr overexpression strongly suppressed g-H2AX formation and apoptosis in response to treatment with ionizing radiation. Overexpression of PPM1Dtr along with H3F3A K27M and PDGFRA D842V was also sufficient to induce tumorigenesis in vivo. Furthermore, CRISPR-Cas9 mediated ablation of PPM1D in a patient-derived PPM1D mutant DIPG cell line significantly impaired the growth of these cells, suggesting that PPM1D is a critical dependency in DIPG. Taken together, our study shows that PPM1Dtr is both an oncogene and dependency in PPM1D mutant DIPG, and represents a potential therapeutic target.
DIPG-22. GENETIC MODELING IMPLICATES RAS AND MYC AS KEY EPIGENETICALLY ACTIVATED TRANSCRIPTIONAL TARGETS OF H3K27M-DRIVEN CANCER
Authors: Robert Siddaway, Sanja Pajovic, Byungjin Kim, Scott Ryall, Sameer Agnihotri, Christopher Li, Cynthia Hawkins
Journal: Neuro-Oncology (2019)

Histone 3 mutations at lysine 27 (H3K27M) are frequent drivers of midline gliomagenesis, occurring in ~80% of diffuse intrinsic pontine gliomas (DIPG) and leading to widespread H3K27me3 changes through PRC2 inhibition. Although H3K27M mutations appear to cooperate with additional mutations including TP53 and PDGFRA, the exact oncogenic function of H3K27M is unknown, and in vivo models have not yielded tumors driven by H3K27M alone. Here we created a genetic mouse model by microinjection, expressing H3.3K27M under control of the Fabp7 promoter, which is active in the brain from approximately E14.5, primarily in radial glia and astrocyte precursors, but also allows expression in non-brain developing and adult tissues. H3.3K27M expression in the developing brainstem led to SOX10 upregulation via loss of H3K27me3 at the Sox10 promoter, resulting in an expression profile consistent with K27M-mutant DIPG, including an oligodendrocyte precursor cell (OPC) signature along with RAS and EMT activation. H3.3K27M induced tumors in multiple organs that were driven by K27M alone and, when combined with Trp53 loss, led to primary high-grade gliomas. The tumors had a cell-type independent expression signature featuring RAS and MYC activation, which overlapped with human DIPG and pointed to a core K27M transcriptome. Furthermore, as in human DIPG, mouse tumors spontaneously mutated the RAS pathway and MYC to lock in pathway activation. Our data suggest that RAS and MYC are core pathways that will need to be targeted in order to effectively treat this devastating disease.
The Arts Dispel Medical Students’ Qualms About Dementia
Authors: Rebecca Voelker
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery
Authors: Servando Hernandez Vargas, Susanne Kossatz, Julie Voss, Sukhen C. Ghosh, Hop S. Tran Cao, Jo Simien, Thomas Reiner, Sadhna Dhingra, William E. Fisher, Ali Azhdarinia
Journal: Clinical Cancer Research (2019)

Clinically available intraoperative imaging tools to assist surgeons in identifying occult lesions are limited and partially responsible for the high rate of disease recurrence in patients with neuroendocrine tumors (NET). Using the established clinical efficacy of radiolabeled somatostatin analogs as a model, we demonstrate the ability of a fluorescent somatostatin analog to selectively target tumors that overexpress somatostatin receptor subtype-2 (SSTR2) and demonstrate utility for fluorescence-guided surgery (FGS).A multimodality chelator (MMC) was used as a "radioactive linker" to synthesize the fluorescently labeled somatostatin analog, 67/68Ga-MMC(IR800)-TOC. In vivo studies were performed to determine the pharmacokinetic profile, optimal imaging time point, and specificity for SSTR2-expressing tissues. Meso- and microscopic imaging of resected tissues and frozen sections were also performed to further assess specific binding, and binding to human NETs was examined using surgical biospecimens from patients with pancreatic NETs.Direct labeling with 67Ga/68Ga provided quantitative biodistribution analysis that was in agreement with fluorescence data. Receptor-mediated uptake was observed in vivo and ex vivo at the macro-, meso-, and microscopic scales. Surgical biospecimens from patients with pancreatic NETs also displayed receptor-specific agent binding, allowing clear delineation of tumor boundaries that matched pathology findings.The radioactive utility of the MMC allowed us to validate the binding properties of a novel FGS agent that could have a broad impact on cancer outcomes by equipping surgeons with real-time intraoperative imaging capabilities.
Abstract 15275: Non Val30met Mutation, Septal Hypertrophy and Delayed Heart/Mediastium Ratio Are Useful Predictors of Poor Clinical Outcome in Japanese Patients With Hereditary Transthyretin Amyloidosis
Authors: Kyoko Hirakawa, Seiji Takashio, Kyohei Marume, Masahiro Yamamoto, Shinsuke Hanatani, Yasuhiro Izumiya, Koichi Kaikita, Seitaro Oda, Daisuke Utsunomiya, Mitsuharu Ueda, Taro Yamashita, Yukio Ando, Kenichi Tsujita
Journal: Circulation (2017)

Introduction: Hereditary transthyretin amyloidosis (ATTRm) often causes cardiac amyloidosis, and cardiac involvements worsen clinical outcome. However, there is little information about predictor o...