tbuckley/cabot-search huggingface dataset:
IMMU-19. PD-1 BLOCKADE ACTIVATES CD4 T CELLS AND THE INNATE IMMUNE RESPONSE FOR GLIOBLASTOMA ERADICATION
Authors: Maria Carmela Speranza, Sarah R Klein, Prafulla C Gokhale, Margaret K Wilkens, Kristen L Jones, Apoorvi Chaudhri, Paul T Kirschmeier, David Reardon, Gordon Freeman
Journal: Neuro-Oncology (2018)

Blockade of immune cell co-inhibitory receptor PD-1 using monoclonal antibodies (mAbs) allows the development of anti-tumor immunity in various solid tumors and lymphoid malignancies. We recently demonstrated that PD-1 blockade elicits an anti-tumor immune response resulting in tumor rejection and long-term survival in approximately 50% of mice with intra-cranial GL-261 glioblastoma, despite the absence of accumulating CD8+ cytotoxic T cells in the tumor or draining lymph nodes. In this investigation, we provide evidence for the role of conventional CD4+ T cells and the innate immune response in PD-1 mediated anti-glioma immunity in this model. In response to anti-PD-1 monotherapy, intratumoral CD4+ T cells, but not CD8+ T cells, expressed significantly elevated levels of IFN-γ and TNF-α pro-inflammatory cytokines and the cytotoxic enzyme, granzyme B. Tbet, GATA3, and EOMES, transcription factors required for T cell proliferation, activation, and effector function, were also up-regulated in CD4+, but not CD8+ T cells in the brains of mice treated with PD-1 mAbs when compared to controls. We demonstrated that depletion of CD4+ or CD8+ T cells, but not NK, was sufficient to completely ablate anti-PD-1-mediated tumor eradication and long-term survival. CD4+ T cell activation was accompanied by the classical activation and M1 polarization of resident microglia and tumor-infiltrating macrophages. Together, these studies demonstrate for the first time a role for CD4+ T cells and the innate immune response in the eradication of glioblastoma by PD-1 blockade.
The Search for an Alternative to [<sup>68</sup>Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of <sup>18</sup>F-labeled Somatostatin Analog Development
Authors: Christopher M. Waldmann, Andreea D. Stuparu, R. Michael van Dam, Roger Slavik
Journal: Theranostics (2019)

The trend to inform personalized molecular radiotherapy with molecular imaging diagnostics, a concept referred to as theranostics, has transformed the field of nuclear medicine in recent years.The development of theranostic pairs comprising somatostatin receptor (SSTR)-targeting nuclear imaging probes and therapeutic agents for the treatment of patients with neuroendocrine tumors (NETs) has been a driving force behind this development.With the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial reporting encouraging results in the treatment of well-differentiated, metastatic midgut NETs, peptide radioligand therapy (RLT) with the 177 Lu-labeled somatostatin analog (SSA) [ 177 Lu]Lu-DOTA-TATE is now anticipated to become the standard of care.On the diagnostics side, the field is currently dominated by 68 Ga-labeled SSAs for the molecular imaging of NETs with positron emission tomography-computed tomography (PET/CT).PET/CT imaging with SSAs such as [ 68 Ga]Ga-DOTA-TATE, [ 68 Ga]Ga-DOTA-TOC, and [ 68 Ga]Ga-DOTA-NOC allows for NET staging with high accuracy and is used to qualify patients for RLT.Driven by the demand for PET/CT imaging of NETs, a commercial kit for the production of [ 68 Ga]Ga-DOTA-TATE (NETSPOT) was approved by the U.S. Food and Drug Administration (FDA).The synthesis of 68 Ga-labeled SSAs from a 68 Ge/ 68 Ga-generator is straightforward and allows for a decentralized production, but there are economic and logistic difficulties associated with these approaches that warrant the search for a viable, generator-independent alternative.The clinical introduction of an 18 F-labeled SSTR-imaging probe can help mitigate the shortcomings of the generator-based synthesis approach, but despite extensive research efforts, none of the proposed 18 F-labeled SSAs has been translated past prospective first-in-humans studies so far.Here, we review the current state of probe-development from a translational viewpoint and make a case for a clinically viable, 18 F-labeled alternative to the current standard [ 68 Ga]Ga-DOTA-TATE.
Campylobacteriosis Outbreak Associated with Contaminated Municipal Water Supply — Nebraska, 2017
Authors: Caitlin Pedati, Samir Koirala, Tom Safranek, Bryan F. Buss, Anna V. Carlson
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In March 2017, the Nebraska Department of Health and Human Services (NDHHS) and the Southwest Nebraska Public Health Department were notified of an apparent cluster of Campylobacter jejuni infections in city A and initiated an investigation. Overall, 39 cases were investigated, including six confirmed and 33 probable. Untreated, unboiled city A tap water (i.e., well water) was the only exposure significantly associated with illness (odds ratio [OR] = 7.84; 95% confidence interval [CI] = 1.69-36.36). City A is served by four untreated wells and an interconnected distribution system. Onsite investigations identified that a center pivot irrigation system intended to pump livestock wastewater from a nearby concentrated animal feeding operation onto adjacent farmland had malfunctioned, allowing excessive runoff to collect in a road ditch near two wells that supplied water to the city. These wells were promptly removed from service, after which no subsequent cases occurred. This coordinated response rapidly identified an important risk to city A's municipal water supply and provided the evidence needed to decommission the affected wells, with plans to build a new well to safely serve this community.
Completing the genetic spectrum influencing coronary artery disease: from germline to somatic variation
Authors: Aniruddh P Patel, Pradeep Natarajan
Journal: Cardiovascular Research (2019)

Genetic and environmental factors influence the development of coronary artery disease (CAD). Genetic analyses of families and the population continue to yield important fundamental insights for CAD. For the past four decades, CAD human genetic research focused largely on the study of germline genetic variation in CAD and its risk factors. The first genes associated with CAD were discovered using basic Mendelian principles and pedigree analysis. Mapping of the human genome and advancement in sequencing technology sparked further discovery of novel genetic associations through exome sequencing and genome wide association analysis in increasingly larger populations. While prior work implicated in situ DNA damage as a feature of atherosclerosis, more recently, somatic mutagenesis in and clonal expansion of haematopoietic stem cells was found to influence risk of CAD. Mutations observed for this condition, termed clonal haematopoiesis of indeterminate potential, frequently occur within epigenetic regulator genes (e.g. DNMT3A, TET2, ASXL1, etc.), which are also implicated in leukaemogenesis. Hypercholesterolaemic mice with Tet2 bone marrow deficiency are predisposed to the development of atherosclerosis that may be partly related to inflammatory cytokines. As the genetic basis of CAD expands from the germline to somatic genome, our fundamental understanding of CAD continues to evolve; these new discoveries represent new opportunities for risk prediction and prevention, and a new facet of cardio-oncology.
Cross-genotype AR3-specific neutralizing antibodies confer long-term protection in injecting drug users after HCV clearance
Authors: Sabrina J. Merat, Camille Bru, Dorien van de Berg, Richard Molenkamp, Alexander W. Tarr, Sylvie Koekkoek, Neeltje A. Kootstra, Maria Prins, Jonathan K. Ball, Arjen Q. Bakker, Menno D. de Jong, Hergen Spits, Tim Beaumont, Janke Schinkel
Journal: Journal of Hepatology (2019)
Abstract 2082: The role of cell-cell contacts in the survival of extracellular matrix detached mammary epithelial cells
Authors: Raju Rayavarapu, Zachary Schafer
Journal: Cancer Research (2012)

Abstract Normal epithelial cells require attachment to the extracellular matrix (ECM) in order to proliferate and survive. Binding to the ECM facilitates the activation of pathways responsible for ATP production and cell survival. When detached from the ECM, normal cells will upregulate apoptotic pathways and will be systematically removed. This detachment-induced apoptosis is known as anoikis. ECM detachment in normal epithelial cells disrupts cellular signaling derived from integrin-mediated basal attachment as well as cadherin assisted signaling from lateral cell contacts. Cadherins, primarily E-cadherin, have been shown to be classic tumor suppressor genes and can prevent the proliferation of cells that fail to assume normal epithelial morphology and cell-cell contacts. The loss of E-cadherin endows an increased invasion capacity to breast tumors and regulation of E-cadherin levels are directly mediated by factors (i.e. Slug) that promote epithelial-to-mesenchymal transition (EMT) and metastasis. Cadherin molecules have previously been reported to interact with other receptor tyrosine kinases, such as EGFR (epithelial growth factor receptor), in order to suppress the ability of the receptor to bind ligand, dimerize and elicit downstream signaling. HER2 is an orphan member of the EGFR family of tyrosine kinases and is a potent oncogene found in 30% of all breast cancer tissue. Previous studies in our laboratory have found a direct correlation between upregulation of survival pathways in ECM detached cells and expression of HER2. In this study, we find that the overexpression of HER2 in non-malignant mammary epithelial cells (MCF-10A) results in substantial aggregation of detached cells, the inhibition of caspase activation and a rescue of ATP production. These data suggest that HER2 plays a role in protecting detached cells from anoikis and this activity may be linked to cell-cell adhesion in suspension. We have found that disruption of cell-cell contacts in HER2-expressing MCF-10A cells utilizing methylcellulose can induce caspase activity and diminish global ATP levels. Preliminary studies also reveal a previously uncharacterized interaction between HER2 and E-cadherin that takes place when E-cadherin dimers are disrupted. Thus, the disruption of E-cadherin dimers in cellular aggregates may facilitate the binding of E-cadherin to HER2 in a fashion that compromises downstream survival signaling. These data together suggest a potential role for E-cadherin as a modulator of HER2 activity and further suggest that the loss of E-cadherin via mechanisms like EMT may function as a means to promote ECM-detached tumor cell survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2082. doi:1538-7445.AM2012-2082
Pre-blocked molecular shuttle as an in-situ real-time theranostics
Authors: Tao Sun, Guangping Zhang, Qingbing Wang, Zhongyuan Guo, Qinjun Chen, Xinli Chen, Yifei Lu, Yu Zhang, Yujie Zhang, Qin Guo, Xiang Gao, Yongzhong Cheng, Chen Jiang
Journal: Biomaterials (2019)
274. Antitumor Effect of Controlled Expression of Interleukin-12 in a Murine Model of Liver Metastases
Authors: Itsaso Mauleon, Julien Crettaz, Gloria Gonzalez-Aseguinolaza, Maider Zabala, Gabriela Kramer, Stephan Kochanek, Jesus Prieto, Ruben Hernandez-Alcoceba
Journal: Molecular Therapy (2006)

Background and aims: Interleukin-12 (IL-12) is a potent immune- stimulant cytokine that has shown antitumor effect in several pre- clinical studies. The mechanism of action of IL-12 is complex and includes the activation of the immune system with stimulation of IFN-g production, and inhibition of angiogenesis. However, the systemic administration of IL-12 causes severe toxicity. Therefore, diverse strategies to achieve controlled expression of IL-12 are being developed.
Fms-like Tyrosine Kinase 3 Ligand Concentration Kinetic Profile during Induction Is Strongly Predictive of Survivals in AML: Results of the FLAM/Flal Study
Authors: Pierre Peterlin, Joelle Gaschet, Thierry Guillaume, Alice Garnier, Marion Eveillard, Amandine Le Bourgeois, Michel Cherel, Camille Debord, Yannick LE Bris, Olivier Theisen, Beatrice Mahe, Viviane Dubruille, Soraya Wuilleme, Catherine Godon, Cyrille Touzeau, Thomas Gastinne, Nicolas Blin, Anne Lok, Antoine Bonnet, Steven LE Gouill, Philippe Moreau, Marie C Bene, Patrice Chevallier
Journal: Blood (2018)
Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial
Authors: Serena Di Cosimo, Valentina Appierto, Sara Pizzamiglio, Paola Tiberio, Marilena V. Iorio, Florentine Hilbers, Evandro de Azambuja, Lorena de la Peña, Miguel Izquierdo, Jens Huober, José Baselga, Martine Piccart, Filippo G. de Braud, Giovanni Apolone, Paolo Verderio, Maria Grazia Daidone
Journal: Clinical Cancer Research (2019)

Abstract Purpose: To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study. Experimental Design: Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training (n = 183) and testing (n = 246) sets. RT-PCR–based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan–Meier method and Cox regression model. Results: In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73–0.98 and 0.71 (0.55–0.86)], respectively; trastuzumab at T1 (0.81; 0.70–0.92); lapatinib + trastuzumab at T1 (0.67; 0.51–0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22–0.84). Conclusions: ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.
Assessing the Role and Optimal Duration of Hormonal Treatment in Association with Salvage Radiation Therapy After Radical Prostatectomy: Results from a Multi-Institutional Study
Authors: Nicola Fossati, Daniele Robesti, R. Jeffrey Karnes, Matteo Soligo, Stephen A. Boorjian, Alberto Bossi, Gabriele Coraggio, Nadia Di Muzio, Cesare Cozzarini, Barbara Noris Chiorda, Giorgio Gandaglia, Simone Scarcella, Detlef Bartkowiak, Dirk Böhmer, Shahrokh Shariat, Gregor Goldner, Antonino Battaglia, Steven Joniau, Karin Haustermans, Gert De Meerleer, Valérie Fonteyne, Piet Ost, Hein Van Poppel, Francesco Montorsi, Thomas Wiegel, Alberto Briganti
Journal: European Urology (2019)
Pevonedistat, a Small Molecule Inhibitor of NEDD8-Activating Enzyme (NAE), Induces Cell Cycle Deregulation, Anaphase Catastrophe, and Apoptosis in T-Cell Lymphoma Cells
Authors: Adam Kittai, Scott R Best, Taylor Rowland, Nur Bruss, Craig Okada, Alexey V Danilov
Journal: Blood (2018)
Omitted Acknowledgment of Local Contributors to Study
Authors: Mark Wade
Journal: JAMA Psychiatry (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 Psychiatry 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 Psychiatry journal
Response to Anti–PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis
Authors: Douglas B. Johnson, Riyue Bao, Kristin K. Ancell, Anthony B. Daniels, Deborah Wallace, Jeffrey A. Sosman, Jason J. Luke
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. Methods: We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti–PD-1 in this setting and to understand the mutational and immunologic profile of this disease. Results: A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with MYC pathway overexpression. Conclusions: Anti–PD-1–based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and MYC overexpression may be factors limiting therapeutic responses. ClinicalTrials.gov identifier: NCT02359851
Melflufen Therapy for Relapsed Refractory Multiple Myeloma (RRMM) Patients Refractory to Daratumumab and/or Pomalidomide: A Report on Early Efficacy
Authors: Maria-Victoria Mateos, Joan Bladé, Alessandra Larocca, Albert Oriol, Paula Rodriguez, Adrián Alegre, Michele Cavo, Jan S Moreb, Agne Paner, Nashat Gabrail, Kathleen G. Halka, Hani Hassoun, Christopher Maisel, Amitabha Mazumder, Jeffrey A Zonder, Enrique M Ocio, Catriona Byrne, Johan Harmenberg, Sara Thuresson, Eva Nordstrom, Jakob Lindberg, Paul G Richardson
Journal: Blood (2017)
Radiation Contamination Following Cremation of a Deceased Patient Treated With a Radiopharmaceutical
Authors: Nathan Y. Yu, William G. Rule, Terence T. Sio, Jonathan B. Ashman, Kevin L. Nelson
Journal: JAMA (2019)

This case report describes contamination of crematory equipment with lutetium Lu 177 after cremation of a patient with a pancreatic neuroendocrine tumor treated with the radioisotope 2 days prior to his death.
Transgender Children and the Right to Transition: Medical Ethics When Parents Mean Well but Cause Harm
Authors: Maura Priest
Journal: The American Journal of Bioethics (2019)

In this article, I argue that (1) transgender adolescents should have the legal right to access puberty-blocking treatment (PBT) without parental approval, and (2) the state has a role to play in publicizing information about gender dysphoria. Not only are transgender children harmed psychologically and physically via lack of access to PBT, but PBT is the established standard of care. Given that we generally think that parental authority should not go so far as to (1) severally and permanently harm a child and (2) prevent a child from access to standard physical care, then it follows that parental authority should not encompass denying gender-dysphoric children access to PBT. Moreover, transgender children without supportive parents cannot be helped without access to health care clinics and counseling to facilitate the transition. Hence there is an additional duty of the state to help facilitate sharing this information with vulnerable teens.
Modified HEART Score and High-Sensitivity Cardiac Troponin in Patients With Suspected Acute Myocardial Infarction
Authors: Beata Morawiec, Jasper Boeddinghaus, Desiree Wussler, Patrick Badertscher, Luca Koechlin, Fabiola Metry, Raphael Twerenbold, Thomas Nestelberger, Damian Kawecki, Christian Mueller
Journal: Journal of the American College of Cardiology (2019)
First-Line Nivolumab Plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers
Authors: Neal Ready, Matthew D. Hellmann, Mark M. Awad, Gregory A. Otterson, Martin Gutierrez, Justin F. Gainor, Hossein Borghaei, Jacques Jolivet, Leora Horn, Mihaela Mates, Julie Brahmer, Ian Rabinowitz, Pavan S. Reddy, Jason Chesney, James Orcutt, David R. Spigel, Martin Reck, Kenneth John O’Byrne, Luis Paz-Ares, Wenhua Hu, Kim Zerba, Xuemei Li, Brian Lestini, William J. Geese, Joseph D. Szustakowski, George Green, Han Chang, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2019)

CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB).Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point.Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
Association of CXCR4 with IgM and IgD BCR Isotypes: Role in B Cell Malignancies
Authors: Eva Gentner, Andrea Nicola Mazzarello, Martin Becker, Antonella Nicolò, Valerio Renna, Nicholas Chiorazzi, Michael Reth, Hassan Jumaa, Palash Chandra Maity
Journal: Blood (2018)