tbuckley/cabot-search huggingface dataset:
Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus*
Authors: S. Ständer, G. Yosipovitch
Journal: British Journal of Dermatology (2019)

Chronic pruritus is a distressing symptom associated with various dermatological conditions and systemic diseases. Current treatment options are often inadequate, resulting in impaired quality of life for many patients. An understanding of the underlying mechanisms of itch across pruritic conditions is important for development of effective, targeted treatments for chronic pruritus. To provide an overview of the pathogenesis of chronic pruritus, focusing on the role of substance P (SP) and neurokinin 1 receptor (NK1R) in itch signalling, and to describe data supporting NK1R antagonism as a potential strategy for the treatment of chronic pruritus. A PubMed search was conducted to determine what data were available that investigated the role of SP and NK1R in itch signalling. SP is a neuropeptide that is a mediator of itch signalling. One of the target receptors for SP is NK1R, which is expressed in the central nervous system and on multiple cell types involved in the initiation and transmission of itch. Studies demonstrating that SP and NK1R are overexpressed across multiple chronic itch‐inducing conditions and that NK1R antagonism disrupts itch signalling and reduces itch provide a rationale for targeting this pathway as a potential treatment of chronic pruritus across multiple diseases. A large and growing body of evidence, including recent phase II clinical studies of NK1R antagonists, demonstrate that SP and NK1R play an important role in itch signalling. Additional studies are ongoing to further evaluate the use of NK1R antagonists for the treatment of chronic pruritus. What's already known about this topic? Chronic pruritus has a significant impact on quality of life. Current treatment options for chronic pruritus are inadequate. Substance P (SP) and neurokinin 1 receptor (NK1R) have been shown to play a role in itch signalling, and may be a rational target for addressing chronic pruritus. NK1R antagonists are being evaluated as potential treatment for chronic pruritus. What does this study add? This review provides a compilation of the most up‐to‐date data elucidating the role of SP and NK1R in itch signalling, which supports targeting this pathway as a potential treatment of chronic pruritus. NK1R antagonism disrupts itch signalling and reduces itch. A summary of the latest data on NK1R antagonists in the treatment of pruritus is provided.
Intestinal Bile Acids Induce a Morphotype Switch in Vancomycin-Resistant Enterococcus that Facilitates Intestinal Colonization
Authors: Peter T. McKenney, Jinyuan Yan, Julien Vaubourgeix, Simone Becattini, Nina Lampen, Andrew Motzer, Peter J. Larson, Daniel Dannaoui, Sho Fujisawa, Joao B. Xavier, Eric G. Pamer
Journal: Cell Host & Microbe (2019)

Vancomycin-resistant Enterococcus (VRE) are highly antibiotic-resistant and readily transmissible pathogens that cause severe infections in hospitalized patients. We discovered that lithocholic acid (LCA), a secondary bile acid prevalent in the cecum and colon of mice and humans, impairs separation of growing VRE diplococci, causing the formation of long chains and increased biofilm formation. Divalent cations reversed this LCA-induced switch to chaining and biofilm formation. Experimental evolution in the presence of LCA yielded mutations in the essential two-component kinase yycG/walK and three-component response regulator liaR that locked VRE in diplococcal mode, impaired biofilm formation, and increased susceptibility to the antibiotic daptomycin. These mutant VRE strains were deficient in host colonization because of their inability to compete with intestinal microbiota. This morphotype switch presents a potential non-bactericidal therapeutic target that may help clear VRE from the intestines of dominated patients, as occurs frequently during hematopoietic stem cell transplantation.
Paclitaxel and Alisertib in Recurrent Ovarian Cancer
Authors: Federica Tomao, Pierluigi Benedetti Panici, Silverio Tomao
Journal: JAMA Oncology (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 Oncology 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 Oncology journal
Six-Minute Walk Test (6MWT) Performance in Adult Patients Receiving Amikacin Liposome Inhalation Suspension (ALIS) for Treatment-Refractory Nontuberculous Mycobacterial (NTM) Lung Disease Caused by Mycobacterium Avium Complex (MAC)
Authors: K. L. Winthrop, G. Eagle, R. M. Thomson, T. R. Aksamit, N. Hasegawa, K. Morimoto, D. J. Addrizzo-Harris, A. E. O'Donnell, T. K. Marras, P. A. Flume, M. R. Loebinger, L. C. Morgan, L. R. Codecasa, A. T. Hill, S. J. Ruoss, J. J. Yim, F. C. Ringshausen, S. K. Field, J. Nezamis, D. E. Griffith
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
HOW STRONG IS THE EVIDENCE SUPPORTING HIGH DEFINITION COLONOSCOPY SUPERIORITY IN INCREASING EXAMINATION OUTCOMES? A META-ANALYSIS OF RANDOMIZED CONTROLLED STUDIES
Authors: G Tziatzios, P Gkolfakis, LD Lazaridis, K Triantafyllou
Journal: Endoscopy (2019)

Previous meta-analysis showed marginal difference between high definition (HD-C) and standard definition (SD-C) colonoscopy in terms of colonic adenomas detection. Due to non-randomized design of the majority of studies included in this meta-analysis, we aimed to elucidate the effect of HD-C on adenoma detection by meta-analyzing results of randomized controlled trials (RCTs) only.
HGG-01. ACQUISITION OF A HYPERMUTATOR PHENOTYPE UNDERLYING DISTANT SPINAL INTRAMEDULLARY SPREAD IN HISTONE-MUTATED DIFFUSE MIDLINE GLIOMA
Authors: Christopher Hong, Adam Kundishora, Elena Fomchenko, Anita Huttner, Zeynep Erson-Omay, Asher Marks, Michael Diluna, Kristopher Kahle
Journal: Neuro-Oncology (2019)

Histone-mutated diffuse midline gliomas are high-grade astrocytic tumors with poor prognosis. While these tumors may spread along fiber tracts to local sites and leptomeninges, intramedullary spinal metastases have not been previously reported and the genetic alterations underlying distant spread are poorly understood. Whole exome sequencing of tumor and germline were performed under standard Yale Center for Genome Analysis practices. A thirteen-year old male with headaches, nausea, and vomiting was diagnosed with a pineal mass, for which resection demonstrated diffuse midline H3K27M-mutated glioma, followed by proton beam radiation and temozolomide. One year later, he developed lower extremity weakness secondary to bulky intramedullary spinal tumor spread. He underwent cervical and lumbar tumor debulking with pathology confirming distant metastatic spread. Whole exome sequencing was performed for his initial pineal and recurrent spinal specimens. The pineal lesion contained 46 total somatic mutations, including key oncogenic driver mutations in FGFR1, NF1, CACA1D, HOXA9, and H3F3A. The spinal metastatic lesions showed a hypermutated phenotype with increased C>T transition ratio and 10-fold (n=418) increase in somatic mutations, including preservation of 20/46 somatic mutations from the pineal tumor including FGFR1, NF1, HOXA9, and H3F3A as well as further hits in hallmark oncogenes APC, KEL, PTPRB, TRIP11, and MAP3K7. There were additional gained copy number variation/loss of heterozygosity (LOH) events during recurrence including LOH of chr1q, which overlapped with the H3F3A locus resulting in increased variable allele frequency for the mutant allele and subsequent greater abundance of mutated H3F3A. Likewise, there was amplification of chr2p, resulting with associated copy number increase in oncogenes DNMT3A and MYCN. Though previously unrecognized, histone-mutated midline gliomas are capable of distant intramedullary spinal metastasis. The underlying genetic alterations may be secondary to acquisition of a hypermutation phenotype, resulting in activation of key oncogenes and enhanced mutated H3F3A activity.
Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma
Authors: Marc Ladanyi, Francisco Sanchez Vega, Marjorie Zauderer
Journal: Genome Medicine (2019)

As trials of immune checkpoint inhibitor (ICI) therapies demonstrate responses in only a minority of pleural mesotheliomas (PlMs) and largely exclude patients with the related peritoneal mesothelioma (PeM), clinicians need predictive biomarkers of response and inclusion of PeM patients in future trials. A new study finds that loss of the deubiquitinase BAP1 in PeM correlates with an inflammatory tumor microenvironment, suggesting that BAP1 status might identify PeM, and possibly PlM, patients who would benefit from ICI therapy.
Human herpesvirus 8 (HHV-8) K1 suppresses Fas-mediated apoptosis and binds to the Fas complex
Authors: Felipe Samaniego, Shu Wang, Daniel Young, Suizhao Wang
Journal: Cancer Research (2005)

5369  HHV-8 is associated with the development of primary effusion lymphoma (PEL) and Kaposi’s sarcoma. PEL-derived cell lines express the HHV-8 K1 gene spontaneously. The K1 gene is expressed at high levels during lytic phase viral replication. K1 codes for a transmembrane protein, containing a short cytosolic tail, with an immunoreceptor tyrosine-based activation motif (ITAM). ITAMs are present in receptors regulating cell activation and survival. K1 spontaneously aggregates and its ITAM is maintained in the constitutively phosphorylated and activated state, which is associated with NF-κB activation. K1 in transgenic mice, driven by a constitutive promoter, is associated with development of lymph node hyperplasia and lymphoma. Given its NF-κB activation inducing properties, we anticipate that K1 contributes to transformation, in part, by suppression of apoptosis. To study the role of HHV8 K1 gene product, we generated K1 stably expressing cell line BJABK1 and vector alone cell line BJABXS, with retrovirus vector pLXSN, and packaging cell line PT67 NIH 3T3. K1 was also expressed in THP, U937 and KS SLK cells. We also expressed a truncated K1 lacking the ITAM (K1m). K1myc was expressed and monitored with anti-myc antibody. Anti-Fas antibody (CH-11) was used to induce apoptosis and cells were monitored for membrane protein Annexin-V, DNA integrity, and morphological features of apoptosis. Apoptosis rates were evaluated with Annexin-V-FITC/PI analysis and DAPI-based nuclear morphological analysis. C-FLIP, caspase 8 and Fas were monitored by immunoblot analysis and flow cytometry. K1 was expressed in mouse hepatocytes by intravenous inoculation of plasmids, expressing K1 and green fluorescent protein. K1-Fas complex interactions were analyzed. Anti-Fas antibody induced apoptosis was suppressed in BJABK1 cells compared with BJABK1m and BJABXS cells in Annexin-V assay and by DAPI staining. A similar pattern of K1-related suppression of anti-Fas antibody induced apoptosis was observed in transfected THP, U937 and KS SLK cells. K1 expression suppressed apoptosis, which had been induced by Fas ligand. K1 expression did not suppress apoptosis induced by TRAIL or radiation. K1 expressing cells showed consistent lower levels of procaspase 8 cleavage products. Immunoprecipitation-immunoblot analysis with anti-Fas and anti-myc antibodies indicated Fas and K1myc were bound to the same complex. Expression of K1myc in mouse liver showed binding of Fas and K1 to the same complex. Taken together, the data indicate that expression of HHV8 K1 can suppress Fas-mediated apoptosis. K1 and Fas bind to the same complex in several cell types and in vivo. We anticipate K1 regulates apoptosis through binding of the Fas complex and represents a novel form of apoptosis regulation.
Abstract 15956: Adenylate Cyclase Type 9 Regulates Body Weight and Adipose Tissue
Authors: Yohann Rautureau, Philippe Pouliot, Marie-Ève Higgins, Pascale Geoffroy, Maria Laura Suarez, Daniel Rivas, Line Lapointe, Géraldine Miquel, Geneviève Brand, Éric Rhéaume, Jean-Claude Tardif
Journal: Circulation (2017)

The cardiovascular (CV) benefits of the CETP inhibitor dalcetrapib (DAL) are dependent on ADCY9 genotype. We also observed genotype-dependent changes in body weight (BW) in DAL-treated patients tha...
Molecular Classification of Neuroendocrine Tumors of the Thymus
Authors: Helen Dinter, Hanibal Bohnenberger, Julia Beck, Kirsten Bornemann-Kolatzki, Ekkehard Schütz, Stefan Küffer, Lukas Klein, Teri J. Franks, Anja Roden, Alexander Emmert, Marc Hinterthaner, Mirella Marino, Luka Brcic, Helmut Popper, Cleo-Aron Weis, Giuseppe Pelosi, Alexander Marx, Philipp Ströbel
Journal: Journal of Thoracic Oncology (2019)

IntroductionThe WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems.MethodsOne hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features.ResultsWhole-genome sequencing data fell into three clusters: CNIlow, CNIint, and CNIhigh. CNIlow and CNIint comprised not only TC and AC, but also six LCNECs. CNIhigh contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2).ConclusionsTNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a morphomolecular grading system, Thy-NET G1-G3, instead of histologic classification for patient stratification and prognostication.
Abstract 11595: Characterization of Human Coronary Atherosclerosis Using Polarization-Sensitive Optical Frequency Domain Imaging
Authors: Kenichiro Otsuka, Antonios Karanasos, Martin Villiger, Pallavi Doradla, Jian Ren, Norman Lippok, Milen Shishkov, Joost Daemen, Roberto Diletti, Robert-Jan van Geuns, Felix Zijlstra, Gijs van Soest, Peter Libby, Seemantini K Nadkarni, Evelyn Regar, Brett E Bouma
Journal: Circulation (2017)

Introduction: Characterizing the content of collagen and smooth muscle cells (SMC), the source of arterial collagen, is central to the understanding of the pathophysiology of coronary atherosclerosis. Plaques that rupture typically have a thin fibrous cap with diminished collagen content and few SMCs. Polarization sensitive (PS-) optical frequency domain imaging (OFDI) provides maps of birefringence (BF), a tissue property elevated in collagen and SMCs, and depolarization, which hints at the presence of lipid, in addition to the conventional image of plaque structure. Hypothesis: We hypothesized that PS-OFDI could elucidate the role of collagen and SMCs in coronary atherosclerosis, and especially in fibrous caps. Methods: We performed PS-OFDI in patients with coronary artery disease (CAD; n=30). Imaged coronary arteries were divided into 340 segments and a single cross-section was analyzed from each segment. Plaques were segmented and classified based on conventional OFDI. The median BF and depolarization...
Abstract MP70: Pre-pregnancy Beta Cell Compensation for Insulin Resistance Associated With Subsequent Gestational Diabetes Mellitus: The CARDIA Study
Authors: Erica P Gunderson, Amy Krefman, Cora E Lewis, Janet Catov, Norrina B Allen
Journal: Circulation (2018)

Hypothesis: Gestational diabetes mellitus (GDM) is a disorder of glucose metabolism during pregnancy characterized by pancreatic beta cell dysfunction and greater insulin resistance, but it is unclear whether dysfunction exists before pregnancy. The disposition index (DI) is a physiologic measure of beta cell compensation for insulin resistance strongly predictive of future diabetes. This prospective study evaluates whether a clinical approximation of DI before pregnancy is associated with risk of GDM. Methods: This analysis included 696 women (45% black, 55% white) enrolled in the CARDIA Study, a U.S. multi-center prospective cohort of young adults aged 18-30 at baseline (1985-86) who gave birth at least once during 30 years of follow up, reported GDM status and had fasting glucose and insulin measured before one or more post-baseline births. DI was defined as HOMA-B divided by HOMA-IR using standard formulas. Multinomial logistic regression models estimated odds ratios (OR) and 95%CI for GDM among pre-pregnancy DI tertiles (low, moderate, high) and fully adjusted for time to birth, race, age, parity, BMI, lifestyle behaviors and family history of diabetes, and also stratified by pre-pregnancy BMI. Results: 9% of women reported GDM (64/696) for 794 births. 55% of GDM and 30% of non-GDM were categorized as low DI. Low pre-pregnancy DI compared to moderate DI was associated with higher fully adjusted odds of GDM (OR=2.71, 95%CI:1.37-5.35) in the entire sample. In models stratified by pre-pregnancy BMI, low DI was associated with 4-fold higher odds of GDM among Overweight/Obese (OR=4.22, 95%CI: 1.35-13.91) and somewhat attenuated higher odds of GDM among Normal BMI (OR=1.94, 95%CI: 0.78–4.86); Table 1. Only family history of diabetes was strongly associated with GDM independent of DI. Conclusions: Inadequate beta cell compensation is present before pregnancy and discriminates greatest risk of GDM among high BMI, and may identify higher risk among women of normal BMI.
Abstract 16347: Hypoalbuminemia and Its Association With Venous Thromboembolism in Acutely Ill Hospitalized Patients: Findings From the APEX Trial
Authors: Gerald Chi, Michael Gibson, Adrian F Hernandez, Russell D Hull, Alexander T Cohen, Robert A Harrington, Yuyin Liu, Sargun Walia, Sadaf Sharfaei, Anmol Pitliya, Hassan A Kazmi, Sudarshana Datta, Farima Kahe, Eiman Ghaffarpasand, Mehrian Jafarizde, Arzu Kalayci, Tarek Nafee, Mathieu Kerneis, Fahad AlKhalfan, Megan K Yee, Ryan S Travis, Samuel Z Goldhaber
Journal: Circulation (2018)

Background: Decreased serum concentration of albumin, an acute-phase reactant with anticoagulant properties, may be associated with unfavorable prognosis in hospitalized patients. Objectives: The s...
IMMU-07. IMMUNOLOGIC TARGETING OF DIPG WITH H3K27M ENCODING RNA-NANOPARTICLES
Authors: James McGuiness, Hector Mendez-Gomez, Brian Stover, Frances Weidert, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2019)

BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) remains uniformly recalcitrant and thus necessitates development of novel targeted therapies. The histone mutation in H3K27M is conserved in the preponderance of DIPG patients and may be exploited as a neoepitope for cancer immunotherapy. We have developed a novel treatment platform, which leverages the use of clinically translatable nanoparticles (NPs) combined with H3K27M mRNA neoantigens for in vivo activation of dendritic cells and generation of DIPG specific T cells. OBJECTIVE/METHODS: Since neoantigens have been shown to mediate immunologic response through MHC class II, we sought to identify MHCII restricted epitopes spanning the H3.1K27M junction for development of RNA-NP vaccines against DIPG. RESULTS: We identified MHCII restricted H3.1K27M epitopes not present in the wild-type sequence. We constructed a 25-mer sequence (75 amino acids) spanning the range of epitopes, before cloning it into our custom pGEM-4z plasmid containing a poly A tail and 5’ UTR with a T7 promoter for amplification of MHC-II restricted H3.1K27M mRNA. We complexed this RNA with our custom NP formulation and investigated its immunogenicity in C57Bl/6 mice. Unlike MHC-I restricted epitopes (i.e. OVAlbumin’s SINFEKL epitope), MHC-II restricted H3K27M epitopes elicited significant increases in activated CD4 and CD8 central memory T cells. We demonstrate that this central memory phenotype correlates with anti-tumor efficacy and long-term survival outcomes in murine tumor models. CONCLUSION: RNA-NPs can be made readily available for all DIPG patients (and not only HLA specific haplotypes) providing a renewable antigen resource that can be used to continuously vaccinate patients for months/years after diagnosis. Herein, we identify MHCII restricted H3.1K27M epitopes for activation of immunologic central memory necessary for long-lived anti-tumor efficacy.
OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL
Authors: Kathryn Evans, JianXin Duan, Tara Pritchard, Connor D. Jones, Lisa McDermott, Zhaohui Gu, Cara E. Toscan, Narimanne El-Zein, Chelsea Mayoh, Stephen W. Erickson, Yuelong Guo, Fanying Meng, Donald Jung, Komal S. Rathi, Kathryn G. Roberts, Charles G. Mullighan, Chi-Sheng Shia, Tillman Pearce, Beverly A. Teicher, Malcolm A. Smith, Richard B. Lock
Journal: Clinical Cancer Research (2019)

Abstract Purpose: OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL). Experimental Design: We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX). Results: AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (B-ALL; n = 1,740; P &amp;lt; 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1–77.8 days (treated/control values 2.5–14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P &amp;lt; 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs. Conclusions: OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.