tbuckley/cabot-search huggingface dataset:
Are immunohistochemical (IHC)/microsatellite instability (MSI) testing necessary as part of Lynch syndrome work-up in the era of multiplex genetic testing?
Authors: Ahmad Fitri Idris, Simon D. Hooper, Michael P. Farrell, Carmel Nolan, Roisin Clarke, E Berkley, David J. Gallagher
Journal: Journal of Clinical Oncology (2014)

425 Background: IHC for mismatch repair proteins and MSI are commonly used to direct genetic testing for Lynch Syndrome. Abnormal results in the setting of a positive family history often lead to genetic testing for Lynch syndrome. The often cumbersome process of completing IHC/MSI requires obtaining stored tissue +/- blood from a family member affected with cancer. Upfront genetic testing is not favoured due to concerns about identifying variants of uncertain significance. We performed a review of Lynch syndrome work-up in Ireland, and propose a model that is the reverse of the current international standard, and may expedite and simplify work up of these families. Methods: Data was ascertained from three cancer genetics services in Dublin and included the following variables: date of birth, date of request and reporting results for IHC, MSI and genetic tests. Time intervals were determined for LS work-up for all patients who had the process initiated in these 3 centres. Results: Probands from 50 families referred for LS work-up were included.The median time from date of IHC request to date of IHC report (total of 50 patients) was 4 weeks (range: 4 days to 36 weeks). The median time between date of IHC request to date of MSI report (n = 32 patients) was 20 weeks (range: 4 to 56 weeks). The median time from date of genetic test request to date of result (n = 9 patients) was 9 weeks (range: 2 to 26 weeks). The median time for completion of all 3 tests in one individual (n=3 patients) was 14 weeks (range: 10 to 60 weeks). Conclusions: The diagnostic pathway for Lynch syndrome is cumbersome and often lengthy. Appropriate upfront multiplex genetic testing would expedite the identification of mismatch repair gene mutation carriers. IHC/MSI testing could be used to characterise variants of uncertain significance.
Hands On
Authors: Mark R. Fleisher
Journal: JAMA (1994)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Abstract 2573: DNA damaging drugs stimulate tRNA cleavage through SLFN11 to inhibit protein synthesis and induce cell death
Authors: Manqing Li, Elaine Kao, Dane Malone, Xia Gao, Jean Y. Wang, Michael David
Journal: Cancer Research (2019)

Abstract DNA damaging agents (DDAs) based chemotherapies are the first and still the most widely used anticancer treatments. However, quickly developed drug resistance of cancer cells often impedes their efficacies. Two independent transcriptome analyses in vast collections of cancer cell lines discovered that human SLFN11 is the only gene whose expression significantly sensitizes cancer cells to DNA damaging agents (DDAs) including Top1 and Top2 inhibitors, DNA alkylating agents, and DNA synthesis inhibitors. But the mechanism was unclear. We showed previously that SLFN11 inhibits HIV viral proteins syntheses by modulating tRNAs abundances and exploiting the biased codon usage of the virus. We hereby report that upon DDAs treatment, SLFN11 preferentially inhibits translation of genes involved in DNA damage response and repair, including ATR and ATM, based on their distinct codon usages, while the early DNA damage response signaling remains unaffected. Type II tRNAs, which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. The syntheses of proteins encoded by genes with high TTA (Leu) codon usage such as ATR display utmost susceptibility to SLFN11 expression due to the extreme low abundance of cognate tRNA-Leu-TAA. Specific inhibition of tRNA-Leu-TAA expression with special antisense oligonucleotides (Gapmers) suppressed ATR protein expression and restored DDA sensitivity of SLFN11-deficient cancer cells. Our study uncovered a novel mechanism of DNA damage response regulation mediated by SLFN11-dependent tRNA cleavage and codon-specific translational inhibition. Further investigation will elucidate the roles of SLFN11 in DNA damage-related tumorigenesis. More importantly, bioinformatics analysis revealed high frequency of codon TTA (Leu) usage in most genes involved in DNA damage response signaling and repair mechanisms including Homology Directed Repair (HDR), Nonhomologous End-Joining (NHEJ), and Mismatch Mediated Repair (MMR). Instead of targeting single gene product, novel therapies based on the modulation of tRNA-Leu-TAA expression would effect by inhibiting the protein synthesis of a wide spectrum of genes involved in DNA damage response and repair, thus preventing the development of drug resistance by cancer cells. Citation Format: Manqing Li, Elaine Kao, Dane Malone, Xia Gao, Jean Y. Wang, Michael David. DNA damaging drugs stimulate tRNA cleavage through SLFN11 to inhibit protein synthesis and induce cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2573.
The Role of Glutathione in Detoxication
Authors: Brian Ketterer, Brian Coles, David J. Meyer
Journal: Environmental Health Perspectives (1983)

Glutathione (GSH) is a strong nucleophile which reacts well with soft electrophiles, but poorly with both weak and strong electrophiles. Weak electrophiles have low reactivity with all nucleophiles while strong electrophiles react well with weak nucleophiles including superabundant H2O. There are enzymes, the GSH transferases, which catalyze GSH conjugation with all the types of electrophiles described above. In order to deal with the wide variety of potential substrates, a multiplicity of GSH transferases exists—each tissue having its own collection and each enzyme having a different substrate specificity. These enzymes are often very abundant, e.g., in the rat liver cytosol, their concentration is 0.2 mM. The following substrates are considered in some detail: 1-chloro-2,4-dinitrobenzene, the electrophile derived metabolically from paracetamol N-acetyliminoquinone?), benzo(a)pyrene-4-5-oxide, cholesterol-5α,6α-oxide, benzo(a)pyrene-7,8-diol-9,10-oxide and the electrophiles derived metabolically from aflatoxin B1 (the 2,3-oxide?). According to the substrate, optimal enzyme rates vary over seven orders of magnitude from 10−5 to 10−12 mole/min/mg. Despite the wide embrace of the GSH transferases, not all metabolically produced electrophiles are substrates. We know of the following examples: N-methylol-4-aminoazobenzene and its 4′-hydroxy derivative (these are soft electrophiles and react well with GSH noncatalytically), N-sulfonyloxy-N-methyl-4-aminoazobenzene, N-sulfonyloxy-N-acetyl-2-aminofluorene (these are strong electrophiles which do not react selectively with GSH) and N-hydroxy-2-aminofluorene which appears to react only slowly with GSH. It is of interest in the present context that all these compounds are derived from either arylamine or arylamide carcinogens. Whether the reaction be enzymic or nonenzymic, conjugation with GSH is a very important means of detoxication accounting in some cases for up to 60% of the biliary metabolites. As seen in the example of aflatoxin B1, very low enzymic rates observed in vitro are sufficient to account for apparently high rates of biliary excretion of GSH conjugates. GSH transferases have evolved other functions apart from the catalysis of GSH conjugation. GSH transferase B participates in the hepatic uptake of bilirubin and the intracellular distribution of the heme prosthetic group. It also has GSH peroxidase activity which suggests that it might participate in the detoxication of by-products of oxygen utilization including those produced by the action of cytochrome P-450. It is shown that GSH transferase B inhibits lipid peroxidation in vitro.
Board Examination
Authors: JONATHAN FREEMAN
Journal: Annals of Internal Medicine (1973)

Comments and Corrections1 May 1973Board ExaminationJONATHAN FREEMAN, M.D.JONATHAN FREEMAN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-78-5-792 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: One feels compelled to comment on Schumacher's study of the American Board of Internal Medicine written examination and the accompanying editorial (pp. 131-135 and 142-144, January 1973 issue). For those of us who work full-time in a teaching institution, certification by the Board will never be a "gateway to professional eminence and its economic advantages." However, as we move toward a more centralized form of health care delivery, certification by the Board may become more important than is suggested by that phrase.Recognizing this importance, a careful scientific eye should be cast on the evaluation proceedures. The...Reference1. EDWARDS A: Experimental Design in Psychological Research, revised ed. New York, Rinehart & Co. Inc., 1960, pp. 94-97, 105-106 Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: JONATHAN FREEMAN, M.D.Affiliations: Department of Medicine Boston City Hospital Harvard Medical School Boston, Massachusetts PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1973Volume 78, Issue 5 Page: 792-793 Keywords Health care ePublished: 1 December 2008 Issue Published: 1 May 1973 PDF downloadLoading ...
Third International Symposium of the World Association of Veterinary Microbiologists, Immunologists, and Specialists in Infectious Diseases
Journal: JNCI Journal of the National Cancer Institute (1975)

Third International Symposium of the World Association of Veterinary Microbiologists, Immunologists, and Specialists in Infectious Diseases JNCI: Journal of the National Cancer Institute, Volume 54, Issue 6, June 1975, Page 1498, https://doi.org/10.1093/jnci/54.6.1498 Published: 01 June 1975
Issue Information
Journal: Medicinal Research Reviews (2018)

The journal publishes timely critical reviews of topics related to medicinal research, broadly defined, to which the authors have made significant contributions.Appropriate topics include, but are not limited to, the underlying pathophysiology of important diseases and disease vectors; therapeutic approaches to the treatment of various diseases; the properties of molecular targets for therapeutic agents; important new methodologies facilitating the search for therapies; genomics and proteomics; structure-activity correlations of drug series; the development of new imaging and diagnostic tools; drug metabolism; drug delivery; and chemical, pharmacological, pharmacokinetic, pharmacodynamic, and clinical characteristics of important drugs.Articles are mainly solicited by the editors; however, voluntary contributions are also encouraged.In the latter case, potential authors are asked to contact the Editor-in-Chief with an outline before beginning to write in order to avoid duplication of effort and to ensure suitability of the topic and the level of coverage.
Achieving global child health goals
Authors: R. Voelker
Journal: JAMA (1995)

AN AFRICAN proverb says it takes an entire village to raise a child. Around the globe, children's health advocates are emulating such traditional wisdom as they measure recent gains and strive for greater improvements for children who suffer and die from such common killers as malnutrition, respiratory disease, and diarrhea. "The time has come to acknowledge that the health and safety of children is an issue of both domestic and global concern," said Wah Jun Tze, MD, professor of pediatrics at the University of British Columbia Faculty of Medicine, Vancouver, and chair of the second international congress on children's health conducted last month in Vancouver. The meeting attracted representatives from more than 60 countries and health ministers from 14 nations, including Egypt, Russia, and Thailand. They all focused on gauging international progress in children's health since the World Summit for Children in 1990. "The gains have been very impressive worldwide,"
BUENOS AIRES
Journal: JAMA (1921)

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 Journals 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 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
<i>A Handbook of Psychology and Mental Disease for use in Training Schools for Attendants and Nurses and in Medical Classes, and as a Ready Reference for the Practitioner</i>. By C. B. Burr, M. D., Medical Director of Oak Grove Hospital (Flint, Mich.) for Mental and Nervous Diseases. Fourth Edition. Revised and Enlarged. With illustrations. (<i>Philadelphia: F. A. Davis Company, Publishers, 1914,</i>.)
Journal: American Journal of Psychiatry (1914)
THE CARE OF THE VETERAN
Journal: JAMA (1924)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
HEALTH PROPAGANDA AT YALE UNIVERSITY.
Journal: JAMA (1907)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
The spectrum of activating <i>EGFR</i> mutations from cell-free DNA (cfDNA) in large pancreatic cancer cohort.
Authors: Kristin Sedgwick Price, Lesli Ann Kiedrowski, Fernando I. De Zarraga, Mike Cusnir, Richard B. Lanman, Rebecca J Nagy
Journal: Journal of Clinical Oncology (2019)

237 Background: Metastatic pancreatic cancer (mPC) is one of the deadliest cancers with a &lt; 10% 5-year survival rate. Poor prognosis is well established with lack of response to or rapid progression on existing chemotherapy options. Targeted therapies, like EGFR-TKIs, have been shown to increase survival in other solid tumors like NSCLC with certain oncogenic drivers. Although treatment with the EGFR-TKI erlotinib, in combination with gemcitabine, is available for patients (pts) with mPC, the survival benefit is small in unselected patients. A better understanding of the spectrum of EGFR mutations in mPC may lead to improved therapy selection. Methods: We retrospectively reviewed genomic results from 2,938 consecutive mPC pt samples sent for ctDNA NGS analysis between 7/2014 - 9/2018 (Guardant Health, Inc.). All reported EGFR mutations were reviewed and activating mutations were determined based on literature review. Results: 19 EGFR activating mutations were identified in 16 unique pts (0.66% of total mPC pts with alterations detected). 3 mutations were identified in the extracellular domain and 16 mutations in the tyrosine kinase domain (3 in exon 18, 3 in exon 19, 6 in exon 20, 4 in exon 21). Alterations in exon 20 included 5 T790M mutations; two of these were reported at allelic frequencies suggestive of germline origin. Analysis of co-mutations revealed 7 pts with EGFR mutations that appeared subclonal relative to other potential drivers (4 KRAS, 2 ERBB2, 1 GNAS). The median number of alterations per sample was 4 (range 2-170) with the latter pt exhibiting a hypermutator phenotype. Multiple pts had more than one activating EGFR alteration including one who was found to have 4 EGFR sequence alterations (S768I, L861Q, T790M, p.Val769_Asp770insMet) plus EGFR amplification (plasma copy number 66.8). We will collect and report clinical details to characterize the treatment context for these pts. Conclusions: Activating EGFR mutations in mPC are rare but may present an opportunity for targeted therapy in this population. Further exploration is warranted to better understand the oncogenic activity of less common, subclonal, or co-occurring EGFR mutations and their sensitivity to EGFR-TKIs in mPC.
Authors' response
Authors: R. Hubbard, D. Baldwin
Journal: Thorax (2010)

<h3>Objective.</h3> Assess whether baseline anticyclic citrullinated peptide antibodies (anti-CCP) status is associated with treatment response in patients with rheumatoid arthritis (RA) initiating abatacept (ABA) or a tumor necrosis factor-α inhibitor (TNFi). <h3>Methods.</h3> Using the Corrona RA registry, patients were identified who initiated ABA or a TNFi (June 2004–January 2015), had a followup visit 6 months (± 3 mos) after initiation, and anti-CCP measured at or prior to initiation. Primary outcome was mean change in Clinical Disease Activity Index (CDAI) from initiation to 6 months. Treatment response was evaluated based on a typical patient profile (female, aged 57 yrs, body mass index of 30 kg/m<sup>2</sup>, baseline CDAI of 20, 1 prior biologic, and no comorbidities other than RA). Secondary outcomes included remission and low disease activity. <h3>Results.</h3> There were 566 ABA initiators [anti-CCP+ (≥ 20 units/ml): n = 362; anti-CCP− (&lt; 20 units/ml): n = 204] and 1715 TNFi initiators (anti-CCP+: n = 1113; anti-CCP−: n = 602). Differences between treatment groups included baseline disease duration, CDAI, and prior biologic use. At 6 months, anti-CCP+ ABA initiators were associated with significantly greater CDAI response versus anti-CCP− ABA initiators; no significant difference was observed for TNFi initiators. When considering a typical RA patient profile, CDAI response was greater in anti-CCP+ versus anti-CCP− ABA initiators; anti-CCP+ versus anti-CCP− TNFi initiators were similar. Secondary outcome responses were also greater in anti-CCP+ versus anti-CCP− ABA initiators; TNFi initiators did not differ by anti-CCP status. <h3>Conclusion.</h3> In a US-based clinical practice setting, anti-CCP status was associated with a differential treatment response to ABA, but not TNFi.
Expanding diagnostic uses of salivary studies
Journal: JAMA (1969)

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 Journals 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 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
Frozen Blood
Authors: C. Robert Valeri
Journal: New England Journal of Medicine (1966)

THIS article reviews developments in the long-term preservation of human red cells with the use of freezing technics. The discussion is concerned primarily with the safety and efficacy of the biologic product resulting from each of the current processes, which differ markedly in the stage of their clinical evaluation. By design, the review excludes consideration of much background material in the nature of the physicochemical phenomena of freezing and in vitro experimentation that is not directly related to clinical situations. Details of this background information may be obtained from some of the principal references cited and from other reviews.1 , 2 It . . .