tbuckley/cabot-search huggingface dataset:
Recurrent rhinovirus infections in a child with inherited MDA5 deficiency
Authors: Ian T. Lamborn, Huie Jing, Yu Zhang, Scott B. Drutman, Jordan K. Abbott, Shirin Munir, Sangeeta Bade, Heardley M. Murdock, Celia P. Santos, Linda G. Brock, Evan Masutani, Emmanuel Y. Fordjour, Joshua J. McElwee, Jason D. Hughes, Dave P. Nichols, Aziz Belkadi, Andrew J. Oler, Corinne S. Happel, Helen F. Matthews, Laurent Abel, Peter L. Collins, Kanta Subbarao, Erwin W. Gelfand, Michael J. Ciancanelli, Jean-Laurent Casanova, Helen C. Su
Journal: The Journal of Experimental Medicine (2017)

MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV infection while increasing IFN-stimulated gene expression and IFN-β/λ. However, wild-type MDA5 did not restrict influenza virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus.
A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia
Authors: V Santini, B Allione, G Zini, D Gioia, M Lunghi, A Poloni, D Cilloni, A Sanna, E Masiera, M Ceccarelli, O Abdel-Wahab, A Terenzi, E Angelucci, C Finelli, F Onida, A Pelizzari, D Ferrero, G Saglio, M Figueroa, A Levis
Journal: Leukemia (2017)

Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1-5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4-57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.
How Pregnancy Impacts Adult Cyanotic Congenital Heart Disease
Authors: Magalie Ladouceur, Louise Benoit, Adeline Basquin, Jelena Radojevic, Quentin Hauet, Sébastien Hascoet, Pamela Moceri, Laurianne Le Gloan, Pascal Amedro, Hugues Lucron, Adelaide Richard, Marielle Gouton, Jacky Nizard
Journal: Circulation (2017)
Mitotic index to predict breast cancer recurrence after neoadjuvant systemic therapy.
Authors: Daniel J. Farrugia, Alessandra Landmann, Emilia Diego, Priscilla F. McAuliffe, Ronald Johnson, Marguerite Bonaventura, Atilla Soran, David J. Dabbs, Beth Clark, Shannon Puhalla, Adam Brufsky, Rachel Catherine Jankowitz, Barry C. Lembersky, Nancy E. Davidson, Gretchen M. Ahrendt, Rohit Bhargava
Journal: Journal of Clinical Oncology (2016)

e23265 Background: For breast cancer patients that do not achieve pathologic complete response (pCR) after neoadjuvant therapy (NAT), a straightforward prognostic indicator is lacking. The mitotic index is routinely measured on breast specimens after completion of NAT along with tubular formation score (TS) and nuclear pleomorphism score (NS) as part of the Nottingham Grade (NG) and is inexpensive and reproducible. We hypothesized that Mitotic Count Score (MCS), that ranges from 1-3, is a predictor of tumor recurrence in patients that do not achieve pCR. Methods: We retrospectively identified consecutive breast cancer patients who received NAT at our institution from 2010-2014. Of 614 patients, we eliminated 160 patients that achieved pCR (no tumor in breast or axilla) and 89 that did not have NG available. 367 remained eligible for inclusion. Of these, 251 were hormone receptor (HR) +ve and 116 were HR -ve. 83 were triple negative tumors (TNBC, 22.6%). 98 were HER2 +ve (26.7%) independent of HR status. Mean follow up was 32.8 months. Chi-Square analysis was performed. Results: Breast cancer recurrence showed a statistically significant proportional relationship with MCS (see table below). MCS remained associated with tumor recurrence on subset analysis for both HR+ (p < 0.0001) and HR- (p = 0.037) tumors independent of HER2 status, and on subset analysis for TNBC (p = 0.043). It also remained associated in premenopausal patients (p < 0.0001), and in the presence of lymph node (LN) metastases at time of surgery (p < 0.0001). NG and its remaining components TS and NS showed a much weaker association with tumor recurrence, and lost statistical significance on subset analysis for HR- and TNBC. The association of either MCS or NHG with recurrence did not reach statistical significance on subset analysis for HER2+ve tumors. Conclusions: In patients who do not achieve pCR after NAT, MCS is a simple inexpensive assay that predicts breast cancer recurrence and is independent of HR, menopausal status or LN positivity. A larger sample is needed to validate these results in HER2+ tumors. Mitotic Count n Deaths Overall Recurrence (%) RR p 95% CI Score 1 191 5 18 (9.4) Score 2 90 10 20 (22.2) 2.39 0.003 1.31, 4.23 Score 3 86 22 35 (40.7) 4.32 < 0.0001 2.60, 7.18 Score 3 vs 2 1.83 0.008 1.15, 2.91
Hunt will ask chancellor to consider lifting NHS pay cap
Authors: Tom Moberly
Journal: BMJ (2017)

Jeremy Hunt, England’s health secretary, has said that he has “sympathy” for calls to increase NHS pay and that he would put the case for lifting the cap on pay rises to the Treasury.

Speaking at the NHS Confederation’s annual conference in Liverpool on 15 June, Hunt was asked about calls to lift the current cap on public sector pay, which limits pay rises for NHS staff to 1% a year until 2019.

NHS doctors’ pay is determined by the recommendations of the Review Body on Doctors’ and Dentists’ Remuneration (DDRB). The DDRB has been told by the Treasury that overall pay awards should be within the 1% cap for all public sector workers, and its recommendation for 2016-17 was for a 1% pay …
Erratum. Increased Risk of Fracture and Postfracture Adverse Events in Patients With Diabetes: Two Nationwide Population-Based Retrospective Cohort Studies. Diabetes Care 2014;37:2246–2252
Authors: Chien-Chang Liao, Chao-Shun Lin, Chun-Chuan Shih, Chun-Chieh Yeh, Yi-Cheng Chang, Yuan-Wen Lee, Ta-Liang Chen
Journal: Diabetes Care (2017)

In the article cited above, the third affiliation was corrected to read “Department of Anesthesiology, School of …
The updated force field parameters for molecular modeling of cisplatin and oxaliplatin adducts with DNA
Authors: Peng Gong, Debadeep Bhattacharyya, Nikolay V. Dolkholyan, Brenda Temple, Stephen G. Chaney
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1566 

Conformational changes in the DNA duplex introduced by the anticancer drugs cisplatin (CP) and oxaliplatin (OX) may be, in part, responsible for their difference in tumor specificity and mutagenicity. The accuracy of force field parameters employed for molecular mechanics modeling is crucial for molecular dynamics (MD) simulations, resulting in agreement with experimental data and meaningful predictions. Here we report force field parameters for molecular mechanics modeling of CP and OX adducts with DNA. We conducted quantum mechanics calculations using Gaussian03 on the 9-methyl-guanine derivatives of CP and OX to determine the atomic partial charges. These charges were determined by Mulliken method based on either NMR structures or geometry optimized structures. The Mulliken method was not sensitive to the geometry of structures and was able to produce consistent and reasonable charges. After averaging the charges of chemically identical atoms, the differences between the two sets of Mulliken charges, one based on distorted NMR structures and the other based on geometry optimized structures, were no more than 0.1 e. The other force field parameters were extended based on AMBER parm99 force field parameters and previous work by Yao et al and Scheeff et al . Forty 10 ns unrestrained MD simulations of a 12-mer DNA duplex d(5’-CCTCAG\*G\*CCTCC-3’)-d(5’-GGAGGCCTGAGG-3’) (G* = G coordinated to platinum) , containing either cis -Pt(NH3)22+ (CP-DNA) or (trans-RR)1,2 -Pt(C6H10)(NH2)22+ (OX-DNA) crosslinking moiety, were conducted under fully solvated condition with counter ions to investigate the impact of the two sets of Mulliken charges. From extensive root mean square standard deviation (RMSD) analysis, we concluded that the differences in the two sets of Mulliken charges did not have significant impacts on the simulations, and that the simulations were independent of the starting structures. The updated force field parameters were capable of driving the structures to a similar conformational ensemble of which the critical inter-proton distances were within the NMR experimental range. Ten out of forty 10 ns simulations starting from our NMR structures are being analyzed extensively, focusing on the central four AG\*G\*C base-pairs. The RMSD analysis of the trajectories of the ten simulations showed less flexibility for the OX-DNA adduct compared to the CP-DNA adduct. In addition, the 5’ end of both platinated adducts shows higher flexibility than the 3’ end. Comparison of interproton distances between the NMR and that of our simulated structures revealed only 11 / 175 violations for the CP-DNA adduct and 3 / 112 for the OX-DNA adduct. (supported by NIH grant CA84480)
The Endothelin-Converting Enzyme-1 (ECE-1) as a novel target in breast cancer therapy
Authors: Martin Smollich, Martin Gotte, Christian Kersting, Johannes Aebi, Jeanett Fischgrabe, Isabel Radke, Ludwig Kiesel, Pia Wulfing
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

631 

The endothelin axis (ET axis), comprising peptide hormones endothelin(ET)-1, -2, -3 and their receptors (ETAR and ETBR), has previously been shown to be of major importance in development and progression of breast carcinomas. Engagement of ET-1 to ETAR induces cell proliferation, angiogenesis and anti-apoptosis. Therefore, the ET axis has been proposed to represent a novel target in cancer therapies. However, so far little is known about the relevance of ET-1 biosynthesizing endothelin-converting enzyme-1 (ECE-1) and ET-1 degrading neprilysin (NEP). In this study, we determined the role of ECE-1 and NEP in breast carcinomas and evaluated their clinical and prognostic significance. First, we analysed expression of ECE-1, NEP, ET-1, ETAR and vascular endothelial growth factor (VEGF) immunohistochemically in 600 tissue samples from paraffin-embedded breast carcinomas applying tissue microarray technology. Results were correlated with pathological and clinical parameters. Furthermore, human breast tissue samples were analysed for their ECE-1 and NEP expression levels by quantitative real-time RT-PCR at different stages of tumorigenesis. Moreover, the effects of the novel, selective ECE-1 inhibitor RO 67-7447 (F. Hoffmann-La Roche) on ET-1 expression as well as breast cancer cell proliferation, migration and invasion have been investigated. Resulting from immunohistochemical staining, 61% (63%) of breast carcinomas were found to express ECE-1 (NEP) at moderate or strong level. For ECE-1 expression, we found a statistically significant correlation with VEGF expression (p < 0.001) and ETAR expression (p = 0.048). Whereas patients with ECE-1 overexpressing tumors had more frequently disease recurrence (p = 0.030), NEP overexpression was found to correlate with longer DFS (p = 0.023) and lower incidence of metastases (p = 0.046). During malignant progression, expression of NEP was strongly reduced, leading to a significant increase of the ECE-1/NEP ratio. Incubation of breast cancer cells with the selective ECE-1 inhibitor RO 67-7447 significantly decreased both ET-1 mRNA and protein expression. Moreover, invasiveness of MCF-7 breast cancer cells was strongly reduced (54.3% of controls) due to ECE-1 inhibition. Our findings suggest that increased ECE-1 expression is associated with unfavourable outcome, whereas increased NEP expression positively influences patient survival. Therefore, expression of ECE-1 and NEP may have prognostic relevance. Moreover, our results for the first time indicate that due to massive reduction of cancer cell invasiveness, selective inhibition of ECE-1 represents an innovative, promising approach in future breast cancer therapy.
The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in <i>IDH1</i>-Mutant Cancers and Potentiates NAD+ Depletion–Mediated Cytotoxicity
Authors: Kensuke Tateishi, Fumi Higuchi, Julie J. Miller, Mara V.A. Koerner, Nina Lelic, Ganesh M. Shankar, Shota Tanaka, David E. Fisher, Tracy T. Batchelor, A. John Iafrate, Hiroaki Wakimoto, Andrew S. Chi, Daniel P. Cahill
Journal: Cancer Research (2017)

IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD+ consumption driven by PARP activation. In IDH1-mutant-expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD+, introducing a window of hypervulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD+ pathways yield potent anticancer efficacy in vivo Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. Cancer Res; 77(15); 4102-15. ©2017 AACR.
Cognitive Function After Testosterone Treatment
Authors: Susan M. Resnick, Alvin M. Matsumoto, Alisa J. Stephens-Shields
Journal: JAMA (2017)

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
PROFILE: Broadly based genomic testing for all patients at a major cancer center.
Authors: Barrett J Rollins, Laura E. MacConaill, Nikhil Wagle, Elizabeth Garcia, Frank C Kuo, Janina A Longtine, Judy Ellen Garber, Katherine A. Janeway, Charles S. Fuchs, Monica M. Bertagnolli, Robert Soiffer, Ursula Matulonis, Nancy U. Lin, William C Hahn, Levi A. Garraway, Philip W. Kantoff, Neal Ian Lindeman
Journal: Journal of Clinical Oncology (2013)

1531 Background: Genotyping plays an increasingly important role in the management of cancer patients. However, the landscape of genomic abnormalities is unknown for many cancers and the influence of specific genotypes on clinical behavior is often unclear. To address these deficiencies, we developed PROFILE, a project designed to obtain genomic information on all patients who come to our hospitals for cancer-related care. Methods: Clinically acquired specimens were genotyped using a mass spectrometry genotyping test (OncoMap) which assays 471 alleles in 41 cancer-related genes. Because the majority of these alleles currently have no known clinical meaning, we implemented PROFILE as a research test. This required developing an "umbrella" protocol governing PROFILE activity, a highly simplified 2-page consenting brochure, and a centralized consenting process. We created process flows for retrieving clinical specimens and performing OncoMap in a CLIA-certified laboratory. We return results on individual participants to their ordering providers who can use actionable findings to guide management. All results are stored in a database which can be queried using a web-based search tool that returns aggregate results. Approval to link specimen to clinical information can be sought by a streamlined process of User Committee and IRB approval, and linkage is performed by IS acting as honest brokers. Results: From August 2011 through December 2012, we consented 12,980 patients (consent rate &gt;70%). We found that 39% of clinical samples are of sufficient quality to yield OncoMap results. We have reported and stored 3,000 genotyping results. OncoMap mutations were detected in 40% of clinical samples. As expected, mutations in KRAS, PIK3CA, TP53, and BRAF were most commonly observed across all tumor types. However, rarer mutations were also detected in RET, PIK3R1, and ERBB2 among others. Conclusions: Novel operational approaches have permitted enterprise-wide, broadly-based genotyping that serves a combination of research and clinical needs. Early insights from this database will be discussed along with information about their impact on clinical management.
Instruction or Education?
Journal: BMJ (1949)

In 1938, a teachers' training college opened in Rufisque, Senegal, for young girls from all parts of French West Africa.   This establishment had a twofold objective: train the first female primary school teachers and educate the future spouses of the men enrolled in higher education.   The political and ideological issues underlying the creation of this institution had less to do with educating young women than with instilling in them the values and behaviors that would help France take root in the colonies.   With the goal of turning out accomplished housewives and worthy mothers, the college's first principal, Germaine Le Goff, advocated, in line with official instructions, a complete moral and practical instruction in parallel to a basic education and a few lessons in the science of education itself.   The principles of education applied at the college tended to be like those that prevailed in secondary schools for girls in late 19th century France.   Nonetheless, creating this college marked a key phase in the professionalization of women, a process that started in French West Africa following WWI.   Opening a section for midwives in the school of medicine in 1918 and institutionalizing nurses' training as of 1930 were other phases therein.   The teachers' training college in Rufisque tended to represent the best of what the French administration did for educating African girls.
E-Cadherin Promoter Hypermethylation in Sporadic Colorectal Cancer
Authors: EJ Fox, DT Leahy, R Geraghty, A Lennon, D Keegan, A White, HE Mulcahy, JM Hyland, D Fennelly, DP O'Donoghue, K Sheahan
Journal: Endoscopy (2004)

Aims: E-cadherin belongs to a family of calcium-dependent adhesion molecules that mediate intercellular contacts critical to morphogenesis and the maintenance of cellular architecture. Previous studies have implicated the loss of E-cadherin in tumour progression, invasion and metastasis. Promoter hypermethylation has been associated with transcriptional silencing of several genes, including E-cadherin, in various forms of cancer.