tbuckley/cabot-search huggingface dataset:
RNF126 as a Biomarker of a Poor Prognosis in Invasive Breast Cancer and CHEK1 Inhibitor Efficacy in Breast Cancer Cells
Authors: Xiaosong Yang, You Pan, Zhaojun Qiu, Zhanwen Du, Yao Zhang, Pengyan Fa, Shashank Gorityala, Shanhuai Ma, Shunqiang Li, Ceshi Chen, Hongbing Wang, Yan Xu, Chunhong Yan, Keri Ruth, Zhefu Ma, Junran Zhang
Journal: Clinical Cancer Research (2018)

Abstract Purpose: (i) To investigate the expression of the E3 ligase, RNF126, in human invasive breast cancer and its links with breast cancer outcomes; and (ii) to test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell-cycle checkpoint kinase, CHEK1. Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive breast cancer and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHEK1 expression was determined by chromatin immunoprecipitation and a CHEK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHEK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. Results: RNF126 protein expression was elevated in breast cancer tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHEK1 transcript expression. Critically, a strong correlation between RNF126 and CHEK1 proteins was identified in breast cancer tissue and cell lines. The inhibition of CHEK1 induced a greater cell killing and a higher level of replication stress in breast cancer cells expressing RNF126 compared to RNF126 depleted cells. Conclusions: RNF126 protein is highly expressed in invasive breast cancer tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive breast cancer and is considered a potential biomarker of a cancer's responsiveness to CHEK1 inhibitors. CHEK1 inhibition targets breast cancer cells expressing higher levels of RNF126 by enhancing replication stress. Clin Cancer Res; 24(7); 1629–43. ©2018 AACR.
Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma
Authors: Roger Stupp, Sophie Taillibert, Andrew Kanner, William Read, David M Steinberg, Benoit Lhermitte, Steven Toms, Ahmed Idbaih, Manmeet S Ahluwalia, Karen Fink, Francesco Di Meco, Frank Lieberman, Jay-Jiguang Zhu, Giuseppe Stragliotto, David D Tran, Steven Brem, Andreas F Hottinger, Eilon D Kirson, Gitit Lavy-Shahaf, Uri Weinberg, Chae-Yong Kim, Sun-Ha Paek, Garth Nicholas, Jordi Burna, Hal Hirte, Michael Weller, Yoram Palti, Monika E Hegi, Zvi Ram
Journal: JAMA (2017)
Should Hormone Therapy Be Used to Prevent Depressive Symptoms During the Menopause Transition?
Authors: Hadine Joffe, Martha Hickey
Journal: JAMA Psychiatry (2018)

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
Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies
Authors: Gaelle Auguste, Priyatansh Gurha, Raffaella Lombardi, Cristian Coarfa, James T. Willerson, Ali J. Marian
Journal: Circulation Research (2018)

Rationale: Mutations in the LMNA gene, encoding nuclear inner membrane protein lamin A/C, cause distinct phenotypes, collectively referred to as laminopathies. Heart failure, conduction defects, and arrhythmias are the common causes of death in laminopathies. Objective: The objective of this study was to identify and therapeutically target the responsible mechanism(s) for cardiac phenotype in laminopathies. Methods and Results: Whole-heart RNA sequencing was performed before the onset of cardiac dysfunction in the Lmna −/− and matched control mice. Differentially expressed transcripts and their upstream regulators were identified, validated, and targeted by adeno-associated virus serotype 9-short hairpin RNA constructs. A total of 576 transcripts were upregulated and 233 were downregulated in the Lmna −/− mouse hearts ( q &lt;0.05). Forkhead box O (FOXO) transcription factors (TFs) were the most activated while E2 factors were the most suppressed transcriptional regulators. Transcript levels of FOXO targets were also upregulated in the isolated Lmna −/− cardiac myocytes and in the myocardium of human heart failure patients. Nuclear localization of FOXO1 and 3 was increased, whereas phosphorylated (inactive) FOXO1 and 3 levels were reduced in the Lmna −/− hearts. Gene set enrichment analysis and gene ontology showed activation of apoptosis and inflammation and suppression of cell cycle, adipogenesis, and oxidative phosphorylation in the Lmna −/− hearts. Adeno-associated virus serotype 9-short hairpin RNA–mediated suppression of FOXO TFs rescued selected molecular signatures, improved apoptosis, and prolonged survival by ≈2-fold. Conclusions: FOXO TFs are activated and contribute to the pathogenesis of cardiac phenotype in laminopathies. Suppression of the FOXO TFs in cardiac myocytes partially rescues the phenotype and prolongs survival. The findings identify FOXO TFs as potential therapeutic targets for cardiac phenotype in laminopathies.
Neutrophils Involvement in Human Thyroid Cancer
Authors: Maria Rosaria Galdiero, Gilda Varricchi, Stefania Loffredo, Claudio Bellevicine, Tiziana Lansione, Anne Lise Ferrara, Raffaella Iannone, Sarah Di Somma, Francesco Borriello, Eduardo Clery, Maria Triassi, Giancarlo Troncone, Gianni Marone
Journal: Journal of Allergy and Clinical Immunology (2018)
Is Neck Circumference Associated with Asthma Severity in Adolescence?
Authors: Heloisa N. Oliveira, Jessica Rosemberger, Alanne M.S. Bonfim, Natalia A. Salata, Amanda M. Vieira, Maria Regina A. Cardoso, Maria Celia C. Ciaccia, Vera E. Rullo
Journal: Journal of Allergy and Clinical Immunology (2018)
Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene-diet interaction analysis in two prospective cohort studies
Authors: Tiange Wang, Yoriko Heianza, Dianjianyi Sun, Tao Huang, Wenjie Ma, Eric B Rimm, JoAnn E Manson, Frank B Hu, Walter C Willett, Lu Qi
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To investigate whether improving adherence to healthy dietary patterns interacts with the genetic predisposition to obesity in relation to long term changes in body mass index and body weight. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> Health professionals in the United States. <h3>Participants</h3> 8828 women from the Nurses’ Health Study and 5218 men from the Health Professionals Follow-up Study. <h3>Exposure</h3> Genetic predisposition score was calculated on the basis of 77 variants associated with body mass index. Dietary patterns were assessed by the Alternate Healthy Eating Index 2010 (AHEI-2010), Dietary Approach to Stop Hypertension (DASH), and Alternate Mediterranean Diet (AMED). <h3>Main outcome measures</h3> Five repeated measurements of four year changes in body mass index and body weight over follow-up (1986 to 2006). <h3>Results</h3> During a 20 year follow-up, genetic association with change in body mass index was significantly attenuated with increasing adherence to the AHEI-2010 in the Nurses’ Health Study (P=0.001 for interaction) and Health Professionals Follow-up Study (P=0.005 for interaction). In the combined cohorts, four year changes in body mass index per 10 risk allele increment were 0.07 (SE 0.02) among participants with decreased AHEI-2010 score and −0.01 (0.02) among those with increased AHEI-2010 score, corresponding to 0.16 (0.05) kg versus −0.02 (0.05) kg weight change every four years (P&lt;0.001 for interaction). Viewed differently, changes in body mass index per 1 SD increment of AHEI-2010 score were −0.12 (0.01), −0.14 (0.01), and −0.18 (0.01) (weight change: −0.35 (0.03), −0.36 (0.04), and −0.50 (0.04) kg) among participants with low, intermediate, and high genetic risk, respectively. Similar interaction was also found for DASH but not for AMED. <h3>Conclusions</h3> These data indicate that improving adherence to healthy dietary patterns could attenuate the genetic association with weight gain. Moreover, the beneficial effect of improved diet quality on weight management was particularly pronounced in people at high genetic risk for obesity.
Food allergen‐sensitized <scp>CCR</scp>9<sup>+</sup> lymphocytes enhance airways allergic inflammation in mice
Authors: L. Castan, M.‐A. Cheminant, L. Colas, S. Brouard, A. Magnan, G. Bouchaud
Journal: Allergy (2018)

The mechanisms of the atopic march, characterized by a natural progression from food and cutaneous allergies to rhinitis and asthma, are still unknown. However, as several organs can be involved, chemokines and their receptors might be implicated in this process and may be instrumental factors. We hypothesized that the T-cell gut-homing receptor CCR9 could be implicated in the evolution of allergic diseases. We characterized the immune response and the role of CCR9 in a murine model combining food allergy to wheat gliadin and a model of acute airways inflammation in response to house dust mite. Compared with solely asthmatic-like mice, we demonstrated that the aggravation of pulmonary symptoms in consecutive food and respiratory allergies, characterized by an increase in pulmonary resistance and a higher Th17/Treg ratio, was abrogated in CCR9 knockout mice. Moreover, transfer of food-allergic CD4+ T cells from wild-type but not from CCR9-/- aggravated airways inflammation demonstrating that CCR9 is involved in food allergy-enhanced allergic airway inflammation to unrelated allergens. Taken together, our results demonstrated a crucial role of the T-cell homing receptor CCR9 in this model and validated its potential for use in the development of therapeutic strategies for allergic diseases.
Efficacy and Safety of Ranibizumab 0.5 mg for the Treatment of Macular Edema Resulting from Uncommon Causes
Authors: Giovanni Staurenghi, Timothy Y.Y. Lai, Paul Mitchell, Sebastian Wolf, Andreas Wenzel, Jun Li, Amitabha Bhaumik, Philip G. Hykin
Journal: Ophthalmology (2018)

<h3>Purpose</h3> To evaluate the efficacy and safety of ranibizumab 0.5 mg in adult patients with macular edema (ME) resulting from any cause other than diabetes, retinal vein occlusion, or neovascular age-related macular degeneration. <h3>Design</h3> A phase 3, 12-month, double-masked, randomized, sham-controlled, multicenter study. <h3>Participants</h3> One hundred seventy-eight eligible patients aged ≥18 years. <h3>Methods</h3> Patients were randomized 2:1 to receive either ranibizumab 0.5 mg (n = 118) or sham (n = 60) at baseline and month 1. From month 2, patients in both arms received open-label individualized ranibizumab treatment based on disease activity. A preplanned subgroup analysis was conducted on the primary end point on 5 predefined baseline ME etiologies (inflammatory/post-uveitis, pseudophakic or aphakic, central serous chorioretinopathy, idiopathic, and miscellaneous). <h3>Main Outcome Measures</h3> Changes in best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study letters) from baseline to month 2 (primary end point) and month 12 and safety over 12 months. <h3>Results</h3> Overall, 156 patients (87.6%) completed the study. The baseline characteristics were well balanced between the treatment arms. Overall, ranibizumab showed superior efficacy versus sham from baseline to month 2 (least squares mean BCVA, +5.7 letters vs. +2.9 letters; 1-sided <i>P</i> = 0.0111), that is, a treatment effect (TE) of +2.8 letters. The mean BCVA gain from baseline to month 12 was 9.6 letters with ranibizumab. The TE at month 2 was variable in the 5 predefined etiology subgroups, ranging from >5-letter gain to 0.5-letter loss. The safety findings were consistent with the well-established safety profile of ranibizumab. <h3>Conclusions</h3> The primary end point was met and ranibizumab showed superiority in BCVA gain over sham in treating ME due to uncommon causes, with a TE of +2.8 letters versus sham at month 2. At month 12, the mean BCVA gain was high (9.6 letters) in the ranibizumab arm; however, the TE was observed to be variable across the different etiology subgroups, reaching a >1-line TE in BCVA in patients with ME resulting from inflammatory conditions/post-uveitis or after cataract surgery. Overall, ranibizumab was well tolerated with no new safety findings up to month 12.
Similar localization of conformational IgE epitopes on the house dust mite allergens Der p 5 and Der p 21 despite limited IgE cross‐reactivity
Authors: M. Curin, T. Garmatiuk, Y. Resch‐Marat, K. W. Chen, G. Hofer, K. Fauland, W. Keller, W. Hemmer, S. Vrtala, M. Focke‐Tejkl, R. Valenta
Journal: Allergy (2018)

Due to high IgE recognition frequency and high allergenic activity, Der p 5 and Der p 21 are clinically important house dust mite (HDM) allergens. The objective of this study was to characterize the immunodominant IgE epitopes of Der p 5 and Der p 21 responsible for their high allergenic activity.A panel of 12 overlapping peptides spanning the Der p 5 and Der p 21 sequence were synthesized to search for sequential IgE epitopes by direct testing for allergic patients' IgE reactivity. Peptide-specific antibodies raised in rabbits were used in inhibition studies for localizing conformational IgE epitopes which were visualized on the surfaces of the allergen structures by molecular modelling. IgE cross-reactivity between the allergens was investigated by IgE inhibition studies.Immunodominant IgE epitopes defined by allergic patients' IgE on Der p 5 and Der p 21 were primarily of the conformational, discontinuous type including N- and C-terminal portions of the protein. They could be located on each allergen on one area with similar localization, but despite similar structure of the allergens, no relevant IgE cross-reactivity could be detected.Our study shows that Der p 5 and Der p 21 contain a major conformational IgE epitope-containing area located on similar portions of their structure, but they lack relevant IgE cross-reactivity. These data are important for the development of modern allergy vaccines based on defined molecules for allergen-specific immunotherapy of HDM allergy.
Analysis of Margin Classification Systems for Assessing the Risk of Local Recurrence After Soft Tissue Sarcoma Resection
Authors: Kenneth R. Gundle, Lisa Kafchinski, Sanjay Gupta, Anthony M. Griffin, Brendan C. Dickson, Peter W. Chung, Charles N. Catton, Brian O’Sullivan, Jay S. Wunder, Peter C. Ferguson
Journal: Journal of Clinical Oncology (2018)

Purpose To compare the ability of margin classification systems to determine local recurrence (LR) risk after soft tissue sarcoma (STS) resection. Methods Two thousand two hundred seventeen patients with nonmetastatic extremity and truncal STS treated with surgical resection and multidisciplinary consideration of perioperative radiotherapy were retrospectively reviewed. Margins were coded by residual tumor (R) classification (in which microscopic tumor at inked margin defines R1), the R+1mm classification (in which microscopic tumor within 1 mm of ink defines R1), and the Toronto Margin Context Classification (TMCC; in which positive margins are separated into planned close but positive at critical structures, positive after whoops re-excision, and inadvertent positive margins). Multivariate competing risk regression models were created. Results By R classification, LR rates at 10-year follow-up were 8%, 21%, and 44% in R0, R1, and R2, respectively. R+1mm classification resulted in increased R1 margins (726 v 278, P &lt; .001), but led to decreased LR for R1 margins without changing R0 LR; for R0, the 10-year LR rate was 8% (range, 7% to 10%); for R1, the 10-year LR rate was 12% (10% to 15%) . The TMCC also showed various LR rates among its tiers ( P &lt; .001). LR rates for positive margins on critical structures were not different from R0 at 10 years (11% v 8%, P = .18), whereas inadvertent positive margins had high LR (5-year, 28% [95% CI, 19% to 37%]; 10-year, 35% [95% CI, 25% to 46%]; P &lt; .001). Conclusion The R classification identified three distinct risk levels for LR in STS. An R+1mm classification reduced LR differences between R1 and R0, suggesting that a negative but &lt; 1-mm margin may be adequate with multidisciplinary treatment. The TMCC provides additional stratification of positive margins that may aid in surgical planning and patient education.
A Prognostic Classifier Based on Early Platelet Drop in Lower-Risk MDS. a Study from the European Leukemianet Lower-Risk MDS (EUMDS) Registry
Authors: Raphael Itzykson, Simon Crouch, Alex Smith, Argiris Symeonidis, Eva Hellstrom-Lindberg, Guillermo Sanz, Jaroslav Cermak, Reinhard Stauder, Luca Malcovati, Ulrich Germing, Moshe Mittelman, Saskia Langemeijer, Krzysztof Madry, Aurelia Tatic, Mette Skov Holm, Antonio Medina de Almeida, Aleksandar Savic, Njetočka Gredelj-Šimec, Elisa Luño Fernandez, Dominic Culligan, Agnes Guerci Bresler, Corine van Marrewijk, David T. Bowen, T. M. M de Witte, Pierre Fenaux
Journal: Blood (2017)
Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN)
Authors: J.-P. Machiels, P. Bossi, J. Menis, M. Lia, C. Fortpied, Y. Liu, R. Lhommel, M. Lemort, S. Schmitz, S. Canevari, L. De Cecco, M. Guzzo, R. Bianchi, P. Quattrone, F. Crippa, T. Duprez, Y. Lalami, M. Quiriny, N. de Saint Aubain, P.M. Clement, R. Coropciuc, E. Hauben, L.F. Licitra
Journal: Annals of Oncology (2018)

BackgroundTo investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsThis study was an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14 days (day –15 until day –1) before surgery (day 0) or no treatment. Tumor biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR).ResultsThirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11 days for grade 3 diarrhea with subsequent renal failure and 24 days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type.ConclusionAfatinib given for 2 weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity.Clinical trial registrationClinicalTrials.gov: NCT01538381
Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism
Authors: Ramachandran Rashmi, Xiaojing Huang, John M. Floberg, Adnan E. Elhammali, Michael L. McCormick, Gary J. Patti, Douglas R. Spitz, Julie K. Schwarz
Journal: Cancer Research (2018)

Abstract Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-deoxyglucose, 2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species were compared before and after treatment. Highly radioresistant cells were the most sensitive to 2-DG, whereas intermediate radioresistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutathione, redox-sensitive dye oxidation, and decreased glucose utilization via multiple metabolic pathways including the tricarboxylic acid cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radioresistant cells and effectively radiosensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radioresistant cervical cancers. Significance: This study suggests a simple metabolic approach to strike at an apparent Achilles' heel in highly glycolytic, radioresistant forms of cervical cancers, possibly with broader applications in cancer therapy. Cancer Res; 78(6); 1392–403. ©2018 AACR.
BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity
Authors: Rob J.W. Arts, Simone J.C.F.M. Moorlag, Boris Novakovic, Yang Li, Shuang-Yin Wang, Marije Oosting, Vinod Kumar, Ramnik J. Xavier, Cisca Wijmenga, Leo A.B. Joosten, Chantal B.E.M. Reusken, Christine S. Benn, Peter Aaby, Marion P. Koopmans, Hendrik G. Stunnenberg, Reinout van Crevel, Mihai G. Netea
Journal: Cell Host & Microbe (2018)