tbuckley/cabot-search huggingface dataset:
Diagnostic timeliness in adolescents and young adults with cancer: a cross-sectional analysis of the BRIGHTLIGHT cohort
Authors: Annie Herbert, Georgios Lyratzopoulos, Jeremy Whelan, Rachel M Taylor, Julie Barber, Faith Gibson, Lorna A Fern
Journal: The Lancet Child & Adolescent Health (2018)

BackgroundAdolescents and young adults (AYAs) are thought to experience prolonged intervals to cancer diagnosis, but evidence quantifying this hypothesis and identifying high-risk patient subgroups is insufficient. We aimed to investigate diagnostic timeliness in a cohort of AYAs with incident cancers and to identify factors associated with variation in timeliness.MethodsWe did a cross-sectional analysis of the BRIGHTLIGHT cohort, which included AYAs aged 12–24 years recruited within an average of 6 months from new primary cancer diagnosis from 96 National Health Service hospitals across England between July 1, 2012, and April 30, 2015. Participants completed structured, face-to-face interviews to provide information on their diagnostic experience (eg, month and year of symptom onset, number of consultations before referral to specialist care); demographic information was extracted from case report forms and date of diagnosis and cancer type from the national cancer registry. We analysed these data to assess patient interval (time from symptom onset to first presentation to a general practitioner [GP] or emergency department), the number of prereferral GP consultations, and the symptom onset-to-diagnosis interval (time from symptom onset to diagnosis) by patient characteristic and cancer site, and examined associations using multivariable regression models.FindingsOf 1114 participants recruited to the BRIGHTLIGHT cohort, 830 completed a face-to-face interview. Among participants with available information, 204 (27%) of 748 had a patient interval of more than a month and 242 (35%) of 701 consulting a general practitioner had three or more prereferral consultations. The median symptom onset-to-diagnosis interval was 62 days (IQR 29–153). Compared with male AYAs, female AYAs were more likely to have three or more consultations (adjusted odds ratio [OR] 1·6 [95% CI 1·1–2·3], p=0·0093) and longer median symptom onset-to-diagnosis intervals (adjusted median interval longer by 24 days [95% CI 11–37], p=0·0005). Patients with lymphoma or bone tumours (adjusted OR 1·2 [95% CI 0·6–2·1] compared with lymphoma) were most likely to have three or more consultations and those with melanoma least likely (0·2 [0·1–0·7] compared with lymphoma). The adjusted median symptom onset-to-diagnosis intervals were longest in AYAs with bone tumours (51 days [95% CI 29–73] longer than for lymphoma) and shortest in those with leukaemia (33 days [17–49] shorter than for lymphoma).InterpretationThe findings provide a benchmark for diagnostic timeliness in young people with cancer and help to identify subgroups at higher risk of a prolonged diagnostic journey. Further research is needed to understand reasons for these findings and to prioritise and stratify early diagnosis initiatives for AYAs.FundingNational Institute for Health Research, Teenage Cancer Trust, and Cancer Research UK.
Intestinal Microbial-Derived Sphingolipids Are Associated with Childhood Food Allergy
Authors: Kathleen Lee-Sarwar, Rachel S. Kelly, Jessica Lasky-Su, D. Branch Moody, Alex R. Mola, Tan-Yun Cheng, Laurie E. Comstock, Robert S. Zeiger, George T. O'Connor, Megan Sandel, Leonard B. Bacharier, Avraham Beigelman, Nancy Laranjo, Diane R. Gold, Jessica Rabe Savage, Scott T. Weiss, Augusto A. Litonjua, Patrick J. Brennan
Journal: Journal of Allergy and Clinical Immunology (2018)
Patients´ competence in oral cancer therapies.
Authors: Manfred Welslau, Christoph Riese, Anja Beylich, Uirassu Borges, Pablo Zamora, Walter Baumann
Journal: Journal of Clinical Oncology (2016)

6517 Background: Oral agents for cancer treatment have been increasingly prescribed due to their benefits. However, oral cancer medications have a considerable potential for side effects. Their inadequate use can lead to ineffectiveness and in some cases to early discontinuation of therapy. Consequently, this type of therapy requires a high level of self-management competence by the patient. A standardized patient education program provided by oncology nurses may influence the handling of the oral agents in a positive way. Hence, we evaluated whether providing patients with adequate information on the clinical picture, treatment options, side effects, and the proper handling of medication influences self-management ability, therapy-related knowledge and therapy adherence. Methods: 178 patients (54% female, mean age 70 years, SD 11.9) from 28 office-based oncology practices from all over Germany participated in this cluster randomized controlled study. Patients of both intervention and control groups received the usual oncologist counseling; in addition, the patients from the intervention group (N= 17 practices) received an education program through special trained oncology nurses. The education program included techniques of motivational communication and usage of oral agents. The time of observation was 3 months per patient. Results: Patients in the intervention group showed a higher level of therapy-related knowledge and a clearer understanding of behavior in critical situations compared to the patients in the control group. Furthermore, patients of the intervention group showed an increase in self-efficacy after the first counselling session at the beginning of the study, while the control group showed a slight decrease; this difference remained stable during the intervention. The patients of the control group had more frequent side effects (e.g. skin rush) for selected oral agents. Patients in the control group interrupted the therapy more frequently without informing their oncologist (25%), compared to the intervention group (14%). Conclusions: Patients benefit from a standardized patient education program provided by specially trained oncology nurses through an improved therapy-related knowledge, adherence and preventing side effects. Clinical trial information: VfD_PACOCT_12_003487.
Detection of myositis-specific antibodies: additional notes
Authors: Michael Mahler, Marvin J Fritzler
Journal: Annals of the Rheumatic Diseases (2018)

With interest we read the recent article by Vulsteke et al 1 showing data derived from an evaluation of three immunoassay systems for the detection of autoantibodies associated with autoimmune inflammatory myopathies (AIM). As stated by the authors, careful evaluation of autoantibody assays for the detection of myositis-specific (MSA) and myositis-associated (MAA) antibodies is of utmost importance since some of these are included or being considered for the AIM classification criteria.2–4 The biomarkers are also relevant for establishing the diagnosis and stratification into specific disease subsets.

The authors compared the performance of three test systems and used primarily clinical diagnoses and features as comparators. In the interests of assay evaluation and standardisation, it is valuable to also provide data showing a more comprehensive statistics-based approach for method comparison. However, this …
Cancer surveillance in northern Africa, and central and western Asia: challenges and strategies in support of developing cancer registries
Authors: Ariana Znaor, Sultan Eser, Hoda Anton-Culver, Ibtihal Fadhil, Anton Ryzhov, Barbara G Silverman, Karima Bendahou, Anna Demetriou, Omar Nimri, Cankut Yakut, Freddie Bray
Journal: The Lancet Oncology (2018)
DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade
Authors: Mehdi Touat, Tony Sourisseau, Nicolas Dorvault, Roman M. Chabanon, Marlène Garrido, Daphné Morel, Dragomir B. Krastev, Ludovic Bigot, Julien Adam, Jessica R. Frankum, Sylvère Durand, Clement Pontoizeau, Sylvie Souquère, Mei-Shiue Kuo, Sylvie Sauvaigo, Faraz Mardakheh, Alain Sarasin, Ken A. Olaussen, Luc Friboulet, Frédéric Bouillaud, Gérard Pierron, Alan Ashworth, Anne Lombès, Christopher J. Lord, Jean-Charles Soria, Sophie Postel-Vinay
Journal: Journal of Clinical Investigation (2018)

Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
Growing Up: Evolving Concepts of Adult Attention Deficit Hyperactivity Disorder
Authors: Philip Shaw
Journal: American Journal of Psychiatry (2018)

Concepts of attention deficit hyperactivity disorder (ADHD) in adulthood have changed greatly.Initially, it was held that ADHD both began and, essentially, ended in childhood.However, in the 1990s a series of prospective studies showed that around 15%220% of children will continue to show the full syndrome into adulthood, and symptoms of inattention persist in a further 50% (1).Most recently, a series of studies found that the syndrome could have its onset in adolescence, or even adulthood-herein referred to as late-onset ADHD-challenging the accepted view of ADHD as a neurodevelopmental disorder with an invariable childhood onset (2-4).In this issue of the Journal, Sibley et al. ( 5) further examine adolescent and adult presentations of ADHD.They leveraged data from a group of children initially without ADHD who served as a comparison group in a well-known ADHD treatment study (the Multimodal Treatment Study of ADHD).This childhood cohort had repeated, detailed clinical assessments into early adulthood.The key finding was that 40% of these participants during adolescence and 20% during adulthood screened positive for ADHD on a symptom checklist that was not dissimilar from several assessment measures in popular use.However, this startling prevalence of apparent late-onset ADHD (i.e., with an onset after the DSM-5 cut-off age of 12) plummeted to 3.3% as soon as three sensible constraints were implemented.First, it was ensured that the symptoms caused impairment across multiple contexts.Second, the symptoms were not better explained by substance misuse or another mental disorder.Finally, the exact chronology of symptom course was mapped to ensure that the onset was indeed after age 12.The prevalence of lateonset ADHD fell further to 2% if those with childhood symptoms that fell near the diagnostic threshold were excluded, suggesting that their ADHD was as much late-recognized as late-onset.The study has two important contexts.First, as a cursory glance of the Internet or any magazine rack will show, there exists a vast number of "questionnaires for ADHD."The Sibley et al. study is a telling demonstration of the likely lack of positive predictive power of such "diagnosis by checklist": only 9% of those who screened positive for late-onset ADHD met the stringent criteria for a diagnosis.Screening tools can be valuable but do not substitute for in-depth assessments by a well-trained team, particularly when trying to establish a new diagnostic entity.
Genetic Ablation of Butyrate Utilization Attenuates Gastrointestinal Salmonella Disease
Authors: Denise N. Bronner, Franziska Faber, Erin E. Olsan, Mariana X. Byndloss, Nada A. Sayed, Gege Xu, Woongjae Yoo, Dajeong Kim, Sangryeol Ryu, Carlito B. Lebrilla, Andreas J. Bäumler
Journal: Cell Host & Microbe (2018)
Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease
Authors: Liming Mao, Atsushi Kitani, Morgan Similuk, Andrew J. Oler, Lindsey Albenberg, Judith Kelsen, Atiye Aktay, Martha Quezado, Michael Yao, Kim Montgomery-Recht, Ivan J. Fuss, Warren Strober
Journal: Journal of Clinical Investigation (2018)

In these studies, we evaluated the contribution of the NLRP3 inflammasome to Crohn's disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified the affected individuals as having a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL-1β in the affected individuals were increased compared with those in healthy controls, and their peripheral monocytes produced increased amounts of IL-1β when stimulated by NLRP3 activators. Immunoblot studies probing the basis of these findings showed that mutated T60 CARD8 failed to downregulate the NLRP3 inflammasome because it did not bind to NLRP3 and inhibit its oligomerization. In addition, these studies showed that mutated T60 CARD8 exerted a dominant-negative effect by its capacity to bind to and form oligomers with unmutated T60 or T48 CARD8 that impeded their binding to NLRP3. Finally, inflammasome activation studies revealed that intact but not mutated CARD8 prevented NLRP3 deubiquitination and serine dephosphorylation. CD due to a CARD8 mutation was not effectively treated by anti–TNF-α, but did respond to IL-1β inhibitors. Thus, patients with anti–TNF-α–resistant CD may respond to this treatment option.
Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation
Authors: Vijaykumar Chennupati, Diogo F.T. Veiga, Kendle M. Maslowski, Nicola Andina, Aubry Tardivel, Eric Chi-Wang Yu, Martina Stilinovic, Cedric Simillion, Michel A. Duchosal, Manfredo Quadroni, Irene Roberts, Vijay G. Sankaran, H. Robson MacDonald, Nicolas Fasel, Anne Angelillo-Scherrer, Pascal Schneider, Trang Hoang, Ramanjaneyulu Allam
Journal: Journal of Clinical Investigation (2018)

Ribosomal proteins (RP) regulate specific gene expression by selectively translating subsets of mRNAs. Indeed, in Diamond-Blackfan anemia and 5q– syndrome, mutations in RP genes lead to a specific defect in erythroid gene translation and cause anemia. Little is known about the molecular mechanisms of selective mRNA translation and involvement of ribosomal-associated factors in this process. Ribonuclease inhibitor 1 (RNH1) is a ubiquitously expressed protein that binds to and inhibits pancreatic-type ribonucleases. Here, we report that RNH1 binds to ribosomes and regulates erythropoiesis by controlling translation of the erythroid transcription factor GATA1. Rnh1-deficient mice die between embryonic days E8.5 and E10 due to impaired production of mature erythroid cells from progenitor cells. In Rnh1-deficient embryos, mRNA levels of Gata1 are normal, but GATA1 protein levels are decreased. At the molecular level, we found that RNH1 binds to the 40S subunit of ribosomes and facilitates polysome formation on Gata1 mRNA to confer transcript-specific translation. Further, RNH1 knockdown in human CD34+ progenitor cells decreased erythroid differentiation without affecting myelopoiesis. Our results reveal an unsuspected role for RNH1 in the control of GATA1 mRNA translation and erythropoiesis.
Nischarin regulates focal adhesion and Invadopodia formation in breast cancer cells
Authors: Mazvita Maziveyi, Shengli Dong, Somesh Baranwal, Suresh K. Alahari
Journal: Molecular Cancer (2018)

During metastasis, tumor cells move through the tracks of extracellular matrix (ECM). Focal adhesions (FAs) are the protein complexes that link the cell cytoskeleton to the ECM and their presence is necessary for cell attachment. The tumor suppressor Nischarin interacts with a number of signaling proteins such as Integrin α5, PAK1, LIMK1, LKB1, and Rac1 to prevent cancer cell migration. Although previous findings have shown that Nischarin exerts this migratory inhibition by interacting with other proteins, the effects of these interactions on the entire FA machinery are unknown.RT-PCR, Western Blotting, invadopodia assays, and immunofluorescence were used to examine FA gene expression and determine whether Nischarin affects cell attachment, as well as the proteins that regulate it.Our data show that Nischarin prevents cell migration and invasion by altering the expression of key focal adhesion proteins. Furthermore, we have found that Nischarin-expressing cells have reduced ability to attach the ECM, which in turn leads to a decrease in invadopodia-mediated matrix degradation.These experiments demonstrate an important role of Nischarin in regulating cell attachment, which adds to our understanding of the early events of the metastatic process in breast cancer.
Towards targeted screening for drugs active against lobular breast carcinoma
Authors: Michiel de Bruin, Tanya Braumuller, Ingrid van der Heijden, Hermien Boerhout, Sven Rottenberg, Patrick Derksen, Sabine Linn, Jos Jonkers
Journal: Cancer Research (2008)

2926  The incidence of lobular breast cancer is 10-15% of newly diagnosed breast cancers. Lobular breast cancer is intrinsically resistant to chemotherapy (pathological complete remission ~ 3%) and almost always characterized by loss of E-cadherin (Cdh1).  A mouse model for lobular carcinoma, produced and characterized in our laboratory will be used to identify drugs, which target lobular breast carcinoma. In this conditional mouse mammary tumor model simultaneous deletion of Trp53 and Cdh1 in mammary epithelium is mediated by Cre expression from the Cytokeratin 14 (K14) promoter (Derksen et al Cancer Cell10(5): 437-449) or Whey acidic protein (WAP) promoter (Derksen et al, unpublished). Whereas combined deletion of Trp53 and Cdh1 resulted in tumors with a lobular phenotype, which are highly metastatic, deletion of Trp53 alone resulted in more ductal-type tumors that were non-metastatic. Cell lines from Trp53-/-;Cdh1-/- mammary tumors were anoikis resistant in vitro and metastatic upon orthotopic transplantation, whereas Trp53-/- tumor cell lines were neither anoikis resistant nor metastatic.  The spontaneous mouse mammary tumor models and corresponding panels of tumor cell lines allow us to screen for drugs active against lobular breast carcinoma on four different levels: 1) in vitro on the panels of tumor cell lines, 2) in vivo on tumor outgrowths from orthotopically grafted cell lines, 3) in vivo on tumor outgrowths from orthotopically grafted tumor fragments (allowing target selection in tumors prior to treatment) and 4) in vivo on the sporadic tumors that develop in the mouse mammary tumor models (thereby allowing intervention at early tumor stages). Advancing through the levels we will obtain a higher predictive power as to the role of potential targets and the activity of drugs against lobular carcinoma.  In 27 well characterized cell lines from 4 WAPcre;Cdh1F/F;p53F/F and 3 WAPcre;p53F/F mammary tumors, IC50s were determined for a series of (classical) drugs from different classes .  In addition we will present the first data benchmarking the 3rd level of our model where we have transplanted tumor pieces into the mammary fat pat of syngeneic animals which were subsequently treated with: docetaxel, doxorubicin, topotecan and cisplatin. Only cisplatin yielded a response in all tumors resulting in prolonged survival. The responses were however heterogeneous, increasing lifespan with several days up to more than 40 days. In this last case the mice were not sacrificed due to increasing tumor mass but due to accumulating toxicity of the treatment.
Genetics of Natural Killer Cells in Human Health, Disease, and Survival
Authors: Peter Parham, Lisbeth A. Guethlein
Journal: Annual Review of Immunology (2018)

Natural killer (NK) cells have vital functions in human immunity and reproduction. In the innate and adaptive immune responses to infection, particularly by viruses, NK cells respond by secreting inflammatory cytokines and killing infected cells. In reproduction, NK cells are critical for genesis of the placenta, the organ that controls the supply of oxygen and nutrients to the growing fetus. Controlling NK cell functions are interactions of HLA class I with inhibitory NK cell receptors. First evolved was the conserved interaction of HLA-E with CD94:NKG2A; later established were diverse interactions of HLA-A, -B, and -C with killer cell immunoglobulin-like receptors. Characterizing the latter interactions is rapid evolution, which distinguishes human populations and all species of higher primate. Driving this evolution are the different and competing selections imposed by pathogens on NK cell–mediated immunity and by the constraints of human reproduction on NK cell–mediated placentation. Promoting rapid evolution is independent segregation of polymorphic receptors and ligands throughout human populations.
Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma
Authors: Margaretha G.M. Roemer, Robert A. Redd, Fathima Zumla Cader, Christine J. Pak, Sara Abdelrahman, Jing Ouyang, Stephanie Sasse, Anas Younes, Michelle Fanale, Armando Santoro, Pier Luigi Zinzani, John Timmerman, Graham P. Collins, Radhakrishnan Ramchandren, Jonathon B. Cohen, Jan Paul De Boer, John Kuruvilla, Kerry J. Savage, Marek Trneny, Stephen Ansell, Kazunobu Kato, Benedetto Farsaci, Anne Sumbul, Philippe Armand, Donna S. Neuberg, Geraldine S. Pinkus, Azra H. Ligon, Scott J. Rodig, Margaret A. Shipp
Journal: Journal of Clinical Oncology (2018)

Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.