tbuckley/cabot-search huggingface dataset:
Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases
Authors: Sira Nanthapisal, Claire Murphy, Ebun Omoyinmi, Ying Hong, Ariane Standing, Stefan Berg, Maria Ekelund, Stephen Jolles, Lorraine Harper, Taryn Youngstein, Kimberly Gilmour, Nigel J. Klein, Despina Eleftheriou, Paul A. Brogan
Journal: Arthritis & Rheumatology (2016)

Objective To describe the clinical features, genotype, and treatment in a series of subjects with confirmed adenosine deaminase 2 (ADA2) deficiency. Methods All symptomatic subjects were referred for genetic testing for suspected ADA2 deficiency; relatives of index cases were also screened. Demographic, clinical, and laboratory characteristics and treatments were recorded. Genetic analyses included whole‐exome sequencing in 4 subjects and Sanger sequencing of CECR1 (the gene for cat eye syndrome chromosome region candidate 1) in all subjects. Assays for ADA2 enzyme activity and quantitative polymerase chain reaction analysis of CECR1 messenger RNA (mRNA) were also performed. Results We identified 15 subjects with ADA2 deficiency, 5 of whom were asymptomatic (relatives of index cases; ages 5–42 years). Homozygous or compound heterozygous mutations in CECR1 were identified in all subjects. Phenotypic manifestations in the patients with symptomatic ADA2 deficiency included livedo racemosa (73.3%), neurologic involvement (53.3%), and immunodeficiency (46.7%). CECR1 mRNA expression in 8 subjects, including 5 who were presymptomatic, was significantly lower than in healthy controls ( P = 0.0016). Subjects with ADA2 deficiency (with or without symptoms) also had lower ADA2 enzyme activity compared to healthy pediatric controls ( P &lt; 0.0001) and patients with sporadic (nonfamilial) childhood polyarteritis nodosa (PAN) without CECR1 mutation ( P = 0.0108). Anti−tumor necrosis factor therapy was required in 9 of the 10 symptomatic subjects. Conclusion The clinical manifestations of ADA2 deficiency ranged in severity from limited cutaneous involvement to severe multisystemic vasculitis; one‐third of our cases (5 of 15) were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for unaffected siblings of index cases, cases of familial vasculitis, and cases of PAN that is resistant to standard treatment.
International Laboratory Comparison of Methodologies for Determining Minimal Residual Disease (MRD) in Childhood Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Authors: Shalini C. Reshmi, Eileen Stonerock, Michael J. Borowitz, William J Geese, Diane Healey, Julie M. Gastier-Foster, Stephen P. Hunger, Andrea Biondi, Giovanni Cazzaniga
Journal: Blood (2015)
Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries
Authors: Pasi Korhonen, Edith M Heintjes, Rachael Williams, Fabian Hoti, Solomon Christopher, Maila Majak, Leanne Kool-Houweling, Helen Strongman, Marie Linder, Paul Dolin, Shahram Bahmanyar
Journal: BMJ (2016)

<b>Objective</b>&nbsp;To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes. <b>Design</b>&nbsp;Retrospective cohort study using propensity score matched cohorts. <b>Settings</b>&nbsp;Healthcare databases from Finland, the Netherlands, Sweden, and the United Kingdom. Data comprised country specific datasets of linked records on prescriptions, hospitals, general practitioners, cancer, and deaths. <b>Participants</b>&nbsp;Patients with type 2 diabetes who initiated pioglitazone (n=56 337) matched with patients with type 2 diabetes in the same country exposed to diabetes drug treatments other than pioglitazone (n=317 109). Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation. <b>Main outcome measures</b>&nbsp;Hazard ratios and 95% confidence intervals were estimated by Cox’s proportional hazards model with adjustments for relevant confounders. To assess the robustness of the findings, several sensitivity and stratified analyses were performed. <b>Results</b>&nbsp;In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean follow‑up time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (&gt;48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); &gt;40 000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort). <b>Conclusions</b>&nbsp;This study shows no evidence of an association between ever use of pioglitzone and risk of bladder cancer compared with never use, which is consistent with results from other recent studies that also included a long follow-up period. <b>Trial registration</b>&nbsp;Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626).
ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways
Authors: Teneema Kuriakose, Si Ming Man, R. K. Subbarao Malireddi, Rajendra Karki, Sannula Kesavardhana, David E. Place, Geoffrey Neale, Peter Vogel, Thirumala-Devi Kanneganti
Journal: Science Immunology (2016)

ZBP1 activates the NLRP3 inflammasome and programmed cell death.
Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy.
Authors: Michael Sangmin Lee, Shailesh M Advani, Jeffrey Morris, Zhi-Qin Jiang, Ganiraju C. Manyam, David Menter, Bradley McIntosh Broom, Cathy Eng, Michael J. Overman, Dipen M. Maru, Stanley R. Hamilton, Scott Kopetz
Journal: Journal of Clinical Oncology (2016)

3506 Background: CRCs originating in the right colon (RC) have features distinct from those in the rectum/left colon, including more frequent CpG island methylator phenotype (CIMP-High) and BRAF mutation (MT). Prognosis and response to therapies, including αEGFR regimens, differ dramatically by 1° site in mCRC, but pathobiologic explanations remain unclear. Methods: 198 KRAS wild-type (WT) mCRC tumors were tested for CIMP status via bisulfite pyrosequencing and PCR amplification. BRAF and NRAS were sequenced. PFS on first αEGFR regimen was retrospectively determined in 167 patients. Univariate and multivariate Cox regression analyses with multiple imputations were performed. Tumors from 179 independent CRC patients were tested for promoter methylation (Illumina HumanMethylation450) and gene expression. Results: Inferior PFS with αEGFR therapy was associated with RC CRC (HR = 1.56, CI 1.01-2.41), CIMP-High (HR = 2.38, 1.47-3.85), BRAF MT (HR = 2.15, 1.26-3.65), and NRAS MT (HR = 2.11, 1.23-3.65). On multivariate analysis, CIMP status (p = 0.041), BRAF MT (p = 0.038), and NRAS MT (p = 0.012) remained significant, but 1° site did not (p = 0.27). Inferior OS was associated with RC CRC (HR = 1.45, 1.04-2.01), CIMP-High (HR = 1.53, 1.08-2.16), BRAF MT (HR = 2.46, 1.61-3.75), and NRAS MT (HR = 1.70, 1.03-2.81). RC 1° site was also associated with CIMP-High (OR = 2.35, 1.22-4.54) and BRAF MT (OR = 5.45, 2.47-12.03). Independent data from MDACC and TCGA showed RC 1° site and CIMP-High were both strongly associated with hypermethylation of promoters and suppression of expression of the EGFR ligands EREG and AREG. 1° site was also strongly associated with consensus molecular subtypes (CMS) 1 and 3 (p < 0.001, p = 0.03), which were previously shown in mCRC patients to have worse outcomes than the 'classic' CMS2 subtype. Conclusions: CRC 1° site is associated with OS and PFS after αEGFR therapy. Molecular analyses suggest that BRAF MT, NRAS MT, molecular subtypes, and tumor methylation account for the effect and may provide a biologic explanation for the association with anatomic location.
Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis
Authors: Martin Pichler, Verena Stiegelbauer, Petra Vychytilova-Faltejskova, Cristina Ivan, Hui Ling, Elke Winter, Xinna Zhang, Matthew Goblirsch, Annika Wulf-Goldenberg, Masahisa Ohtsuka, Johannes Haybaeck, Marek Svoboda, Yoshinaga Okugawa, Armin Gerger, Gerald Hoefler, Ajay Goel, Ondrej Slaby, George Adrian Calin
Journal: Clinical Cancer Research (2016)

Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting.
Pituitary Non-Functioning Adenoma Disclosed at 18F-Choline PET/CT to Investigate a Prostate Cancer Relapse
Authors: Anna Margherita Maffione, Giovanni Mandoliti, Felice Pasini, Patrick M. Colletti, Domenico Rubello
Journal: Clinical Nuclear Medicine (2016)

We report the incidental finding of a pituitary macroadenoma on an 18F-choline PET/CT in a patient with recurrent prostate cancer. The pituitary gland was clearly enlarged and intensely FDG avid (SUVmax, 6.6). The diagnosis was confirmed by a subsequent contrast-enhanced MR evaluation, and the macroadenoma was classified as nonfunctioning on the basis of normality of the specific serum hormonal profile. A follow-up 18F-choline PET/CT scan performed after 6 months revealed stable dimension, and uptake of the pituitary macroadenoma patient deceased 1 month later. At autopsy, intracytoplasmic vesicles containing growth and prolactin hormones were observed at immunohistochemistry.
Arhgap21 Expression in Bone Marrow Niche Is Crucial for Hematopoietic Progenitor Homing and Short Term Reconstitution after Transplantation
Authors: Juliana M. Xavier, Lauremilia Ricon, Karla Priscila Vieira, Longhini Ana Leda, Carolina Bigarella, Gilberto C Franchi, Sara T O Saad
Journal: Blood (2014)
Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer
Authors: Giuseppe Toffoli, Manish R. Sharma, Elena Marangon, Bianca Posocco, Elizabeth Gray, Quan Mai, Angela Buonadonna, Blase N. Polite, Gianmaria Miolo, Gianna Tabaro, Federico Innocenti
Journal: Clinical Cancer Research (2016)

Abstract Purpose: UGT1A1*28 confers a higher risk of toxicity in patients treated with irinotecan. Patients with *1/*1 and *1/*28 genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with *1/*1 and *1/*28 genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics. Experimental Design: Previously untreated patients with mCRC (25 *1/*1; 23 *1/*28) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m2. The MTD was the highest dose at which &amp;lt;4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab). Results: For *1/*1 patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2 was not tolerated (2 DLTs in 4 patients). For *1/*28 patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2 was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal. Conclusions: The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m2 for UGT1A1 *1/*1 patients and 260 mg/m2 for *1/*28 patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab. Clin Cancer Res; 23(4); 918–24. ©2016 AACR.
B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Specific Copy Number Alterations Are Unique For Progressive Pediatric Chronic Myeloid Leukemia (CML)
Authors: Naomi E. van der Sligte, Manuela Krumbholz, Agata Pastorczak, Blanca Scheijen, Josephine T. Tauer, Christina Nowasz, Edwin Sonneveld, de Truuske Bock, Tiny G. Meeuwsen-de Boer, Simon V. van Reijmersdal, Roland P. Kuiper, Jutta Bradtke, Markus Metzler, Meinolf Suttorp, de Eveline Bont, Frank N. van Leeuwen
Journal: Blood (2013)
Organic Food in the Diet: Exposure and Health Implications
Authors: Anne Lise Brantsæter, Trond A. Ydersbond, Jane A. Hoppin, Margaretha Haugen, Helle Margrete Meltzer
Journal: Annual Review of Public Health (2016)

The market for organic food products is growing rapidly worldwide. Such foods meet certified organic standards for production, handling, processing, and marketing. Most notably, the use of synthetic fertilizers, pesticides, and genetic modification is not allowed. One major reason for the increased demand is the perception that organic food is more environmentally friendly and healthier than conventionally produced food. This review provides an update on market data and consumer preferences for organic food and summarizes the scientific evidence for compositional differences and health benefits of organic compared with conventionally produced food. Studies indicate some differences in favor of organic food, including indications of beneficial health effects. Organic foods convey lower pesticide residue exposure than do conventionally produced foods, but the impact of this on human health is not clear. Comparisons are complicated by organic food consumption being strongly correlated with several indicators of a healthy lifestyle and by conventional agriculture "best practices" often being quite close to those of organic.
Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis
Authors: Luca Di Martino, Maneesh Dave, Paola Menghini, Wei Xin, Kristen O. Arseneau, Theresa T. Pizarro, Fabio Cominelli
Journal: Cancer Research (2016)

Abstract Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its proapoptotic effects. Colitis was induced in Fn14−/− and Fn14+/+ wild-type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2-week recovery; azoxymethane (AOM) administration followed by two cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and nonhematopoietic-specific effector tissues. Fn14−/− mice had enhanced susceptibility to colitis compared with Fn14+/+ controls as assessed by endoscopic and histologic inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and nonhematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14−/− mice, but not Fn14+/+ controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14−/− mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer. Cancer Res; 76(22); 6533–42. ©2016 AACR.
Inter-interpreter reliability of neuropathological assessment of disease status after early repeat resection for suspected recurrent glioblastoma.
Authors: Matthias Holdhoff, Anna F. Piotrowski, Xiaobu Ye, Roy E. Strowd, Yao Lu, Shannon Seopaul, Fausto J Rodriguez, Stuart A. Grossman, Peter C. Burger
Journal: Journal of Clinical Oncology (2016)

2050 Background: Distinction of true progression from pseudo-progression in patients with suspected recurrent glioblastoma (rGBM) is an important and common diagnostic challenge in neuro-oncology. The “gold standard” for assessment of post-treatment disease status has remained surgery with histologic evaluation. However, after chemoradiation, tissue frequently contains a variable mixture of scar tissue and tumor cells. Neuropathologists are left to determine whether patients have active tumor or treatment effect. As validity and reliability are critical for any diagnostic test, our study assessed inter-interpreter reliability in the pathological assessment of disease status in this setting. Methods: Histopathology images from 13 patients with GBM who underwent surgery within one year of diagnosis for suspected rGBM were selected. 101 neuropathologists at 50 NCI-designated Cancer Centers received a case scenario of a patient with suspected rGBM, including histopathological information of the initial diagnosis. Participants were asked to grade each case for percentage of 1) active tumor, 2) treatment effect, 3) cellularity, 4) mitotic activity, and 5) to give an overall assessment of disease activity (‘active tumor’ vs. ‘pseudo-progression’ vs. ‘unable to classify’). Fleiss’ kappa statistics were calculated to measure the inter-interpreter reliability among all readers. Kappa < 0.4 = marginal agreement, > 0.75 = excellent agreement. Results: We received responses from 48 pathologists from 30 centers, of whom 44 were neuropathologists by training (48% response rate). The kappa score for agreement in overall assessment of disease activity was 0.228. Individually, the Kappa scores were 0.288 for ‘active tumor’, 0.323 for ‘pseudo-progression’, and 0.036 for ‘unable to classify’. Conclusions: Our findings demonstrate marginal inter-interpreter reliability in pathological assessment of disease status in re-biopsied GBM. More formal and consistent criteria are urgently needed as inconsistent assessment of disease status directly impacts on patient selection for clinical trials, as well as on decision making in clinical practice.
Abstract 14839: Association of Silent Brain Infarction With CHADS2 Score and Left Atrial Abnormalities in Patients With Nonvalvular Atrial Fibrillation
Authors: Yu Kawai, Kenichi Sugioka, Shinichi Iwata, Suwako Fujita, Asahiro Ito, Yoshiki Matsumura, Akihisa Hanatani, Masahiko Takagi, Minoru Yoshiyama
Journal: Circulation (2015)

Introduction: The CHADS2 score is widely used for risk stratification of thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). Furthermore, LA abnormalities detected by transesophageal echocardiography (TEE) are also well known risk factors for thromboembolism in NVAF patients. On the other hand, silent brain infarction (SBI) relates to subsequent symptomatic brain infarction; however little is known regarding association among CHADS2 score, TEE parameters and SBI. Methods: The study population consisted of 103 neurologically asymptomatic patients with NVAF (mean age 63 ± 10 years) who underwent TEE. All participating patients underwent brain MRI and were calculated CHADS2 score. SBI was defined as an area of hypointense lesions that measured &gt;3 mm on T1-weighted images and hyperintense lesions on T2-weighted images by brain magnetic resonance imaging (MRI). LA abnormalities were defined as LA thrombus, spontaneous echo contrast, or low LA appendage emptying velocity (&lt;20 cm/s) detected by TEE. Results: Of 103 patients, 31 (30%) showed SBI on brain MRI. Over all mean CHADS2 score was 1.1 ± 0.9, and LA abnormalities were detected in 24 patients by TEE (23%). Mean CHADS2 score in patients with SBI was significantly higher than that in patients without SBI (P&lt;0.05). The prevalence of SBI increased along with increases in CHADS2 score (CHADS2 score of 0, 1, 2 and 3-6 in 13%, 23%, 47% and 80%, respectively, P&lt;0.05). Patients with SBI had a higher prevalence of LA abnormalities than those without SBI (P&lt;0.05). In patients with SBI with CHADS2 score of 0-1, LA abnormalities were detected in 5 of 14 patients (36%). Conclusions: In this study, both CHADS2 score and prevalence of LA abnormalities by TEE were higher in patients with SBI on MRI. LA abnormalities detected by TEE may discriminate risk for SBI even in patients with low CHADS2 score.
NHS winter pressures are becoming an all year reality, warn experts
Authors: Adrian O’Dowd
Journal: BMJ (2016)

The type of intense extra workload pressure often experienced by the NHS in winter has become a year long experience, say experts responding to the publication of the latest official data on the performance of the NHS in England.

NHS England’s combined performance summary data show an NHS that is missing many of its targets and hitting new record lows for performance in some areas.1

The data for July 2016 show that 90.3% of patients were seen within four hours in hospital emergency departments, down from 95% in the same month last year, and that 37 500 waited more than four hours for admission after the decision to admit, double the 17 300 in the same month last year.

Waiting times for elective treatment were also up, with 91.3% of patients starting consultant led treatment within 18 weeks, the worst performance since …
Случай из практики: рентген-диагностика аскаридоза
Authors: V.B. Yahmur,  I.O. Saus-Kachanova, T.V. Dorokhina, N.A. Skudnova
Journal: GASTROENTEROLOGY (2016)

Приведен случай аскаридоза у 60-летней женщины, который не выявлялся при копрологическом исследовании. Кроме этого, отсутствовали косвенные признаки паразитарной инвазии в виде увеличения содержания эозинофилов крови. Диагноз был выставлен благодаря ирригографии и выявлению антител к аскаридам в сыворотке крови методом иммуноферментного анализа.