tbuckley/cabot-search huggingface dataset:
DNA Methylation of the Human Klotho Gene: Associations with IGF-I, IGF-II, and IGFBP-3 Expression and Ovarian Cancer Survival
Authors: Andrew Wiley, Dionyssios Katsaros, Lingeng Lu, I. A. Rigault de La Longrais, Manuela Puopolo, Jingsheng Si, Herbert Yu
Journal: Cancer Research (2006)

1204  The klotho gene encodes a protein that inhibits insulin and IGF-I signaling and functions as an anti-aging hormone. The klotho gene contains a large CpG island that spans the putative promoter site and much of the first exon. To date, no studies have evaluated DNA methylation in this region and few studies have explored the role of klotho in human cancers. We designed two methylation-specific PCR (MSP) assays to examine methylation in either the promoter or exon region of the klotho gene. The association of methylation with local expressions of IGF-I, IGF-II, and IGFBP-3, disease characteristics, and patient survival was then evaluated in a group of 215 epithelial ovarian cancer patients. Genomic DNA samples were extracted from fresh frozen tissues, treated with sodium bisulfite, and analyzed using MSP. IGF-I, IGF-II, and IGFBP-3 expression was measured using quantitative RT-PCR for mRNA and ELISA for protein extracts from tumor tissue. Chi-square or Fisher’s exact tests were performed to evaluate the associations between methylation, expression, and disease characteristics; Cox proportional hazards regression and Kaplan-Meier estimates were used to evaluate methylation association with survival outcome. Methylation of the klotho gene was found in 14% (promoter) and 55% (exon) of ovarian cancer patients. Promoter methylation was not significantly associated with patient or tumor characteristics; methylation in the exon region, however, was found more frequently in older individuals (p = 0.047). While not statistically significant, levels of IGF-I and IGF-II were higher among patients with promoter methylation; conversely, IGFBP-3 expression was found to be lower among patients with promoter methylation. In the exon region, methylation was significantly associated with higher IGF-II levels (p = 0.049). Survival analysis showed that progression-free survival time was significantly reduced in patients with klotho promoter methylation after adjustment for patient age at surgery, disease stage, tumor grade, and residual tumor size (HR = 1.92, 95% C.I.: 1.13-3.27). In summary, methylation rates differed between the promoter and exon regions of the klotho gene; results suggest that methylation in this region may affect expression of IGF-I, IGF-II, and IGFBP-3 and ultimately may lead to poor prognosis in ovarian cancer patients.
Final Overall Survival Analysis From a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non–Small-Cell Lung Cancer
Authors: Benjamin J. Solomon, Dong-Wan Kim, Yi-Long Wu, Kazuhiko Nakagawa, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Tiziana Usari, Yiyun Tang, Keith D. Wilner, Fiona Blackhall, Tony S. Mok
Journal: Journal of Clinical Oncology (2018)

Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.
Type 1 Diabetes Self-Management From Emerging Adulthood Through Older Adulthood
Authors: Margaret M. McCarthy, Margaret Grey
Journal: Diabetes Care (2018)

The purpose of this study of adults with type 1 diabetes was to analyze patterns of diabetes self-management behaviors and predictors of glycemic control across the adult life span.This study was a secondary cross-sectional analysis of data of 7,153 adults enrolled in the T1D Exchange Clinic Registry who were divided into four developmental stages (emerging, young, middle-aged, and older adults). Data were collected by questionnaire and medical record review at enrollment. Statistical analyses compared sociodemographic, clinical, and diabetes-related factors across groups. Logistic regressions were conducted for each group to identify factors associated with hemoglobin A1c ≥7%.The sample was divided according to adult developmental stage: emerging adults, age 18 to <25 years (n = 2,478 [35%]); young adults, age 25 to <45 years (n = 2,274 [32%]); middle-aged adults, age 45 to <65 years (n = 1,868 [26%]); and older adults, age ≥65 years (n = 533 [7%]). Emerging adults had the highest mean hemoglobin A1c level (8.4 ± 1.7% [68 mmol/mol]), whereas older adults had the lowest level (7.3 ± 0.97% [56 mmol/mol]; P < 0.0001). Emerging adults were less likely to use an insulin pump (56%) or a continuous glucose monitor (7%) but were more likely to miss at least one insulin dose per day (3%) and to have had an episode of diabetic ketoacidosis in the past year (7%) (all P < 0.0001). Different factors were associated with hemoglobin A1c ≥7% in each age-group, but two factors were noted across several groups: the frequency of blood glucose checks and missed insulin doses.When discussing diabetes self-management, providers may consider a patient's developmental stage, with its competing demands (such as work and family), psychosocial adjustments, and the potential burden of comorbidities.
CD103+CD8+ Lymphocytes Characterize the Immune Infiltration in a Case With Pseudoprogression in Squamous NSCLC
Authors: Pedro Rocha, Max Hardy-Werbin, Dolores Naranjo, Álvaro Taus, Maite Rodrigo, Flavio Zuccarino, René Roth, Oliver Wood, Christian H. Ottensmeier, Edurne Arriola
Journal: Journal of Thoracic Oncology (2018)
The Link Between Mental Illness and Being Subjected to Crime in Denmark vs the United States
Authors: Jeffrey W. Swanson, Charles M. Belden
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
Aldosterone Antagonist Therapy and Mortality in Patients With ST-Segment Elevation Myocardial Infarction Without Heart Failure
Authors: Khagendra Dahal, Aditya Hendrani, Sharan P. Sharma, Sampath Singireddy, George Mina, Pratap Reddy, Paari Dominic, Kalgi Modi
Journal: JAMA Internal Medicine (2018)

Treatment with aldosterone antagonists is recommended and has been shown to have beneficial effects in patients with ST-segment elevation myocardial infarction (STEMI) and left ventricular ejection fraction (LVEF) less than 40%. However, the role of aldosterone antagonists in patients with ejection fraction greater than 40% or without congestive heart failure is not well known.To perform a systematic review and meta-analysis using standard techniques to determine the role of therapy with aldosterone antagonists in this patient population.PubMed, Embase, CINAHL, and Cochrane Central databases were searched and a manual search for relevant references from the selected articles and published reviews was performed from database inception through June 2017.Randomized clinical trials that evaluated treatment with aldosterone antagonists in patients with STEMI without clinical heart failure or LVEF greater than 40% were included.Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to conduct and report the meta-analysis, which used a random-effects model. Two investigators independently performed the database search and agreed on the final study selection. A manual search was performed for relevant references from the selected articles and published reviews.The outcomes analyzed were mortality, new congestive heart failure, recurrent myocardial infarction, ventricular arrhythmia, and changes in LVEF, serum potassium level, and creatinine level at follow-up.In all, 10 randomized clinical trials with a total of 4147 unique patients were included in the meta-analysis. In patients who presented with STEMI without heart failure, treatment with aldosterone antagonists compared with control was associated with lower risk of mortality (2.4% vs 3.9%; odds ratio [OR], 0.62; 95% CI, 0.42-0.91; P = .01) and similar risks of myocardial infarction (1.6% vs 1.5%; OR, 1.03; 95% CI, 0.57-1.86; P = .91), new congestive heart failure (4.3% vs 5.4%; OR, 0.82; 95% CI, 0.56-1.20; P = .31), and ventricular arrhythmia (4.1% vs 5.1%; OR, 0.76; 95% CI, 0.45-1.31; P = .33). Similarly, treatment with aldosterone antagonists compared with control was associated with a small yet significant increase in LVEF (mean difference, 1.58%; 95% CI, 0.18%-2.97%; P = .03), a small increase in serum potassium level (mean difference, 0.07 mEq/L; 95% CI, 0.01-0.13 mEq/L; P = .02), and no change in serum creatinine level (standardized mean difference, 1.4; 95% CI, -0.43 to 3.24; P = .13).Treatment with aldosterone antagonists is associated with a mortality benefit in patients with STEMI with LVEF greater than 40% or without heart failure.
Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study
Authors: Marie O. Collet, Jesús Caballero, Romain Sonneville, Fernando A. Bozza, Peter Nydahl, Anna Schandl, Hilden Wøien, Giuseppe Citerio, Mark van den Boogaard, Johanna Hästbacka, Matthias Haenggi, Kirsten Colpaert, Louise Rose, Marija Barbateskovic, Theis Lange, Aksel Jensen, Martin B. Krog, Ingrid Egerod, Helle L. Nibro, Jørn Wetterslev, Anders Perner
Journal: Intensive Care Medicine (2018)
Abstract PR08: Altered nucleolar trafficking of the Blm helicase in the mouse reduces size, increases DNA damage and tumor susceptibility, and facilitates premature aging
Authors: Michael McIlhatton, Max Fernandez, Samir Acharya, Vincenzo Coppola, Joanna L. Groden
Journal: Cancer Research (2018)

Abstract Bloom's syndrome (BS) is a recessive human chromosome breakage disorder caused by mutations in the recQ-like helicase BLM, sometimes known as RECQL2. Its clinical phenotype invariably includes male infertility, dwarfism, cancer susceptibility, and growth defects related to now characterized biochemical functions in DNA repair and rDNA transcription. The BLM protein includes two serines within a highly conserved carboxy-terminal nuclear localization sequence (NLS) that are critical for dynamic nucleolar trafficking of BLM where it facilitates rRNA transcription through direct interactions with RNA polymerase I and topoisomerase 1. CRISPR/Cas9-directed gene editing techniques generated homozygous murine models with these two conserved amino acids substituted by aspartic acids or alanines, and Blm proteins that were invariably excluded (DD) or constitutively localized (AA) within the nucleolus. Both protein isoforms retain biochemical functions and nuclear localization; BLM-/- cells transfected with the DD transgene display increases in nucleolar DNA damage compared to those transfected with the wild-type gene. BlmDD/DD mice with excluded Blm, but not BlmAA/AA mice, are smaller than their wild-type littermates at 8, 12, and 16 weeks of age; BlmDD/DD mice develop significantly more adenomas than littermates when crossed to the ApcMin/+ model of intestinal tumor formation. Finally, BlmDD/DD mice, but not their wild-type littermates, display signs of premature aging by one year of age, with weight loss, changes in coat color and quality, and spontaneous tumor formation. Our studies demonstrate functions for dynamic Blm nucleolar localization in maintaining stability of both the nucleolar and non-nucleolar genomes. A role for Blm/BLM in the prevention of aging is also exposed by these mouse models as only RecqL4 (RECQL4 mutations lead to Rothmund-Thomson syndrome in the human), but not Wrn/RecqL3 (WRN mutations lead to Werner's syndrome in the human), localizes to the murine nucleolus. Both Werner's syndrome and Rothmund-Thomson syndrome are associated with DNA repair deficiency, tumor susceptibility, and premature aging in the human. Our murine models also permit the definition of amino acid sequences and mechanisms that target or exclude proteins from the nucleolus. This abstract is also being presented as Poster A30. Citation Format: Michael McIlhatton, Max Fernandez, Samir Acharya, Vincenzo Coppola, Joanna L. Groden. Altered nucleolar trafficking of the Blm helicase in the mouse reduces size, increases DNA damage and tumor susceptibility, and facilitates premature aging [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR08.
Patient preferences for topical treatment of actinic keratoses: a discrete‐choice experiment
Authors: D. Kopasker, A. Kwiatkowski, R.N. Matin, C.A. Harwood, F. Ismail, J.T. Lear, J. Thomson, Z. Hasan, G.N. Wali, A. Milligan, L. Crawford, I. Ahmed, H. Duffy, C.M. Proby, P.F. Allanson
Journal: British Journal of Dermatology (2018)

The treatment of actinic keratosis (AK) is a potentially effective strategy for the prevention of cutaneous squamous cell carcinoma (cSCC). However, the patient perspective on potential benefits of AK treatment in terms of skin cancer reduction has received little attention to date.(i) To investigate patient preferences for topical treatments for AK using a discrete-choice experiment (DCE); (ii) to evaluate patient willingness to trade between clinical benefit and medical burden.The DCE was conducted as part of a study to establish the feasibility of a phase III randomized controlled trial evaluating the prevention of cSCC using currently available topical interventions. Preferences were elicited by asking patients to make a series of choices between treatment alternatives with different hypothetical combinations of attribute levels. Willingness to trade between treatment attributes was estimated using a flexible-choice model that allows for the heterogeneity of patient preferences.A total of 109 patients with AK completed the DCE. The majority of patients who expressed valid preferences were willing to accept some reduction in both prophylactic and cosmetic efficacy to reduce the burden of the treatment regimen, the severity of skin reaction and other adverse effects. Patients may reject treatment if the perceived therapeutic benefit is outweighed by the subjective burden of treatment.Evidence of significant variation in the perceived utility of treatments across patients highlights the importance of taking individual patient preferences into account to improve AK treatment acceptability and adherence.
Brock malignancy risk calculator for pulmonary nodules: validation outside a lung cancer screening population
Authors: Kaman Chung, Onno M Mets, Paul K Gerke, Colin Jacobs, Annemarie M den Harder, Ernst T Scholten, Mathias Prokop, Pim A de Jong, Bram van Ginneken, Cornelia M Schaefer-Prokop
Journal: Thorax (2018)

Objective To assess the performance of the Brock malignancy risk model for pulmonary nodules detected in routine clinical setting. Methods In two academic centres in the Netherlands, we established a list of patients aged ≥40 years who received a chest CT scan between 2004 and 2012, resulting in 16 850 and 23 454 eligible subjects. Subsequent diagnosis of lung cancer until the end of 2014 was established through linking with the National Cancer Registry. A nested case–control study was performed (ratio 1:3). Two observers used semiautomated software to annotate the nodules. The Brock model was separately validated on each data set using ROC analysis and compared with a solely size-based model. Results After the annotation process the final analysis included 177 malignant and 695 benign nodules for centre A, and 264 malignant and 710 benign nodules for centre B. The full Brock model resulted in areas under the curve (AUCs) of 0.90 and 0.91, while the size-only model yielded significantly lower AUCs of 0.88 and 0.87, respectively (p&lt;0.001). At 10% malignancy risk, the threshold suggested by the British Thoracic Society, sensitivity of the full model was 75% and 81%, specificity was 85% and 84%, positive predictive values were 14% and 10% at negative predictive value (NPV) of 99%. The optimal threshold was 6% for centre A and 8% for centre B, with NPVs &gt;99%. Discussion The Brock model shows high predictive discrimination of potentially malignant and benign nodules when validated in an unselected, heterogeneous clinical population. The high NPV may be used to decrease the number of nodule follow-up examinations.
Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.
Authors: Akihito Kawazoe, Yasutoshi Kuboki, Yoshito Komatsu, Tomohiro Nishina, Eiji Shinozaki, Hiroki Hara, Satoshi Yuki, Kohei Shitara, Hideaki Bando, Koji Takahashi, Yuichi Mikamoto, Hiromi Hasegawa, Nami Hirano, Shogo Nomura, Yosuke Togashi, Hiroyoshi Nishikawa, Akihiro Sato, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2018)

760 Background: The anti–programmed death 1 (PD-1) antibody, pembrolizumab provided an objective response rate (ORR) of 40% in patients (pts) with Mismatch Repair–Deficient (dMMR) or Microsatellite Instability–High (MSI-H) metastatic colorectal cancer (mCRC) vs 0% in pts with MMR-proficient/Microsatellite Stable (MSS) mCRC. The WNT/β-catenin signaling has been reported to prevent anti-tumor immunity and promote resistance of anti-PD-1/PD-L1 antibodies. This study investigates efficacy and safety of the combination of BBI608, which blocks phosphorylated STAT3 and downregulates WNT/β-catenin signaling, with pembrolizumab in pts with mCRC (both MSS and MSI-H). Here, we present the results of the phase I part. Methods: Phase I part was designed to determine the recommended phase II dose (RP2D) in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). We also conduct biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: Five pts were enrolled in level 1, and 3 pts in level 2. All pts were MSS mCRC. Seven pts were included in the safety analyses. Two pts in level 1 were excluded from dose-limiting toxicity (DLT) evaluation because of disease progression during DLT evaluation period. No DLTs were observed at either level. Grade 3 or worse treatment-related adverse events (TRAEs) were not observed. Grade 1 or 2 TRAEs included diarrhea related to BBI608 (57%), hyperthyroidism (14%), hypothyroidism (14%), and fever (14%) without unexpected safety signals. One patient in level 2 showed a tumor shrinkage lasting more than 12 weeks for lung and lymph node metastases with remarkable decline of CEA level. Analysis of repeated tumor samples from this case demonstrated that CD8+ T-cells infiltration inside the tumor on treatment was observed by immunohistochemistry and flow-cytometry. Conclusions: BBI608 480mg BID with pembrolizumab was tolerable and determined as RP2D. This combination showed a hint of activity and might evoke immunity in MSS mCRC, which will be confirmed by ongoing phase II part. Clinical trial information: NCT02851004..
Mutational analysis of matched initial and recurrent TP53 WT primary GBM.
Authors: David M. Ashley, Andrea Muscat, Julia Yin, Elizabeth Algar, Kate Drummond, Mustafa Khasraw, Kathryn Maree Field, Nicholas Wong, Mark Rosenthal, Kerrie Leanne McDonald
Journal: Journal of Clinical Oncology (2015)

2043 Background: Glioblastoma (GBM) present as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Tumours at diagnosis are distinct from their recurrences, the latter being more therapy resistant. Pinpointing the associated molecular alterations may better inform new therapeutic options to tackle resistance of recurrent disease. Methods: A study cohort of 29 patients with primary, TP53 wild-type GBM, with associated annotated clinical data were examined. Of these, 409 cancer associated genes, were examined in 21 paired primary/relapse FFPE extracted DNA specimens using the Comprehensive Cancer Panel (Life Technologies) with sequencing to a mean depth of 1200x. Whole exome sequencing (WES; Illumina HiSeq 2000) was conducted on an additional eight patients (paired primary/relapse) to an average of 70-fold coverage. Results: An average of 67±3 (range 49-101) non-synonymous variants or frameshift insertion/deletions were detected in tumour specimens at diagnosis and 53±4 (range 32-127) at relapse. Of these, an average of 27±2 and 13±3 variants were unique to tumours at diagnosis and relapse respectively and 50% of variants that were detected in the initial tumour were also present at relapse. WES revealed an average of 9112 somatic mutations across the genome per sample (range 603-47701). As distinct from recent reports of recurrent lower grade glioma very few patients showed a “hypermutable” signature that is characterized by numerous temozolamide (TMZ) associated specific mutations after treatment. In total, only 2/29 samples (7%) appeared to be hypermutated at relapse, with 55.6% of these mutations being attributable to TMZ-associated mutagenesis in the first patient and 44.3% in the second. Conclusions: Overallwe observed few consistent differences between paired diagnosis and relapse specimens. In contrast to previous studies we found evidence of hypermutation associated with TMZ treatment in the minority of patients. We propose that this may be related to the wild-type TP53 status in these patient's tumours.