tbuckley/cabot-search huggingface dataset:
Reducing Pollution From the Health Care Industry
Authors: Jodi D. Sherman, Andrea MacNeill, Cassandra Thiel
Journal: JAMA (2019)

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<i>BAP1</i>: The first mutated gene causing familial uveal melanoma.
Authors: Johan Hansson, Charlotta All-Eriksson, Hildur Helgadottir, Daniel Edsgard, Rainer Tuominen, Joakim Lundeberg, Ivayla Ivanova, Olof Emanuelsson, Veronica Hoiom
Journal: Journal of Clinical Oncology (2012)

10521 Background: Uveal melanoma (UM) is a rare malignancy with a poor prognosis. Familial predisposition to UM is rare and accounts for only a few percent of all cases. The genetic background of hereditary UM is unknown and the aim of our project was to identify susceptibility gene(s) for UM. Methods: We identified a family with hereditary predisposition for UM – the proband of which is a young female diagnosed with UM at age 16 who within 6 months developed liver metastases. We also identified two older paternal relatives who were diagnosed with UM at 39 and 44 years of age, respectively. We performed massively parallel sequencing using the Illumina Hiseq2000 technology on germline DNA from the proband, her parents and a healthy sibling. After QC and mapping against the human reference genome the average coverage across the exome was between 35 and 86 for the four sequenced samples. Results: Out of more than 260,000 single nucleotide variants (SNVs) and small insertion / deletion variants (indels), 51 gene variants were filtered out by being novel, shared by the affected proband and her father (considered an obligate mutation carrier), but not by the healthy mother, of predicted functional importance and /or located within strongly conserved regions. The strongest candidate among these was a loss of function-variant in the BAP1 gene, since BAP1 has been suggested as a tumor suppressor in several cancer-related syndromes, including cases of UM. The sequence data indicated an insertion of one base-pair in exon 3 of the BAP1 genecausing a frame-shift and subsequently a truncated protein lacking all its functional domains. The mutation was also present in UM tumor tissue from the two deceased paternal relatives and was found to segregate with the UM phenotype in the family. We also detected loss of heterozygosity in the tumor of the proband, supporting BAP1 as the causative gene in this family. Conclusions: The identification of BAP1 as the gene responsible for this syndrome is the first demonstration of a germline mutation causing UM. This enables us to identify and monitor risk individuals belonging to mutation positive families with predisposition to UM, and possibly other cancer syndromes. We are continuously screening other cases of familial UM for mutations in BAP1.
The novel autophagy inhibitor ROC-325 augments the antileukemic activity of azacitidine
Authors: Steffan T. Nawrocki, Yingchun Han, Valeria Visconte, Bartlomiej Przychodzen, Claudia M. Espitia, James Phillips, Faiz Anwer, Anjali Advani, Hetty E. Carraway, Kevin R. Kelly, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Jennifer S. Carew
Journal: Leukemia (2019)
A single-center analysis of initial imaging in multiple myeloma (MM).
Authors: Justin M. Markow, Amishi Desai, Harry Staszewski
Journal: Journal of Clinical Oncology (2012)

e18554 Background: Current recommendations for the evaluation of MM include a skeletal survey (SS) and possibly an MRI. The literature documents a discrepancy in the detection of important skeletal lesions between these two techniques. There is limited data on the relationship between symptoms and spinal MRI findings. We analyzed the correlation of symptoms with an abnormal MRI in our patients. Methods: We analyzed 66 unselected,retrospectively identified patients with MM using lab values, ISS scores, the initial SS, and MRI. Skeletal symptoms, interval between studies, discordance between imaging by modality, and interventions were also tabulated. Risk ratios (RR) were calculated for the probability of radiologic abnormalities based on symptoms. Fischer's exact test was applied. Results: The baseline characteristics by age, gender, race, ISS score, and other lab values were similar between groups. 53% (35/66) of patients had an MRI at diagnosis. 51.4% (18/35) of these had different findings from the SS (95% CI, 35.6% - 67.0%). 30.8% (8/26) of patients with an MRI abnormality were asymptomatic or had symptoms in a different location than seen on MRI (95% CI, 16.3% - 50.1%). 15.4% (4/26) of these patients were asymptomatic at presentation (95% CI, 5.5% - 34.2%). (RR) for patients with any reported symptom and abnormal MRI finding is 2.6 (95% CI, 1.1 - 5.6, p&lt; 0.01), while the RR for a symptom corresponding to its anatomic area on MRI is 1.3 (95%CI .8 - 2.1, p = 0.23). Conclusions: 30% of our patients with an abnormal MRI were asymptomatic or reported symptoms in a different area. The RR for an abnormal MRI result in patients with any symptom was significant, but the symptomatic area did not correlate with the anatomic MRI abnormality. This suggests that a significant amount of disease is missed because imaging may be confined to the symptomatic area and asymptomatic patients are less likely to have an MRI. Within this limited data set, there appears to be an advantage to performing routine initial MRI
Abstract 15065: Detection of Interstitial Fibrosis in Hypertrophic Cardiomyopathy by Post-gadolinium Bolus CMR T1 Mapping
Authors: Tevfik F Ismail, Niraj Mistry, Andrew Jabbour, Callum Ettles, Taigang He, Ricardo Wage, Ankur Gulati, Susan Clark, Dudley J Pennell, Sanjay K Prasad
Journal: Circulation (2011)

Background: Fibrosis is an important pathogenic driver of adverse cardiac events in hypertrophic cardiomyopathy (HCM). Post-gadolinium cardiovascular magnetic resonance (CMR) T1 mapping holds promi...
High-Deductible Insurance and Delay in Care
Authors: Michael Goulet, Jennifer Goldstein
Journal: Annals of Internal Medicine (2019)

Letters6 August 2019High-Deductible Insurance and Delay in CareMichael Goulet, DO and Jennifer Goldstein, MD, MScMichael Goulet, DOChristiana Care Health System, Newark, Delaware (M.G., J.G.)Search for more papers by this author and Jennifer Goldstein, MD, MScChristiana Care Health System, Newark, Delaware (M.G., J.G.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L19-0204 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We commend Wharam and colleagues (1) on a well-executed study on the potential unintended consequences of high-deductible insurance. However, we are concerned that excluding patients with myocardial infarction (MI) and cerebrovascular accident (CVA) from the analysis could have detracted from the validity of their findings.The Methods section states that major symptoms of coronary heart disease were defined as angina as well as acute and subacute forms of ischemic heart disease, but patients with MI were excluded. In a similar manner, although symptoms of cerebrovascular disease were defined as transient ischemic attack, patients with CVA were excluded. ...Reference1. Wharam JF, Lu CY, Zhang F, et al. High-deductible insurance and delay in care for the macrovascular complications of diabetes. Ann Intern Med. 2018;169:845-54. [PMID: 30458499]. doi:10.7326/M17-3365 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Christiana Care Health System, Newark, Delaware (M.G., J.G.)Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L19-0204. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHigh-Deductible Insurance and Delay in Care for the Macrovascular Complications of Diabetes J. Frank Wharam , Christine Y. Lu , Fang Zhang , Matthew Callahan , Xin Xu , Jamie Wallace , Stephen Soumerai , Dennis Ross-Degnan , and Joseph P. Newhouse High-Deductible Insurance and Delay in Care J. Frank Wharam and Joseph P. Newhouse Metrics 6 August 2019Volume 171, Issue 3Page: 226KeywordsAnginaCerebrovascular diseasesConflicts of interestCoronary heart diseaseDisclosureHealth care policyHeartMyocardial infarctionStrokeTransient ischemic attacks ePublished: 6 August 2019 Issue Published: 6 August 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Bleomycin-associated lung toxicity in childhood cancer survivors.
Authors: Alexandra Patricia Zorzi, Connie L Yang, Sharon Dell, Paul C. Nathan
Journal: Journal of Clinical Oncology (2012)

9591 Background: Bleomycin has been established as a pulmonary toxin, but the risk for toxicity in survivors of childhood cancer is poorly characterized. Methods: We conducted a cross-sectional study of lung function in survivors of childhood Hodgkin lymphoma and germ cell tumor treated with bleomycin at our institution between 1997 and 2010. We assessed their most recent post-therapy pulmonary function test (PFT). Spirometry and lung volumes were categorized as normal, restrictive, obstructive or mixed. Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or abnormal. Results: 195 patients were treated with bleomycin. Ten died of non-pulmonary causes. Of 185 survivors, 143 (77%) had complete data available for analysis. Median cumulative bleomycin dose was 60U/m 2 (IQR 30-60). Three patients (2%) had a history of acute bleomycin toxicity. PFTs were performed a median of 2.3 years (IQR 1.4-4.9) from completion of therapy. Spirometry was abnormal in 58 patients (41%); of whom 5 (9%) had respiratory symptoms. 42 (70%) had obstructive, 11 (18%) restrictive and 5 (9%) mixed ventilatory defects. Abnormalities were mild in 53 (91%), moderate in 3 (5%) and severe in 2 (4%). DLCO was abnormal in 27 patients, 26 (96%) of whom had mildly reduced DLCO and were asymptomatic. Univariate analysis did not demonstrate a significant association between gender, smoking, lung metastases, lung radiation, chemotherapy regimen, or autologous transplant and abnormal lung function. Disease relapse was associated with abnormal lung function (p=0.01). Smoking (p=0.04) and relapse (p=0.03) were associated with abnormal DLCO. The odds ratio of developing abnormal spirometry for each 1unit/m 2 increase in bleomycin was 1.01 (95% CI 1.00-1.02, p=0.07). Conclusions: Childhood cancer survivors treated with bleomycin frequently have evidence of asymptomatic abnormalities on PFT. The current recommendation for pulmonary function testing in childhood cancer survivors appears justified.
Multiplatform assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in signet ring cell carcinoma of the gastrointestinal tract.
Authors: Olatunji Boladale Alese, Bassel F. El-Rayes, Gabriel Sica, Guojing Zhang, Michael R. Rossi, Volkan Adsay, Dianne Alexis, Francisco G. La Rosa, Marileila Varella-Garcia, Zhengjia Chen, John S. Kauh, Suresh S. Ramalingam, Fadlo Raja Khuri, Taofeek Kunle Owonikoko
Journal: Journal of Clinical Oncology (2013)

e14612 Background: ALK-EML4 translocation is an established driver aberration in NSCLC, with reported predilection for cases with signet ring histology. We assessed the presence of ALK gene rearrangements in signet ring cancers arising in the stomach and colon. Methods: Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified from the pathology archive of Emory University Hospital. Presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) method. Cases showing break-apart signal in more than 15% of enumerated cells were considered positive; at least 10% of enumerated cells was considered “possibly positive”. Immunohistochemistry of the fused gene product was assessed using previously validated antibodies ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) and positive controls of ALK-translocated lung cancer. Positive or possibly positive cases by FISH were further analyzed by RT-PCR using specific primers for the most common translocation pairs (EML4 Ex13/ALK Ex20 and EML4 Ex6/ALK Ex20) along with positive (H228, HEK293) and negative (H460, H1975) control cell lines. Results: We retrieved 44 cases of signet ring carcinoma diagnosed between 2001 and 2011; 26 gastric and 18 colon cancer. Median age - 63 yrs; M/F 17/27; Black - 47.5%; White - 47.5%; Others - 5%; Stage I - 21.4%; II - 31%; III - 26.2; IV - 21.4%. One of 44 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50-70 cells counted per case). 7 cases (16%) were considered possibly positive [1 of 18 (6%) colon cancer and 6 of 26 (26%) gastric cancer cases]. IHC showed 0 of 44 (0%) cases positive. Molecular analysis using RT-PCR did not confirm the suspected ALK gene rearrangements in any of the 7 cases considered possibly positive by FISH. Conclusions: The overall frequency of ALK gene rearrangement detected by FISH in signet ring cancer of the GI tract was low, but appears comparable to the reported frequency in lung cancer. Signet ring histology failed to enrich for cases with ALK gene translocation in this histologic subtype.
Some needed psychological clarifications on the experience(s) of shamanism
Authors: Etzel Cardeña, Stanley Krippner
Journal: Behavioral and Brain Sciences (2018)

Abstract The target article's use of core concepts is confused and excessively broad. Two main types of experiences have been described in relation to shamanism: magical flight and mediumship/possession. The first refers to visual and remembered experiences of events in other realms, the second to embodied experiences of ceding mental control and personality to a preternatural entity. These experiences grossly correspond to two main experience modalities exhibited by highly hypnotizable individuals in a secular setting.
Assessment of Publication Trends of Systematic Reviews and Randomized Clinical Trials, 1995 to 2017
Authors: Joshua D. Niforatos, Matt Weaver, Michael E. Johansen
Journal: JAMA Internal Medicine (2019)

Systematic reviews and meta-analyses (SRMAs) and randomized clinical trials (RCTs) are considered the most robust and reliable forms of evidence to guide clinical practice.Previous research has demonstrated year-over-year increases in the number of published RCTs between 1950 and 2007 1 as well as increases in the number of published SRMAs through 2016. 2,3The increase in SRMAs is needed to update cumulative evidence, 2 although some investigators speculate that SRMAs may also serve as "easily publishable units or marketing tools." 2,3Given this context, we sought to compare publication trends overall and across clinical topic areas among SRMAs and RCTs over the past 22 years.
Use of serum markers in prediction of survival in the trapeze factorial trial evaluating docetaxel with zoledronic acid, strontium-89, or both in castrate-refractory prostate cancer (CRPC) metastatic to bone.
Authors: Vivek K Wadhwa, Sarah Pirrie, Kai Sheng Wen, Darren Barton, Nicholas David James
Journal: Journal of Clinical Oncology (2013)

5057 Background: There is emerging interest in the use of bone turnover markers in CRPC to compliment current modalities and aid therapeutic management decisions. We report the preliminary results of investigation into the clinical utility of P1NP, total alkaline phosphatase (ALP) and PSA as parameters of survival in a representative sample of patients from TRAPEZE. Methods: Baseline and post treatment (cycle six or end of treatment if sooner) samples were taken from 120 patients equally distributed across the trial arms of TRAPEZE. Absolute and percentage change in the markers were investigated in relation to overall survival (OS) using the Cox Regression model. Results: Of the 120 patients, 38(32%) failed to complete 6 cycles. No relationship was observed between P1NP and OS using either absolute or percentage change (p=0.59, p=0.64). Absolute change in log PSA was significantly related to OS (HR=1.22 (95%CI 1.01, 1.48), p&lt;0.05, respectively) however percentage change in log PSA did not reach statistical significance (HR=1.006 (95%CI 0.99, 1.01), p=0.095). Absolute change in ALP was found to be inversely related to OS (HR=0.999 (95%CI 0.998, 0.999), p&lt;0.001) but percentage change in ALP was not significant (p=0.89). When the PSA and ALP models were applied to the entire trial set (757 patients) the predictive value of both absolute and percentage change in log PSA remained highly significant (HR=1.23, p&lt;0.001 &amp; HR=1.01, p&lt;0.001). In addition the significance of absolute change in ALP also remained (HR=0.999, p&lt;0.05). Conclusions: Changes in P1NP were not related to OS in CRPC patients metastatic to bone. Absolute change in ALP was inversely related to OS and both absolute and percentage changes in log PSA were also related to OS in this sub-study. When applied to the entire TRAPEZE patient group all remained statistically significant. The utility of changes in ALP and PSA, as prospective markers for studies in CRPC patients metastatic to bone, merit further evaluation.
ERCC1, KRAS mutation, redox status, and oxaliplatin sensitivity in colorectal cancer: “Radical” change in an old model.
Authors: Armando Orlandi, Mariantonietta Di Salvatore, Michele Basso, Cinzia Bagalà, Antonia Strippoli, Francesca Plastino, Enzo Dadduzio, Simona Di Lascio, Elisabetta Cursio, Alessia Amoruso, Mariagrazia Rodriquenz, Alessandra Cassano, Antonio Astone, Carlo Barone
Journal: Journal of Clinical Oncology (2012)

e14156 Background: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxa in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1 and cellular Redox status. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8, HT-29) and two K-RAS mt (SW620, SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test and the ERCC1 levels before and after 24h exposure to Oxa by RT-PCR. We silenced K-RAS in a K-RAS mt cell lines to evaluate the impact on Oxa sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxa resistance factor. Cellular oxidative stress was determined by DCFDA. Results: The K-RAS mt cell lines were more sensitive to Oxa (p&lt;0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24h exposure to Oxa, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (p&lt;0.005). The silencing of K-RAS in K-RAS mt cell lines (SW620s) demonstrated to reduce sensitivity to Oxa associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxa. The levels of reactive oxygen species were higher in K-RAS mt cell lines. The Pearson correlation test showed a statistically significant relationship between basal levels of ROS and sensitivity to Oxa ("r" -0,988, p&lt;0.01). The baseline levels of ROS were higher SW620 than the line SW620s. The administration of Oxa in these cell lines resulted in a statistically higher fluorescence index in SW620 versus SW620s (p&lt;0.003). Conclusions: The K-RAS mutated cell lines were more sensitive to Oxa. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxa and to the synergism between K-RAS mutation and Oxa in increasing oxidative stress. K-RAS can thus be a predictor of response to Oxa in colorectal cancer.
A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
Authors: Danuta R. Gawel, Jordi Serra-Musach, Sandra Lilja, Jesper Aagesen, Alex Arenas, Bengt Asking, Malin Bengnér, Janne Björkander, Sophie Biggs, Jan Ernerudh, Henrik Hjortswang, Jan-Erik Karlsson, Mattias Köpsen, Eun Jung Lee, Antonio Lentini, Xinxiu Li, Mattias Magnusson, David Martínez-Enguita, Andreas Matussek, Colm E. Nestor, Samuel Schäfer, Oliver Seifert, Ceylan Sonmez, Henrik Stjernman, Andreas Tjärnberg, Simon Wu, Karin Åkesson, Alex K. Shalek, Margaretha Stenmarker, Huan Zhang, Mika Gustafsson, Mikael Benson
Journal: Genome Medicine (2019)

Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.