tbuckley/cabot-search huggingface dataset:
Identification of Recurrent Activating<i>HER2</i>Mutations in Primary Canine Pulmonary Adenocarcinoma
Authors: Gwendolen Lorch, Karthigayini Sivaprakasam, Victoria Zismann, Nieves Perdigones, Tania Contente-Cuomo, Alexandra Nazareno, Salvatore Facista, Shukmei Wong, Kevin Drenner, Winnie S. Liang, Joseph M. Amann, Sara L. Sinicropi-Yao, Michael J. Koenig, Krista La Perle, Timothy G. Whitsett, Muhammed Murtaza, Jeffrey M. Trent, David P. Carbone, William P.D. Hendricks
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Naturally occurring primary canine lung cancers share clinicopathologic features with human lung cancers in never-smokers, but the genetic underpinnings of canine lung cancer are unknown. We have charted the genomic landscape of canine lung cancer and performed functional characterization of novel, recurrent HER2 (ERBB2) mutations occurring in canine pulmonary adenocarcinoma (cPAC). Experimental Design: We performed multiplatform genomic sequencing of 88 primary canine lung tumors or cell lines. Additionally, in cPAC cell lines, we performed functional characterization of HER2 signaling and evaluated mutation-dependent HER2 inhibitor drug dose-response. Results: We discovered somatic, coding HER2 point mutations in 38% of cPACs (28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. The majority (93%) of HER2 mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations were located in the extracellular domain and TMD. HER2V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2V659E tumors. HER2V659E cPAC cell lines displayed constitutive phosphorylation of AKT and significantly higher sensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines (IC50 &amp;lt; 200 nmol/L in HER2V659E vs. IC50 &amp;gt; 2,500 nmol/L in HER2WT). Conclusions: This study creates a foundation for molecular understanding of and drug development for canine lung cancer. These data also establish molecular contexts for comparative studies in dogs and humans of low mutation burden, never-smoker lung cancer, and mutant HER2 function and inhibition.
Abstract 5584: Circulating tumor cells in the peripheral blood and leukapheresis product of non-small cell lung cancer patients
Authors: Kiki C. Andree, Menno Tamminga, Anouk Mentink, T Jeroen Hilterman, Harry J. Groen, Leon W. Terstappen
Journal: Cancer Research (2018)

Abstract Introduction The number of circulating tumor cells (CTC) isolated by the FDA approved CellSearch (CS) system in 7.5 mL of blood of metastatic and non-metastatic non-small cell lung cancer (NSCLC) patients is low or absent. Processing a larger blood volume could yield a greater amount of CTC from these patients. An approach to probe larger volumes is using diagnostic leukapheresis (DLA) where the blood can be split into its components after which selective harvesting of mononuclear cells (MNC) including CTC can take place. Methods Patients with histologically proven NSCLC who either have been recently diagnosed or are eligible for new therapy can participate in this ongoing study. Patients had DLA for MNC collection derived from one total body blood volume. Before and after DLA, whole blood was drawn in a CellSave blood collection tube and analyzed by CS. The obtained DLA product was divided for analysis. 2x108 cells (on average 2mL of DLA product, representing ~100mL of blood) was diluted in 7.5 mL buffer, and analyzed by CS. 9 mL of the DLA product (on average 1x109 cells) was fixed and depleted of leukocytes using the RosetteSep CD45 depletion kit (Stemcell Technologies), allowing processing of a larger volume, followed by CS analysis. Results of molecular characterization of the detected CTC is pending. Results So far, a total of 8 DLA's were performed in 7 stage 4 NSCLC patients. Sample collection took place before (t=0) and/or after (t=1) treatment. Patients underwent DLA in about 110 minutes, at this time an average of 4860 mL of blood was processed. No complications occurred, no post-procedure complaints were recorded. Similar DLA products with an average of 95 mL were obtained. CTC counts for these patient samples are shown in the table below. CTC counts blood and DLAPatientt=#CTC pre blood#CTC post blood#CTC DLA (~2mL, 200x106 cells)#CTC depleted DLA (~9mL, 900x106 cells)101n/a114113020203514602031000040n/a04495000166000029020114 Conclusion DLA is a novel method to collect CTC from the blood. DLA can result in the detection of CTC where the use of 7.5mL of blood is not sufficient. Additionally, DLA shows an increase of CTC yield in patients with CTC detected in 7.5 mL of blood. Citation Format: Kiki C. Andree, Menno Tamminga, Anouk Mentink, T Jeroen Hilterman, Harry J. Groen, Leon W. Terstappen. Circulating tumor cells in the peripheral blood and leukapheresis product of non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5584.
Candidate SNPs enhance prediction of cognitive impairment after blood or marrow transplantation (BMT) for hematologic malignancy (HM).
Authors: Noha Sharafeldin, Joshua Richman, Alysia Bosworth, Yanjun Chen, Purnima Singh, Sunita K. Patel, Xuexia Wang, Emily Morse, Molly Mather, Can-Lan Sun, Liton Francisco, Stephen J. Forman, F. Lennie Wong, Smita Bhatia
Journal: Journal of Clinical Oncology (2019)

11520 Background: We tested the hypothesis that candidate genetic variants are associated with cognitive impairment in BMT recipients for HM, and that inclusion of genetic variants improves the performance of a risk prediction model that includes only clinical and demographic characteristics. Methods: We used standardized tests to assess cognitive function in 277 adult BMT recipients at City of Hope (COH). Global Deficit Score (GDS) ≥0.50 was used as indicator of cognitive impairment. Generalized estimating equation models and logic regression were used to identify single-SNP and gene-level associations with cognitive impairment post-BMT. Three risk prediction models were developed in the COH cohort using elastic net regression: Base Model (sociodemographics); Clinical Model (Base Model + clinical characteristics, therapeutic exposures and baseline cognitive reserve); Combined Model (Clinical + Genetic Model). The Genetic Model included significant SNPs in blood brain barrier, telomere homeostasis and DNA repair identified from single- and gene-level analyses. Models were validated in an independent cohort of long-term BMT survivors (BMTSS) with (n = 141) and without (n = 258) memory problems. Results: Training set (COH): The cohort included 58.5% males; 68.6% non-Hispanic whites; 46.6% allogeneic BMT recipients; median age at BMT: 51.6y. The mean area under the receiver operating characteristic curve (AUC) was: Base Model: 0.69 (95%CI: 0.63-0.75); Clinical Model: 0.77 (95%CI: 0.71-0.83); Combined Model: 0.89 (95%CI: 0.84-0.92). Test set (BMTSS): Median age at BMT was 45y; 53.5% were males; 88.4% non-Hispanic whites. Testing the models in BMTSS yielded mean AUC of 0.57 (95%CI: 0.49-0.63) in the Clinical Model and 0.72, (95%CI: 0.65-0.78) in the Combined Model. Conclusions: These findings provide evidence on the utility of a validated risk prediction tool that incorporates genetic factors that could identify BMT recipients at risk for cognitive impairment, providing opportunities for targeted interventions.
Abstract 16457: Inappropriate Noise Sensing is a Common Finding in St Jude Tendril Leads
Authors: Matthew M Chu, Andrew J Zager, Chad M House, Emily W Zhi, Leah L Zhu, Kristen A Lavell, William B Nelson, Dennis W Zhu
Journal: Circulation (2018)

Introduction: St. Jude Medical Tendril are popular 6F active-fixation bipolar pacing leads approved by the U.S. regulatory agency from 2003 to 2009. According to the company’s 2012 product performa...
The evolution of long noncoding RNA acceptance in prostate cancer initiation, progression, and its clinical utility in disease management
Authors: Varune Rohan Ramnarine, Maxim Kobelev, Ewan A. Gibb, Mannan Nouri, Dong Lin, Yuzhuo Wang, Ralph Buttyan, Elai Davicioni, Amina Zoubeidi, Colin C. Collins
Journal: European Urology (2019)

It is increasingly evident that non–protein-coding regions of the genome can give rise to transcripts that form functional layers of the cancer genome. One of most abundant classes in these regions is long noncoding RNAs (lncRNAs). They have gained increasing attention in prostate cancer (PCa) and paved the way for a greater understanding of these cryptic regulators in cancer. To review current research exploring the functional biology of lncRNAs in PCa over the past three decades. A systematic review was performed using PubMed to search for reports with terms "long noncoding RNA", "prostate", and "cancer" over the past 30 yr (1988–2018). We comprehensively surveyed the literature collected and summarise experiments leading to the characterisation of lncRNAs in PCa. A historical timeline of lncRNA identification is described, where each lncRNA is categorised mechanistically and within the primary areas of carcinogenesis: tumour risk and initiation, tumour promotion, tumour suppression, and tumour treatment resistance. We describe select lncRNAs that exemplify these areas. We also review whether these lncRNAs have a clinical utility in PCa diagnosis, prognosis, and prediction, and as therapeutic targets. The biology of lncRNA is multifaceted, demonstrating a complex array of molecular and cellular functions. These studies reveal that lncRNAs are involved in every stage of PCa. Their clinical utility for diagnosis, prognosis, and prediction of PCa is well supported, but further evaluation for their therapeutic candidacy is needed. We provide a detailed resource and view inside the lncRNA landscape for other cancer biologists, oncologists, and clinicians. In this study, we review current knowledge of the non–protein-coding genome in prostate cancer (PCa). We conclude that many of these regions are functional and a source of accurate biomarkers in PCa. With a strong research foundation, they hold promise as future therapeutic targets, yet clinical trials are necessary to determine their intrinsic value to PCa disease management.
Five‐Year Outcome of Operative and Nonoperative Management of Meniscal Tear in Persons Older Than Forty‐Five Years
Authors: Jeffrey N. Katz, Swastina Shrestha, Elena Losina, Morgan H. Jones, Robert G. Marx, Lisa A. Mandl, Bruce A. Levy, Lindsey A. MacFarlane, Kurt P. Spindler, Genevieve S. Silva, Jamie E. Collins
Journal: Arthritis & Rheumatology (2019)

Objective To determine the 5‐year outcome of treatment for meniscal tear in osteoarthritis. Methods We examined 5‐year follow‐up data from the Meniscal Tear in Osteoarthritis Research trial (METEOR) of physical therapy versus arthroscopic partial meniscectomy. We performed primary intent‐to‐treat (ITT) and secondary as‐treated analyses. The primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain scale; total knee replacement (TKR) was a secondary outcome measure. We used piecewise linear mixed models to describe change in KOOS pain. We calculated 5‐year cumulative TKR incidence and used a Cox model to estimate hazard ratios (HRs) for TKR, with 95% confidence intervals (95% CIs). Results Three hundred fifty‐one participants were randomized. In the ITT analysis, the KOOS pain scores were ~46 (scale of 0 [no pain] to 100 [most pain]) at baseline in both groups. Pain scores improved substantially in both groups over the first 3 months, continued to improve through the next 24 months (to ~18 in each group), and were stable at 24–60 months. Results of the as‐treated analyses of the KOOS pain score were similar. Twenty‐five participants (7.1% [95% CI 4.4–9.8%]) underwent TKR over 5 years. In the ITT model, the HR for TKR was 2.0 (95% CI 0.8–4.9) for subjects randomized to the arthroscopic partial meniscectomy group, compared to those randomized to the physical therapy group. In the as‐treated analysis, the HR for TKR was 4.9 (95% CI 1.1–20.9) for subjects ultimately treated with arthroscopic partial meniscectomy, compared to those treated nonoperatively. Conclusion Pain improved considerably in both groups over 60 months. While ITT analysis revealed no statistically significant differences following TKR, greater frequency of TKR in those undergoing arthroscopic partial meniscectomy merits further study.
The Climate Crisis — Health and Care Delivery
Authors: Renee N. Salas, Caren G. Solomon
Journal: New England Journal of Medicine (2019)

Interview with Dr. Renee Salas on the effects of climate change on human health and health systems. (13:09)Download The consequences of climate change directly affect human health, the practice of medicine, and the stability of health care systems. This Interactive Perspective elucidates these effects and some approaches to mitigating them. In this new feature, clinicians will find the climate-related information most relevant to their medical specialty, as well as a broader exploration of this major public health emergency.
FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults
Authors: Ruo-Jing Li, Runyan Jin, Chao Liu, Xianhua Cao, Michael L. Manning, Xu Michael Di, Donna Przepiorka, Frances Namuswe, Albert Deisseroth, Kirsten B. Goldberg, Gideon M. Blumenthal, Richard Pazdur
Journal: Clinical Cancer Research (2019)

On December 20, 2018, the Food and Drug Administration approved calaspargase pegol-mknl (CALASP), an asparagine-specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years. Efficacy was determined on the basis of achievement and maintenance of steady-state nadir serum asparaginase activity (NSAA) above 0.1 U/mL when using CALASP, 2,500 U/m2 intravenously, every 3 weeks. In a randomized comparison to pegaspargase (PEGASP) every 2 weeks, treatment with CALASP every 3 weeks had a similar safety profile and no substantial impairment in event-free survival. The pharmacokinetics of CALASP were studied when administered in combination with multiagent chemotherapy in 124 patients with B-cell ALL in Study AALL07P4 and Study DFCI 11-001. The results showed that 123 [99%, 95% confidence interval (CI), 96%-100%] of the 124 patients maintained NSAA >0.1 U/mL at weeks 6, 12, 18, 24, and 30 of post-induction phase. Maintaining adequate NSAA levels is critical to successful treatment of ALL. Herein, we describe the FDA review and approval of CALASP.See related commentary by Lew, p. 325.
Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma
Authors: Pei-Yi Wu, I-Shing Yu, Yueh-Chien Lin, Yu-Tzu Chang, Chien-Chin Chen, Kuan-Hung Lin, Tzu-Hsuan Tseng, Mati Kargren, Yu-Ling Tai, Tang-Long Shen, Yen-Lin Liu, Bo-Jeng Wang, Chi-Hao Chang, Wei-Min Chen, Hsueh-Fen Juan, Shiu-Feng Huang, Ya-Yun Chan, Yung-Feng Liao, Wen-Ming Hsu, Hsinyu Lee
Journal: Cancer Research (2019)

Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. SIGNIFICANCE: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.
Intragraft donor-specific anti-HLA antibodies in phenotypes of chronic lung allograft dysfunction
Authors: Annelore Sacreas, Jean-Luc Taupin, Marie-Paule Emonds, Liesbeth Daniëls, Dirk E. Van Raemdonck, Robin Vos, Geert M. Verleden, Bart M. Vanaudenaerde, Antoine Roux, Stijn E. Verleden
Journal: European Respiratory Journal (2019)

Introduction Circulating anti-human leukocyte antigen (HLA) serum donor-specific antibodies (sDSAs) increase the risk of chronic lung allograft dysfunction (CLAD) and mortality. Discrepancies between serological and pathological/clinical findings are common. Therefore, we aimed to assess the presence of tissue-bound graft DSAs (gDSAs) in CLAD explant tissue compared with sDSAs. Methods Tissue cores, obtained from explant lungs of unused donors (n=10) and patients with bronchiolitis obliterans syndrome (BOS; n=18) and restrictive allograft syndrome (RAS; n=18), were scanned with micro-computed tomography before elution of antibodies. Total IgG levels were measured via ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples. Results Overall, mean fluorescence intensity was higher in RAS eluates compared with BOS and controls (p&lt;0.0001). In BOS, two patients were sDSA + /gDSA + and two patients were sDSA − /gDSA + . In RAS, four patients were sDSA + /gDSA + , one patient was sDSA + /gDSA − and five patients were sDSA − /gDSA + . Serum and graft results combined, DSAs were more prevalent in RAS compared with BOS (56% versus 22%; p=0.04). There was spatial variability in gDSA detection in one BOS patient and three RAS patients, who were all sDSA − . Total graft IgG levels were higher in RAS than BOS (p&lt;0.0001) and in gDSA + versus gDSA − (p=0.0008), but not in sDSA + versus sDSA − (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= −0.39; p=0.02). Conclusions This study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.
Implementation of national policies for a total asbestos ban: a global comparison
Authors: Ro-Ting Lin, Lung-Chang Chien, Masamine Jimba, Sugio Furuya, Ken Takahashi
Journal: The Lancet Planetary Health (2019)

BackgroundTwo international Conventions from the International Labor Organization (ILO; C162 Asbestos Convention) and the UN (Basel Convention) offer governments guidelines for achieving a total asbestos ban policy, but the long-term effect of these Conventions on policy implementation, and the role of government effectiveness, remains unknown. We aimed to investigate associations between government ratification of the ILO and UN international Conventions, government effectiveness, and implementation of a national total asbestos ban.MethodsWe obtained data for year of a national asbestos ban, year of ratification of one or both international Conventions, and World Bank government effectiveness scores for 108 countries that ever used asbestos. We did a survival analysis for countries with data in the follow-up period (March 22, 1989, to Feb 2, 2018) to assess whether ratification of the international Conventions and greater government effectiveness were associated with time of implementation of a national total asbestos ban.FindingsOf 108 countries with data for asbestos consumption, nine were excluded because they implemented an asbestos ban before 1989. Therefore, 99 countries were included in the survival analysis. 26 countries ratified both international Conventions and 73 ratified either one or no Convention. Countries that ratified both Conventions had a shorter time to adoption of a total asbestos ban (mean 8·9 [SD 6·4] years) than did countries that ratified one or no Conventions (16·9 [6·1] years). After controlling for government effectiveness, countries that ratified both Conventions had a significantly higher conditional probability of banning asbestos than did those ratifying one or no Convention (hazard ratio [HR] 41·8, 95% CI 4·5–383·3; p=0·0010). For every 1 point increment in government effectiveness, the percentage change in HR for persistent asbestos consumption significantly increased by 127% (95% CI 13–354; p=0·021).InterpretationThis study confirms that adoption of both the C162 Asbestos Convention and the Basel Convention facilitates countries in moving towards a total asbestos ban. The effect was reinforced by government effectiveness. Both international programmes and new agreements towards total asbestos bans and government commitments are needed.FundingChina Medical University, and the Ministry of Science and Technology (Taiwan).
Cryobiopsy for Diagnosis of Interstitial Lung Disease: Discussion from the University of Toronto Respirology Journal Club
Authors: Jason Rajchgot, Matthew Stanbrook, Anju Anand
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

methodology to obtain tissue for histopathology and new diagnostic paradigms such as the use of molecular profiling of transbronchial biopsy samples (5) and behavioral classifications (6, 7).As this study shows, we need to use a deliberative process when investigating novel approaches to improve our diagnostic methods.While we await additional data, the current study should give clinicians pause before they consider further implementation of TBLC in ILD.Despite the frustration inherent in this approach, increasing diagnostic confidence, minimizing adverse outcomes, and lowering barriers against substantive progress will remain our community's common goals.
Does diet quality or nutrient quantity contribute more to health?
Authors: Justin B. Echouffo-Tcheugui, Rexford S. Ahima
Journal: Journal of Clinical Investigation (2019)

Diet and disease riskWestern diet is a leading risk factor for chronic illness and death (1).A recent study in the journal Lancet addressed key questions pertaining to the health-related effects of nutrition as assessed through the dietary components (2).The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 Diet Collaborators evaluated 15 dietary factors for their effects on mortality and disability from cardiovascular diseases, diabetes, and cancer across 195 countries (2).Adding to their previous findings (3), the GBD study made a number of key observations.First, the consumption of healthy diet was suboptimal worldwide (i.e., low intake of nuts and seeds, milk, and whole grains), whereas the consumption of unhealthy diet (i.e., sugary beverages, salt, and processed and red meat) was more common.Second, the examined dietary factors were potentially responsible for a high disease burden, including 11 million (95% uncertainty interval, 10-12) deaths and 255 million (95% uncertainty interval, 234-274) disability-adjusted life-years (DALYs; 22% of all deaths and 15% of all DALYs in adults aged 25 years or older).Third, three factors, including high intake of sodium, low intake of whole grains, and low intake of fruit, accounted for more than 50% of diet-related deaths and two-thirds of diet-related DALYs.These findings were consistent across different regions of the world. Conflict of interest:The authors have declared that no conflict of interest exists.