tbuckley/cabot-search huggingface dataset:
A comparison of microsatellite instability analysis methods in colorectal cancer.
Authors: Samantha Lewis, Shaun Peterson, Kathryn Oostdik, Heather Tomlinson
Journal: Journal of Clinical Oncology (2019)

46 Background: Use of biomarkers for patient treatment stratification is an increasingly important topic with the recent FDA approval of Pembrolizumab and Nivolumab for microsatellite instability (MSI) high/mismatch repair (MMR) deficient cancers. This ground-breaking approval allows physicians to make patient treatment decisions based on molecular biomarker status. Thus, performance of detection methods for these biomarkers is of great importance. The gold standard for MSI analysis in a research setting is PCR followed by fragment analysis to resolve DNA size. Recently, PCR followed by melt curve analysis has been presented as an alternative approach. In this set of experiments these two methods are compared using a subset of human colorectal cancer samples. Methods: A cohort of matched human colorectal cancer and adjacent normal FFPE samples were used for this comparison. Eight pairs were selected that contained subtle shifts, low tumor volume or heterozygosity at microsatellite loci. These samples were then tested for MSI by fragment or melt curve analysis. Samples were then classified as MSI-H, MSI-L or microsatellite stable (MSS) according to manufacturer specifications for melt curve analysis or by an interpretive software for fragment analysis. Results: 40 mononucleotide markers were examined for each method. Melt curve analysis was concordant with fragment analysis in 70% of markers tested (28/40). Of discordant markers, 92% (11/12) were identified as unstable with fragment analysis but were stable by melt curve analysis. Additionally, two of the samples identified as MSI-H by fragment analysis were called MSS or MSI-L using the melt curve analysis method. These preliminary results suggest there may be differences in sensitivity when using challenging samples with melt curve compared to the gold standard method, fragment analysis. Conclusions: The standard method for determining MSI status utilizes PCR and fragment analysis. Recently, melt curve analysis has been proposed as an alternative method. We present preliminary findings of decreased sensitivity with melt curve compared to fragment analysis. Additional studies with a larger, more diverse sample set will be required to define this relationship further.
Countertraction applied using clips and a rubber band: a new simple method for cannulation of intradiverticular or hidden papillae
Authors: Marion Schaefer, Bastien Dirrenberger, Mathilde Morin, Arthur Belle, Sophie Gueyl, Jérémie Jacques, Jean-Baptiste Chevaux
Journal: Endoscopy (2019)

A juxtapapillary diverticulum is a frequent age-related condition that may affect 10 % – 20 % of patients undergoing endoscopic retrograde cholangiopancreatography, and increases the prevalence of stones in the principal bile duct [1]. This can render biliary duct cannulation difficult. Papillae can also be hidden by lipomas, gastrointestinal stromal tumors, or mucosal folds. To facilitate cannulation, the two-devices-in-one-channel technique of Fujita et al. can be used. A pediatric biopsy forceps is employed to evert the papilla out of the diverticulum, and other devices are inserted in parallel, in the operative channel [2]. The principal drawback is the poor maneuverability of both the duodenoscope and the elevator. Scotiniotis et al. used a clip to apply traction (the weight of the clip) to the papilla [3]. This allowed for good scope maneuverability but traction was minimal; the papilla remained unstable. We here report two cases of difficult biliary access ([Video 1]).
Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
Authors: Irène Baccelli, Yves Gareau, Bernhard Lehnertz, Stéphane Gingras, Jean-François Spinella, Sophie Corneau, Nadine Mayotte, Simon Girard, Mélanie Frechette, Valérie Blouin-Chagnon, Koryne Leveillé, Isabel Boivin, Tara MacRae, Jana Krosl, Clarisse Thiollier, Vincent-Philippe Lavallée, Evgeny Kanshin, Thierry Bertomeu, Jasmin Coulombe-Huntington, Corinne St-Denis, Marie-Eve Bordeleau, Geneviève Boucher, Philippe P. Roux, Sébastien Lemieux, Mike Tyers, Pierre Thibault, Josée Hébert, Anne Marinier, Guy Sauvageau
Journal: Cancer Cell (2019)
Human Positron Emission Tomography Neuroimaging
Authors: Jacob M. Hooker, Richard E. Carson
Journal: Annual Review of Biomedical Engineering (2019)

Neuroimaging with positron emission tomography (PET) is the most powerful tool for understanding pharmacology, neurochemistry, and pathology in the living human brain. This technology combines high-resolution scanners to measure radioactivity throughout the human body with specific, targeted radioactive molecules, which allow measurements of a myriad of biological processes in vivo. While PET brain imaging has been active for almost 40 years, the pace of development for neuroimaging tools, known as radiotracers, and for quantitative analytical techniques has increased dramatically over the past decade. Accordingly, the fundamental questions that can be addressed with PET have expanded in basic neurobiology, psychiatry, neurology, and related therapeutic development. In this review, we introduce the field of human PET neuroimaging, some of its conceptual underpinnings, and motivating questions. We highlight some of the more recent advances in radiotracer development, quantitative modeling, and applications of PET to the study of the human brain.
Patient and public involvement in biomedical research: training is not a substitute for relationship building
Authors: Anthony G Wilson, John Sherwin, Emma R Dorris
Journal: Annals of the Rheumatic Diseases (2019)

Public and patient involvement (PPI) is increasingly an expectation of funders and policy-makers. Not all areas of health research are obvious or accessible to patients. Involving the public in preclinical and laboratory-based research in a mutually beneficial way can be challenging. Fundamentally, there is confusion among preclinical researchers as to what PPI is and how it is applied.1 PPI is not about unleashing the public into your laboratory; rather it is about increasing research relevance and cooperating with people living with rheumatic disease to enable careful and deliberate study design.

In practice, how can you involve patients meaningfully and in line with European League Against Rheumatism recommendations2 if you have not already established mutual respect, a supportive environment and a relationship built on equal status?

Too often, the literature aimed at guiding researchers …
Thyroid Function and Conception
Authors: Angela X. Chen, Angela M. Leung, Tim I.M. Korevaar
Journal: New England Journal of Medicine (2019)

This interactive feature about a woman who has recently had a spontaneous miscarriage and tests positive for thyroid peroxidase antibodies offers a case vignette accompanied by essays that either support or discourage the use of levothyroxine to increase her chances of becoming pregnant.
Minimum Tolerable Interval of Radioimmunotherapy and Autologous Stem Cell Transplantation after High-Dose Chemotherapy for Relapsed or Refractory Aggressive B Cell Non-Hodgkin-Lymphoma Provides Excellent Disease Control
Authors: Justin Hasenkamp, Georg Hess, Bernd Hertenstein, Mathias Witzens-Harig, Lutz Uharek, Martin Gramatzki, Michael Pfreundschuh, Gerald Wulf, Lorenz H. Truemper, Norbert Schmitz, Bertram Glass
Journal: Blood (2014)
State-Specific Prevalence of Quit Attempts Among Adult Cigarette Smokers — United States, 2011–2017
Authors: Kimp Walton, Teresa W. Wang, Gillian L. Schauer, Sean Hu, Henraya F. McGruder, Ahmed Jamal, Stephen Babb
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

From 1965 to 2017, the prevalence of cigarette smoking among U.S. adults aged ≥18 years decreased from 42.4% to 14.0%, in part because of increases in smoking cessation (1,2). Increasing smoking cessation can reduce smoking-related disease, death, and health care expenditures (3). Increases in cessation are driven in large part by increases in quit attempts (4). Healthy People 2020 objective 4.1 calls for increasing the proportion of U.S. adult cigarette smokers who made a past-year quit attempt to ≥80% (5). To assess state-specific trends in the prevalence of past-year quit attempts among adult cigarette smokers, CDC analyzed data from the 2011-2017 Behavioral Risk Factor Surveillance System (BRFSS) surveys for all 50 states, the District of Columbia (DC), Guam, and Puerto Rico. During 2011-2017, quit attempt prevalence increased in four states (Kansas, Louisiana, Virginia, and West Virginia), declined in two states (New York and Tennessee), and did not significantly change in the remaining 44 states, DC, and two territories. In 2017, the prevalence of past-year quit attempts ranged from 58.6% in Wisconsin to 72.3% in Guam, with a median of 65.4%. In 2017, older smokers were less likely than younger smokers to make a quit attempt in most states. Implementation of comprehensive state tobacco control programs and evidence-based tobacco control interventions, including barrier-free access to cessation treatments, can increase the number of smokers who make quit attempts and succeed in quitting (2,3).
Abstract 16628: Treatment of Metabolic Acidosis in Chronic Kidney Disease With Fruits and Vegetables but Not Sodium Bicarbonate Yields Fewer Adverse Cardiovascular Events After Five-years Follow Up
Authors: Nim Goraya, Yolanda Munoz-Maldonado, Jan Simoni, Donald E Wesson
Journal: Circulation (2017)

Background: Chronic kidney disease (CKD) patients have increased risk for myocardial infarction (MI) and cerebrovascular accident (CVA) and metabolic acidosis further increases this risk. Neverthel...
HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure
Authors: Beth A Firulli, Rajani M George, Jade Harkin, Kevin P Toolan, Hongyu Gao, Yunlong Liu, Wenjun Zhang, Loren J Field, Ying Liu, Weinian Shou, Ronald Mark Payne, Michael Rubart-von der Lohe, Anthony B Firulli
Journal: Cardiovascular Research (2019)

Abstract Aims To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium. Methods and results Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5–13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (αMhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure. Conclusion Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development.
Abstract 14208: Versican is Essential for Chamber Formation by Recruiting Cardiac Progenitor Cells from the Outflow Tract in Medaka Fish
Authors: Sung Han Yoon, Shinji Makino, Atsushi Shimizu, Yuta Higashikuse, Mayumi Oda, Misato Fujita, Atsushi Kawakami, Akira Kudo, Shinsuke Yuasa, Motoaki Sano, Keiichi Fukuda
Journal: Circulation (2010)

Background: Heart tube formation from primary heart field precedes rightward looping and chamber formation. Ventricular chamber growth requires cardiomyocyte proliferation and progenitor cells migr...
Tumor-specific delivery of gemcitabine with activatable liposomes
Authors: Samantha T. Tucci, Azadeh Kheirolomoom, Elizabeth S. Ingham, Lisa M. Mahakian, Sarah M. Tam, Josquin Foiret, Neil E. Hubbard, Alexander D. Borowsky, Mo Baikoghli, R. Holland Cheng, Katherine W. Ferrara
Journal: Journal of Controlled Release (2019)
The clinical course of actinic keratosis correlates with underlying molecular mechanisms
Authors: A. Bakshi, R. Shafi, J. Nelson, W.C. Cantrell, S. Subhadarshani, A. Andea, M. Athar, C.A. Elmets
Journal: British Journal of Dermatology (2019)

Actinic keratoses (AKs) are common premalignant skin lesions triggered by excessive ultraviolet exposure. The majority of AKs regress or persist, but some progress to squamous cell carcinomas. Biomarkers associated with their persistence, progression and regression have not been characterized.We performed skin biopsies in patients with extensive actinic damage to identify biomarkers that correlate with clinical progression and regression of AKs.This was an observational study of a cohort of patients with extensive actinic damage. AKs were mapped on a clear plastic template in 26 patients at months 3, 6, 9 and 11. Biopsies were taken from randomly selected, predetermined AKs and were evaluated for p53, E-cadherin, Snail, Slug and Twist. The study is registered at Clinicaltrials.gov: NCT00027976.p53 exhibited greater expression in clinically apparent AKs (histological score 2·89 ± 1·45) than in regressed AKs (0·75 ± 0·96); P < 0·01. There was also significantly less membrane E-cadherin, the lack of which is a marker of epithelial-mesenchymal transition, in clinically apparent AKs (1·89 ± 1·81) than in sun-exposed skin (3·07 ± 1·75); P < 0·005. The E-cadherin transcription repressors Snail, Slug and Twist were increased in AKs compared with sun-exposed skin. A limitation of the study is that measurement of histological biomarkers was not a primary end point. In addition, patients were allowed to apply sunscreens.At the molecular level, loss of E-cadherin and an increase in p53 are linked to the dynamic interplay between the persistence, progression and regression of AKs. What's already known about this topic? Actinic keratoses (AKs) are common dysplastic epidermal lesions that result from chronic and excessive ultraviolet exposure. Biomarkers associated with progression and regression of AK have not been characterized. What does this study add? Decreased E-cadherin and increased p53, Snail, Slug and Twist (E-cadherin transcription factors) were associated with progression from AK to nonmelanoma skin cancer. What is the translational message? Strategies targeting these molecules may be effective in reversing rising skin cancer rates. E-cadherin, p53, Snail, Slug and Twist are potential biomarkers that may be used to assess the efficacy of existing chemopreventive agents.
Association of high baseline metabolic tumor volume with response following axicabtagene ciloleucel in refractory large B-cell lymphoma.
Authors: Erin Dean, Hong Lu, Aleksandr Lazaryan, Gabriel S Krivenko, Christina A Bachmeier, Julio C. Chavez, Marco L. Davila, Farhad Khimani, Hien D Liu, Javier Pinilla-Ibarz, Bijal D. Shah, Michael D. Jain, Yoganand Balagurunathan, Frederick Lundry Locke
Journal: Journal of Clinical Oncology (2019)

7562 Background: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 targeted Chimeric Antigen Receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). High tumor burden, by sum of the product of diameters (SPD) in ≥ 6 reference lesions, was associated with lower durable responses rates in the ZUMA-1 trial (Locke F.L. ASCO. 2018). Although metabolic tumor volume (MTV) predicts worse outcomes with chemotherapy in lymphoma (Guo B. PLoSOne. 2019), its prognostic significance remains unclear with axi-cel therapy. Methods: MTV was measured by MIM Software using a 41% SUVmax threshold with manual lesion contour adjustment and radiologist review. Low and high MTV groups were defined based on median cutoff value. Cytokine release syndrome (CRS) was graded by Lee et al. ( Blood. 2014). Neurotoxicity (NT) was graded by CTCAEv4. Toxicities, overall response rate (ORR), and complete response rate (CR) were evaluated via Fisher’s test; PFS and OS via Kaplan-Meier and log-rank test. Results: 48 patients with LBCL, or its variants, that received axi-cel at Moffitt from June 2015 to October 2018 were included. 31 were male, and median age was 63 years (range, 28-76). CRS occurred in 43/47 (91.5%) and NT in 32/47 (68.1%) patients. Grade 3-4 CRS in 2/47 (4.3%) and NT in 12/47 (25.5%). Median follow up for survivors was 8.9 months (range, 1.4- 36.8 months). CR was achieved in 31/48 (64.6 %) and ORR in 39/48 (81.3%). Median for the low MTV group was 35.1 mL (range, 4.24-132.8 mL), and for the high MTV group 455.5 mL (range, 162.2-1221.4 mL). High MTV was not predictive of G1-4 NT or G3-4 NT (OR = 1.14, P = 0.99; OR = 1.66, P = 0.52). Similarly, high MTV was not predictive of G1-4 CRS or G3-4 CRS (OR = 0.29, P = 0.348; OR = 1.05, P = 0.99). Low MTV was predictive of ORR (OR = 11.50, P = 0.026) and CR (OR = 9.8, P = 0.002). Patients with high MTV had inferior PFS (HR = 3.296, 95% CI 1.42-7.64, P = 0.008) and OS (HR = 6.68, 95% CI 2.56-17.32, P = 0.003). Conclusions: High baseline MTV is associated with decreased and less durable response following axi-cel. As survival data mature, future analyses will aim to assess the role of MTV as an independent prognostic tool in axi-cel recipients with LBCL.
Long-term clinical outcomes and transcriptional analysis following partial and complete tumor SBRT plus pembrolizumab.
Authors: Sandeep Ramesh Bhave, Jason J. Luke, Jeffrey Lemons, Yuanyuan Zha, Timothy C. Carll, Thomas Krausz, Hua Liang, Linda A. Janisch, Robyn D. Hseu, Nikolai Khodarev, Ralph R. Weichselbaum, Sean Pitroda, Steven J. Chmura
Journal: Journal of Clinical Oncology (2019)

34 Background: Preclinical models support a combinatorial role of high-dose irradiation with immunotherapy. Multi-site stereotactic body radiotherapy (SBRT) with pembrolizumab (P) has been demonstrated as safe in advanced solid tumors. Here, we report extended follow-up of treated metastasis control (TMC), progression-free survival (PFS), overall survival (OS) and describe transcriptional changes associated with TMC, PFS and OS. Methods: Patients (pts) with AST received 3-5 SBRT doses (30-50 Gy total dose) to 2-4 metastases based on anatomic location. Pembrolizumab (200 mg IV Q3W) began one week following the final SBRT. Mets &gt;65cc received partial-tumor SBRT. Response was measured by RECIST principles. TMC, PFS, and OS were estimated by Kaplan-Meier method. Pre- and post-SBRT biopsies from 24 pts were assayed via RNA microarray. Results: 68 pts (140 mets) were enrolled. 18 pts (21 mets) received partial tumor SBRT. Median volume of partially irradiated tumors was 121cc vs 7cc of fully irradiated (p=0.001). Median follow-up was 8.4 months (mo; range 1.1-24.2). 1-year TMC was 89.6%. At 12 mo TMC of partial versus full tumor irradiation was not significantly different (p=0.09). On multiple Cox regression, metastasis size, histology, volume of irradiated tumor and PD-L1 status were not predictive of TMC, PFS or OS. However, irradiated metastasis response predicted OS (HR = 0.37; 95% CI, 0.19-0.71; p = 0.003). Pts with irradiated met PR or CR had 17.8 mo median OS vs 9.1 and 3.4 in pts with mixed response or PD, respectively (p=0.005). Unsupervised transcriptional analysis of tumor biopsies demonstrated that the magnitude of DNA repair and innate/adaptive immune pathways induced in irradiated mets following SBRT was significantly associated with irradiated met response (p=0.009) and OS (p=0.007) to SBRT+P. Conclusions: Partial tumor SBRT+P approximates full tumor SBRT+P despite major differences in tumor volume. Transcriptional changes and clinical response of irradiated mets to SBRT+P are highly predictive of OS. Further research is needed to optimize immuno-radiotherapy. Clinical trial information: NCT02608385.
Postoperative radiotherapy for stage II or III non–small cell lung from 1988 to 2014.
Authors: Dawei Chen, Yintao Li, Wang Jing, Jinming Yu, Ligang Xing
Journal: Journal of Clinical Oncology (2019)

e20013 Background: In 2006 ASCO, Brian E. Lally et al. reported the association between survival and postoperative radiotherapy (PORT) in patients with resected non–small-cell lung cancer (NSCLC). We now undertook a update analysis using the latest data. Methods: Updated data were obtained by the Surveillance, Epidemiology and End Results database. We analyzed stage II or III NSCLC patients diagnosed between 1988 and 2014. Results: A total of 20645 patients were selected, with a median follow-up time of 3.3 years. Predictors for the use of PORT included age less than 50 years, higher AJCC stage, T3-4 tumor stage, larger tumor size, advanced node stage, greater number of lymph nodes involved, and a higher ratio of lymph nodes involved to lymph nodes sampled. On multivariate analysis, male sex, older age, T3-4 tumor stage, N2 node stage, fewer sampled lymph nodes, higher positive lymph nodes and higher ratio of lymph nodes involved to lymph nodes sampled had a negative impact on survival. PORT had a significant adverse effect on survival, regardless of all patients (P &lt; 0.001), or N0 subgroup ( P&lt; 0.001) or N1 subgroup (P&lt; 0.001). For N2 subgroup, PORT did not have a significant effect of on survival (P &lt; 0.117). This is different from the result Brian E. Lally et al. reported in ASCO 2006. Conclusions: Postoperative radiotherapy is detrimental to resected N0 or N1 NSCLC patients and should not be used routinely for such patients. The role of postoperative radiotherapy in the treatment of N2 tumours is not clear and may warrant further research.
A Near-Infrared Phosphorescent Nanoprobe Enables Quantitative, Longitudinal Imaging of Tumor Hypoxia Dynamics during Radiotherapy
Authors: Xianchuang Zheng, Liyang Cui, Min Chen, Luis A. Soto, Edward E. Graves, Jianghong Rao
Journal: Cancer Research (2019)

Hypoxia plays a key role in tumor resistance to radiotherapy. It is important to study hypoxia dynamics during radiotherapy to improve treatment planning and prognosis. Here, we describe a luminescent nanoprobe, composed of a fluorescent semiconducting polymer and palladium complex, for quantitative longitudinal imaging of tumor hypoxia dynamics during radiotherapy. The nanoprobe was designed to provide high sensitivity and reversible response for the subtle change in hypoxia over a narrow range (0-30 mmHg O2), which spans the oxygen range where tumors have limited radiosensitivity. Following intravenous administration, the nanoprobe efficiently accumulated in and distributed across the tumor, including the hypoxic region. The ratio between emissions at 700 and 800 nm provided quantitative mapping of hypoxia across the entire tumor. The nanoprobe was used to image tumor hypoxia dynamics over 7 days during fractionated radiotherapy and revealed that high fractional dose (10 Gy) was more effective in improving tumor reoxygenation than low dose (2 Gy), and the effect tended to persist longer in smaller or more radiosensitive tumors. Our results also indicated the importance of the reoxygenation efficiency of the first fraction in the prediction of the radiation treatment outcome. In summary, this work has established a new nanoprobe for highly sensitive, quantitative, and longitudinal imaging of tumor hypoxia dynamics following radiotherapy, and demonstrated its value for assessing the efficacy of radiotherapy and radiation treatment planning. SIGNIFICANCE: This study presents a novel nanoagent for the visualization and quantification of tumor hypoxia.