tbuckley/cabot-search huggingface dataset:
Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with or without docetaxel, in elderly patients with locally advanced esophagogastric cancer.
Authors: Sylvie Lorenzen, Claudia Pauligk, Nils Homann, Harald Schmalenberg, Felix Tauchert, Elke Jäger, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2012)

4080 Background: The aim of this study was to determine feasibility and efficacy of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients. Methods: Patients aged 65 or older with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four preoperative and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) with or without docetaxel 50mg/m² (FLOT), every 2 weeks. Results: 44 patients with a median age of 70 years were randomized to either FLO (22) or FLOT (22) chemotherapy. In the FLO and FLOT group, 20 and 18 patients completed four cycles of preoperative chemotherapy and 17(77.3%) and 15(68.2%) patients proceeded to surgery, with 88.2% and 93.3% R0 resections, respectively. FLOT was associated with significantly more treatment-related NCI-CTC grade 3/4 adverse events, including neutropenia (p&lt;.0001), leukopenia (p&lt;.0001), stomatitis (p=0.02) and nausea (p=0.02) and a higher rate of patients experiencing a ≥10-points deterioration of EORTC QoL global health status scores (FLOT, 54%; FLO 23.1%) at 8 weeks. No perioperative mortality was observed, however postoperative morbidity was nearly doubled with the FLOT regimen (60% versus 35.3% for FLO), mostly due to wound infections in the FLOT group (20%). 11 (64.7%) and 9 (60.0%) of patients in the FLO/FLOT group were able to undergo postoperative chemotherapy. Compared with the FLO group, the FLOT group had a better response rate (61.9% vs. 18.2%) and a trend towards an improved median disease free survival (21.1 vs. 12.0 months; p=0.09). Conclusions: Age alone is not a contra-indication for the selection of patients for three-drug regimens in the multimodal treatment approach. FLOT seems to be more effective than FLO, but is associated with an increased toxicity and higher postoperative morbidity. Therefore, careful patient selection is warranted.
A phase I/II trial of perioperative paclitaxel (P), carboplatin (C), and erlotinib (E) with concurrent accelerated hyperfractionated radiation (HFRT) followed by maintenance E for stage III non-small cell lung cancer (NSCLC)
Authors: N. A. Pennell, G. M. Videtic, S. Murthy, D. Mason, T. W. Rice, P. Mazzone, J. Samsa, T. Rich, M. Shapiro, T. Mekhail
Journal: Journal of Clinical Oncology (2009)

7557 Background: Concurrent chemoradiotherapy (CRT) is standard treatment for stage III NSCLC, although the management of resectable patients (pts) remains controversial. We report an open-label phase I/II trial of the epidermal growth factor receptor inhibitor E added to perioperative CRT for resectable stage III NSCLC pts, followed by maintenance (m) E. Methods: Eligible pts had stage IIIA/B NSCLC, PS 0–1, and were resectable as determined by a thoracic surgeon. Pts received weekly P (50 mg/m2), and C (AUC 2) with daily oral E for 28 days concurrent with twice daily thoracic radiation (1.5 Gy/fraction) to 30 Gy, followed by restaging. Non-progressors underwent resection followed by the same CRT regimen and 2 years of mE (150mg). The primary endpoint of the phase I portion was the maximum tolerated dose (MTD) of E given with CRT; and for the phase II was safety and tolerability. Secondary endpoints were pathologic complete response (pCR) rate, pathologic downstaging of mediastinal nodes, progression free survival (PFS), and overall survival (OS). Results: 9 pts were enrolled in the phase I trial. The MTD of E was150mg, which was the phase II dose used. 25 pts were treated in the phase II component: median age 60, 92% stage IIIA, 64% female, 72% PS 0, 64% adenocarcinoma, and 16% never smokers. The median duration of mE was 5.5 months, with the most common reason for discontinuation being pt preference. There was no grade 4 toxicity. Grade 3 toxicity seen in &gt;5% of pts: rash (12%), diarrhea (9%), nausea (9%), and encephalopathy (6%). The most common toxicities during mE: grade 1/2 diarrhea (72%), rash (61%), fatigue (56%), nausea (22%), and dry eyes (17%).1 pt (4%) had a pCR after neoadjuvant CRT, and 46% were downstaged to pN0–1 at surgery. At a median follow-up of 36.5 mos the median PFS is 41.8 mos (95% CI 9.3-not yet reached). The median OS has not been reached. 3 year survival is 69%. Pts downstaged to pN0–1 vs those with persistent pN2–3 had a median PFS of 41.8 vs 18.1 mos (p=0.11). Conclusions: Perioperative P, C, and E given concurrently with HFRT was well tolerated and showed promising efficacy, while compliance was poor with maintenance E. [Table: see text]
Cloning and Characterization of Exodus, a Novel β-Chemokine
Authors: Robert Hromas, Patrick W. Gray, David Chantry, Ronald Godiska, Mitchell Krathwohl, Kenneth Fife, Graeme I. Bell, Jun Takeda, Susan Aronica, Michael Gordon, Scott Cooper, Hal E. Broxmeyer, Michael J. Klemsz
Journal: Blood (1997)
High nicotine exposure in rodents is unlikely to inform about its toxicity in humans
Authors: Rosalia Emma, Riccardo Polosa, Massimo Caruso
Journal: European Respiratory Journal (2019)

We read with interest the research letter by Reinikovaite et al . [1], in which the authors reported same level of damage in the lungs of Sprague Dawley rats subjected to whole body chronic exposure of e-cigarette vapour emissions and cigarette smoke, as well as to subcutaneous injection of nicotine. Their conclusion is that e-cigarette use and long-time consumption of nicotine are just as toxic as tobacco cigarettes. We appreciate the authors' intention to address concerns related to the potential long-term health effects of e-cigarette use and nicotine exposure, but there are a number of methodological considerations that lessen the impact of their findings. More realistic exposures protocols are required to provide reliable toxicological information about electronic cigarette use in the context of smoking harm reduction <http://bit.ly/2YkZHWG>
Disruption in colonic polypectomy: rocking the trend
Authors: Phillip S. Ge, Gottumukkala S. Raju
Journal: Endoscopy (2019)

Endoscopic resection is well established as first-line management of benign colorectal polyps. Even though a “complete cut” and a “safe cut” are cornerstones of colonoscopic resection, the risk of incomplete resection of large flat polyps is as high as 31 % [1]. Unless we assure high rates of complete (R0) endoscopic resection, patients may continue to be referred to surgery for fear of recurrence and cancer development [2].
Association Between Educational Attainment and Causes of Death Among White and Black US Adults, 2010-2017
Authors: Isaac Sasson, Mark D. Hayward
Journal: JAMA (2019)

There are substantial and increasing educational differences in US adult life expectancy. To reduce social inequalities in mortality, it is important to understand how specific causes of death have contributed to increasing educational differences in adult life expectancy in recent years.To estimate the relationship of specific causes of death with increasing educational differences in adult life expectancy from 2010 to 2017.Serial cross-sectional study of 4 690 729 deaths recorded in the US National Vital Statistics System in 2010 and 2017.Sex, race/ethnicity, and educational attainment.Life expectancy at age 25 years and years of life lost between ages 25 and 84 years by cause of death.The analysis included a total of 2 211 633 deaths in 2010 and 2 479 096 deaths in 2017. Between 2010 and 2017, life expectancy at age 25 significantly declined among white and black non-Hispanic US residents from an expected age at death of 79.34 to 79.15 years (difference, -0.18 [95% CI, -0.23 to -0.14]). Greater decreases were observed among persons with a high school degree or less (white men: -1.05 years [95% CI, -1.15 to -0.94], white women: -1.14 years [95% CI, -1.24 to -1.04], and black men: -0.30 years [95% CI, -0.56 to -0.04]). White adults with some college education but no 4-year college degree experienced similar declines in life expectancy (men: -0.89 years [95% CI, -1.07 to -0.73], women: -0.59 years [95% CI, -0.77 to -0.42]). In contrast, life expectancy at age 25 significantly increased among the college-educated (white men: 0.58 years [95% CI, 0.42 to 0.73], white women: 0.78 years [95% CI, 0.57 to 1.00], and black women: 1.70 years [95% CI, 0.91 to 2.53]). The difference between high- and low-education groups increased from 2010 to 2017, largely because life-years lost to drug use increased among those with a high school degree or less (white men: 0.93 years [95% CI, 0.90 to 0.96], white women: 0.50 years [95% CI, 0.47 to 0.52], black men: 0.75 years [95% CI, 0.71 to 0.79], and black women: 0.28 years [95% CI, 0.25 to 0.31]).In this serial cross-sectional study, estimated life expectancy at age 25 years declined overall between 2010 and 2017; however, it declined among persons without a 4-year college degree and increased among college-educated persons. Much of the increasing educational differences in years of life lost may be related to deaths attributed to drug use.
Master Protocol Trial Design for Efficient and Rational Evaluation of Novel Therapeutic Oncology Devices
Authors: Danielle S Bitterman, Daniel N Cagney, Lisa Singer, Paul L Nguyen, Paul J Catalano, Raymond H Mak
Journal: JNCI Journal of the National Cancer Institute (2019)

Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field.
The metabolic regulator Lamtor5 suppresses inflammatory signaling via regulating mTOR-mediated TLR4 degradation
Authors: Wei Zhang, Ningtong Zhuang, Xiaoyi Liu, Long He, Yan He, Paween Mahinthichaichan, Hang Zhang, Yanhua Kang, Yin Lu, Qinan Wu, Dakang Xu, Liyun Shi
Journal: Cellular and Molecular Immunology (2019)
P066 miR-342-3p promotes cell survival and motility of osteoclast precursors
Authors: C Lozano, V Estibals, I Duroux-Richard, F Apparailly
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Young investigator. <h3>Introduction</h3> Chronic inflammatory joint disorders are associated with bone destruction by osteoclasts (OC), which derive from myeloid precursors. Recent findings reveal that OC are not only professional bone-resorbing cells but also directly involved in controlling inflammatory responses. Depending on the pathophysiological context, OC can polarize the immune response towards tolerance or inflammation. Aiming at identifying key regulators of inflammatory OC functions, we have defined a miRNA-based signature, which includes miR-342-3p. MiRNAs are key regulators of gene expression that control cellular processes, including osteoclastogenesis, and few miRNAs have been described in the differentiation of myeloid precursors into mature OC. <h3>Objectives</h3> To study the role of miR-342-3p in inflammatory OC. <h3>Methods</h3> OC were derived from the murine monocyte RAW264.7 cells. The expression levels of miR-342-3p and OC-specific genes were monitored by qRT-PCR. RAW264.7 cells were transfected with either miR-342-3p mimics, neutralizing molecules or control miRNAs. Cell survival and proliferation were assessed at 48 hour after RANKL incubation using quantification of the caspase3-7 activity, ATP production and BrDU incorporation. Motility of OC precursors was monitored using time-laps during the course of OC differentiation. The K/BxN serum-transfer arthritis (STA) model was performed in 8 weeks old C57BL/6 males and bone marrow was flushed. Primary OC were generated from either total bone marrow or sorted CD11b<sup>+</sup> and CD11c<sup>+</sup> cell subsets of healthy and arthritic mice. <h3>Results</h3> The expression of miR-342-3p was transiently up-regulated in the early phase of OC generation and was down-regulated after 24–48 hour in OC precursors. While pre-miR-342-3p promoted the motility of RAW264.7 cells, anti-miR-342-3p inhibited all motility parameters recorded (p&lt;0.0001, ANOVA test). Anti-miR-342-3p reduced the proliferation (p&lt;0.01) and cell survival of OC precursors through a pro-apoptotic effect, as assessed by increased caspase3-7 activity (p&lt;0.01). Overall, miR-342-3p neutralization in OC precursors reduced OC numbers (p&lt;0.001) compared to the pre-miR-342-3p condition. In primary cells, miR-342-3p was up-regulated in bone marrow-derived mature OC from arthritic mice compared to healthy controls (p=0.03; STA n=5/group). <h3>Conclusions</h3> Our data suggest that miR-342-3p promotes the early phase of osteoclastogenesis by enhancing the cell survival and motility of OC precursors. The up-regulation of miR-342-3p in OC isolated from arthritic mice may reflect the increased osteoclastogenic potential of inflammatory precursors in arthritis. <h3>Disclosure of Interest</h3> None declared.
Stochastic Gene Expression Influences the Selection of Antibiotic Resistance Mutations
Authors: Lei Sun, Peter Ashcroft, Martin Ackermann, Sebastian Bonhoeffer
Journal: Molecular Biology and Evolution (2019)

Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme's catalytic rate alone may contribute to resistance if drug binding is not rate limiting. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.
Combining multigene profiling of molecular subtypes with the 70-gene profile for classification of breast cancer
Authors: L. Stork-Sloots, O. Krijgsman, P. Roepman, F. A. de Snoo, R. A. Bender, A. M. Glas
Journal: Journal of Clinical Oncology (2009)

11083 Background: Classification of breast cancers into molecular subtypes may be important for accurate selection of therapy for patients. Herein we report a multigene profile for classification of breast cancer into molecular subtypes. The profile separates tumors into hormone receptor (HR)+/luminal-like, HER2+/ERBB2-like, and triple negative/basal-like subclasses. Methods: A multi-gene profile was developed based on a series of 200 tumor samples of known ER, PR and HER2 receptor status (concordant IHC and gene expression result) hybridized on 44k microarrays. The profile classifies 96% concordant to the molecular subtypes named luminal-, ERBB2- or basal-type as published by Perou et al (Perou et al, Nature, 2000; Fan et al, NEJM, 2005). The profile was validated using 469 independent samples as well as on two publically available gene expression datasets (n=251 and n=159). Results: The profile classified 66% (712) as luminal-like, 18% (194) ERBB2-like, and 16% (173) as basal-like. As compared to single-marker readout for the presence of ER, PR and HER2, 13% of the samples that were scored positive for presence of ER/PR did not express a luminal-like gene profile. Samples with a ERBB2-like or basal-like gene profile showed equally poor 5-year survival rates of ∼65%. However, the ERBB2-like subset of MammaPrint low risk patients (15%) showed an 89% (95%CI, 71–100) survival rate without trastuzumab treatment. When the luminal-like subtype was separated into “high-” and “low-risk” by MammaPrint the survival rate was 56% (95%CI, 46–68) for high-risk luminal-like samples and 94% (95%CI, 90–99) for low-risk samples. Conclusions: The developed multigene profile can classify breast tumors into luminal-, ERBB2- and basal-like subgroups. By combining this molecular subtyping with MammaPrint risk-classification specific groups of patients can be recognized that that are at high risk of recurrence. The low risk patients within the luminal- and ERBB2-like subclasses have a very low risk of recurrence. Implementation of this knowledge can improve the clinical management of breast cancer patients. [Table: see text]
TGFb signature at 2 weeks to predict response to preoperative therapy (PT) with bevacizumab (B) and chemotherapy (CT) in early breast cancer (EBC).
Authors: Nicole Williams, Vinay Varadan, Aditi Vadodkar, Kristy Miskimen, Hannah L. Gilmore, Nicholas Beckloff, Simone Edelheit, Dhivya Prabhakar, Angel Janevski, Nila Banerjee, Sitharthan Kamalakaran, Maysa M. Abu-Khalaf, William M. Sikov, Nevenka Dimitrova, Lyndsay Harris
Journal: Journal of Clinical Oncology (2013)

1046 Background: Gene expression profiles from core biopsies taken during PT for EBC may identify markers associated with benefit. B was recently shown to improve pathologic complete response (pCR) to CT in two randomized trials, but is associated with increased toxicity. Predictive signatures are critical to optimizing benefit. We have shown that changes in TGF-β pathway activity after one dose of B are associated with pCR. To confirm these results and understand the mechanism of alteration of the TGFb pathway, we evaluated the 61-gene TGFb signature by RT-PCR, measured markers of TGFb pathway activation and assessed TGFb gene mutations. Methods: Real-time PCR was performed on paired (pre/post) core biopsy RNA samples from 21 patients (pts) who received B, trastuzumab (T) or nab-paclitaxel prior to combined CT and targeted therapy using Custom RT2 Profiler PCR Arrays (384-well plate, 64x6 format) containing 60 genes from our TGF-beta signature and 3 housekeeping genes, IPO8, ALAS1, and SDHA. RT- PCR reactions containing Qiagen RT 2 SYBR Green qPCR Mastermix and 5 ng of amplified cDNA were run on a Roche LightCycler480 machine. Cp values were determined using the Roche LightCycler480 software. Antibodies to p-Smad2, TGFBR1 and TGFBR2 were analyzed in FFPE IHC pre and post therapy. TGFb pathway genes with known mutations in TCGA were assessed using an Illumina Custom Amplicon and miSeq next generation sequencing. Results: The log 2 FPKM value of the 60 genes correlated well with the ΔC P values calculated normalized to ALAS1 housekeeping gene. The ΔΔC P values was determined by subtracting the 60 gene ΔC P values of baseline samples from post-exposure samples. Patients were clustered using the ΔΔC P . Pts exposed to B who achieved a pCR showed down-regulation of signatures genes, in contrast to a strong non-pCR cluster. Signature evaluation showed no association with response in the T arm. TGFb pathway protein expression and mutation frequency is under analysis. Conclusions: TGFb signature predicts response to B containing chemotherapy after one dose of B and is validated by RT- PCR as a potential predictive tool. TGFb pathway activation and gene mutation analysis will be presented. Clinical trial information: NCT00617942.
Novel reassortant H7N2 originating from the H7N9 highly pathogenic avian influenza viruses in China, 2019
Authors: Yuan Qiu, Rongzhao Sun, Guangyu Hou, Xiaohui Yu, Yang Li, Jinping Li, Qiang Zhang, Fasheng Zou, Hualei Liu, Wenming Jiang
Journal: Journal of Infection (2019)
No role for infection with human papillomavirus in upper aerodisgestive tract cancers in smokers and alcoholics.
Authors: Luis Carlos Moreira Antunes, Antonio de Barros Lopes, Luisa Silva Pacheco, Patricia Chaves Brites, Leandro Bizarro Muller, Renato Borges Fagundes
Journal: Journal of Clinical Oncology (2012)

e14597 Background: The highest rates of esophageal cancer in Brazil occur in Rio Grande do Sul (18/100,000/year for men and 6/100,000/year for women). Furthermore, the incidence of head and neck squamous cell carcinoma (HNSCC) is significant in this region (11/100,000/year for cancer of the oral cavity and 10/100,000/year for laryngeal cancer in men). Tobacco smoking and alcohol consumption are the major risk factors for esophageal squamous cell carcinoma (ESCC) and HNSCC. The role of HPV in the development of ESCC remains controversial. Otherwise, there are some evidence that HPV-related HNSCC is a distinct entity compared with HNSCC associated with smoking and alcohol consumption. Methods: In order to investigate the association of HPV infection with ESCC and HNSCC in smokers/alcoholics in southern Brazil, we evaluated, prospectively, samples from three groups. Group 1 was formed by patients with ESCC where we evaluated esophageal samples from tumor and from non-tumoral areas. Group 2 was formed by HNSCC patients. We assessed biopsies from primary tumor and esophageal biopsies from either iodine negative or positive areas. Group 3 was formed by dyspeptic patients, no smokers/non alcoholics, with normal appearing esophageal mucosa in Upper GI Endoscopy. Biopsies were taken from middle esophagus. With extreme care to prevent DNA contamination, we used nested PCR with the general primer sets MY09/11 and GP5/GP6 for HPV L1 in formalin fixed paraffin-embedded tissue. We planned to genotype the final PCR product for 73 HPV types. Results: Group 1 included 48 samples from ESCC and 48 samples of esophageal non-tumoral areas. In Group 2, there were 37 patients with 35 biopsies taken from primary tumor, 32 from iodine positive esophageal areas and 17 from unstained esophageal areas (15 normal and 2 esophagitis). In this group, 1 patient had synchronous tumors of HNSCC and ESCC. Group 3 included 37 patients, 35 with normal esophageal mucosa and 2 with mild esophagitis. HPV DNA was negative in all samples. Therefore, we did not carry out the genotyping. Conclusions: In smokers/alcoholics patients from Southern Brazil, there is no evidence that HPV is involved in upper aerodigestive carcinogenesis.