tbuckley/cabot-search huggingface dataset:
Rational therapeutic decision-making using mutational analysis for tyrosine kinase inhibitor therapy in BCR-ABL positive leukemias
Authors: Charles Chuah, Yeow Tee Goh, Lay Cheng Lim, Gee Fung How, Vallalan Natesan, Wen Tian Sun, Li Yi Yang
Journal: Clinical Cancer Research (2007)

A13  Introduction: Although imatinib is highly efficacious for the treatment of BCR-ABL positive leukaemias, imatinib-resistance due to the selection of BCR-ABL kinase domain (KD) mutations is an emerging problem. Two newer tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, are more potent than imatinib and have in vitro activity against most imatinib-resistant mutations. However some mutations retain varying degrees of resistance in vitro to dasatinib and/or nilotinib and can be recovered in mutagenesis assays in the presence of either one or both drugs. This in vitro data can be used to guide therapeutic-decision making, depending on which mutations are detected.  Methods: RNA was extracted from peripheral blood and BCR-ABL KD amplified by a hemi-nested RT/PCR approach and the PCR products subjected to direct sequencing.  Results: BCR-ABL KD mutations were detected in 43 out of 83 imatinib-resistant chronic myeloid leukemia or Philadelphia-positive acute lymphoblastic leukemia patients. These mutations were located in the ATP-binding site (n=18), imatinib-binding site (n=10), catalytic domain (n=2), activation loop (n=2) and other sites (n=13). The imatinib-binding site mutant, F317L is known to be nilotinib-sensitive but dasatinib-resistant in vitro. This mutant was detected in 2 patients and both were treated with nilotinib, rather than dasatinib and achieved a major cytogenetic remission. Patients which had dasatinib- and nilotinib-sensitive mutations achieved hematologic and cytogenetic remission with either drug. However new mutations were detected which led to nilotinib- and dasatinib-resistance in 7 out of 10 and 13 out of 23 patients respectively. The T315I mutant was detected in 11 of these patients. This was not surprising as this mutant had been recovered in mutagenesis assays with dasatinib and nilotinib and were highly resistant to both drugs. A clinical trial with a new TKI with activity against the T315I mutant is underway and will benefit patients who harbor this mutant. Mutational analysis has also allowed rational switching from nilotinib to dasatinib and vice versa with favorable clinical outcomes in 2 patients. The F317V mutant was detected in the first patient who developed progressive disease on dasatinib. This mutant was known to be selected in vitro in the presence of dasatinib but remains sensitive to nilotinib. The patient was switched to nilotinib and achieved a complete cytogenetic remission (CCR). The Y253H mutant is recovered in mutagenesis assays in the presence of nilotinib and was detected in the second patient who progressed while on nilotinib. This mutant is sensitive to dasatinib and the patient achieved a CCR after switching to dasatinib.  Conclusions: The detection of BCR-ABL KD mutants is important in the understanding of TKI resistance and also allows a rational molecular-based approach for TKI treatment.
Population-level impact of an accelerated HIV response plan to reach the UNAIDS 90-90-90 target in Côte d’Ivoire: Insights from mathematical modeling
Authors: Mathieu Maheu-Giroux, Juan F. Vesga, Souleymane Diabaté, Michel Alary, Stefan Baral, Daouda Diouf, Kouamé Abo, Marie-Claude Boily
Journal: PLoS Medicine (2017)

Background National responses will need to be markedly accelerated to achieve the ambitious target of the Joint United Nations Programme on HIV/AIDS (UNAIDS). This target aims for 90% of HIV-positive individuals to be aware of their status, for 90% of those aware to receive antiretroviral therapy (ART), and for 90% of those on treatment to have a suppressed viral load by 2020, with each individual target reaching 95% by 2030. We aimed to estimate the impact of various treatment-as-prevention scenarios in Côte d'Ivoire, one of the countries with the highest HIV incidence in West Africa, with unmet HIV prevention and treatment needs, and where key populations are important to the broader HIV epidemic. Methods and findings An age-stratified dynamic model was developed and calibrated to epidemiological and programmatic data using a Bayesian framework. The model represents sexual and vertical HIV transmission in the general population, female sex workers (FSW), and men who have sex with men (MSM). We estimated the impact of scaling up interventions to reach the UNAIDS targets, as well as the impact of 8 other scenarios, on HIV transmission in adults and children, compared to our baseline scenario that maintains 2015 rates of testing, ART initiation, ART discontinuation, treatment failure, and levels of condom use. In 2015, we estimated that 52% (95% credible intervals: 46%–58%) of HIV-positive individuals were aware of their status, 72% (57%–82%) of those aware were on ART, and 77% (74%–79%) of those on ART were virologically suppressed. Reaching the UNAIDS targets on time would avert 50% (42%–60%) of new HIV infections over 2015–2030 compared to 30% (25%–36%) if the 90-90-90 target is reached in 2025. Attaining the UNAIDS targets in FSW, their clients, and MSM (but not in the rest of the population) would avert a similar fraction of new infections (30%; 21%–39%). A 25-percentage-point drop in condom use from the 2015 levels among FSW and MSM would reduce the impact of reaching the UNAIDS targets, with 38% (26%–51%) of infections averted. The study's main limitation is that homogenous spatial coverage of interventions was assumed, and future lines of inquiry should examine how geographical prioritization could affect HIV transmission. Conclusions Maximizing the impact of the UNAIDS targets will require rapid scale-up of interventions, particularly testing, ART initiation, and limiting ART discontinuation. Reaching clients of FSW, as well as key populations, can efficiently reduce transmission. Sustaining the high condom-use levels among key populations should remain an important prevention pillar.
Receipt of recommended surveillance with imaging in survivors of early stage non-small cell lung cancer.
Authors: Jyoti Malhotra, David Rotter, Salma Jabbour, Joseph Aisner, Yong Lin, Sharon Manne, Kitaw Demissie
Journal: Journal of Clinical Oncology (2017)

10017 Background: Lung cancer survivors have a high risk for recurrence and second cancers and a 5-year survival of only 50%. Imaging surveillance for early cancer detection in this group is recommended for life. We measured the rates and determinants of regular surveillance imaging in non-small cell lung cancer (NSCLC) survivors. Methods: Using the Surveillance Epidemiology and End Results (SEER)-Medicare linked database, we identified 10680 patients with stage I and II NSCLC, age ≥ 66 years diagnosed from 2001-2011 and treated with surgery. Patients were censored at the time of recurrence/second cancer, loss of insurance or 3 months before death. Receipt of a CT and/or PET scan during the surveillance periods of 7 to 18, 19 to 30, 31 to 42 and 43 to 60 months from the date of surgery was assessed. Percentage of patients’ receiving regular imaging up to 18, 30 and 60 months of follow-up was determined. Adjusted cox regression was used to measure the effect of receiving recommended imaging on survival. Results: Overall, 79% and 40% survivors had follow-up information till the end of 30-month and 60-month surveillance periods respectively. Forty nine percent survivors were male and 86% were white. With a median follow-up of 7.6 years, 71% of the survivors received imaging in the first 18 months after surgery, but only 56% and 44% of survivors continued to receive regular imaging by 30-month and 60-month of follow-up periods respectively. Survivors were less likely to receive imaging if they were older (≥80 years), black, not married, had rural residence, did not receive adjuvant therapy, had stage I disease (compared to stage II) and were diagnosed in 2006 or earlier. In adjusted analysis, survivors receiving recommended imaging up to 18 months from surgery had improved survival compared to survivors who did not (HR 0.86; 95% CI 0.81-0.92). Survival benefit was also observed in survivors who had regular imaging up to 5 years from surgery (HR 0.68; 95% CI 0.60-0.76). Conclusions: More than half the lung cancer survivors did not receive recommended long-term surveillance imaging especially if older, black or with rural residence. Adherence to regular surveillance even at 5 years from initial surgery is associated with improved survival.
Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer
Authors: Anusha-Preethi Ganesan, James Clarke, Oliver Wood, Eva M Garrido-Martin, Serena J Chee, Toby Mellows, Daniela Samaniego-Castruita, Divya Singh, Grégory Seumois, Aiman Alzetani, Edwin Woo, Peter S Friedmann, Emma V King, Gareth J Thomas, Tilman Sanchez-Elsner, Pandurangan Vijayanand, Christian H Ottensmeier
Journal: Nature Immunology (2017)
Targeting apoptosis and autophagy by a novel bcl-2 inhibitor, GX15-070, in neuroblastoma.
Authors: Herve Sartelet, Sonia Cournoyer, Anissa Addioui, Assila Belounis, Mona Beaunoyer, Carine Nyalendo, Pierre Teira, Gilles Vassal, Elie Haddad
Journal: Journal of Clinical Oncology (2013)

10048 Background: Neuroblastoma (NB) is a frequent pediatric tumor with poor prognosis. The disregulation of the anti-apoptotic protein Bcl-2 is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate the in vitro and in vivo therapeutic efficiency of GX 15-070, a Bcl-2 inhibitor, used alone and in combination with conventional drugs used in the treatment of NB and hydroxychloroquine (HCQ), a known autophagy inhibitor. Methods: Using 6 NB cell lines, cell viability (MTT) assays were done at progressively increased concentrations of GX 15-070 alone or in combination with cisplatin or with Z-VAD-FMK, a broad-spectrum caspase inhibitor. Apoptosis was tested by evaluating the cleavage of caspase 3 by western blots (WB) and the Annexin V/7-AAD staining studied by FACS. To assess if autophagy was modified by GX 15-070, the cleavage of LC3 protein was tested by WB and cell survival were tested with combination of GX 15-070 and HCQ. To verify the anti-tumor activity in vivo of GX 15-070, orthotopic injections were made on NSG mice treated with GX 15-070 alone and in combination with HCQ. Results: It was observed a high sensitivity of the NB cells to GX 15-070 with increase of cell death and a potential synergistic of this molecule when it’s combined with cisplatin or HCQ. This cell death was due to apoptosis and may also be inhibited by Z-VAD-FMK. GX 15-070 alone or associated to cisplatin increased the autophagy. The in vivo study showed that GX 15-070 treatment used alone or in combination with HCQ significantly decreased the size of the tumor. Conclusions: Our results support the interest of GX 15-070 in the treatment of NB alone or in combination with classical drugs. Our studies also support that activation of apoptosis associated with inhibition of autophagy have a synergistic potential against tumoral progression and must have to be considered in further mechanistic studies for the optimization of more efficient combined therapies in the treatment of NB.
Potential of dobutamine echocardiography and different myocardial contrast echocardiography perfusion patterns in identifying dysfunctioning viable myocardial segments after acute myocardial infarction
Authors: P Colonna, C Cadeddu, R Montisci, Lj Chen, M Ruscazio, L Meloni, S Iliceto
Journal: Journal of the American College of Cardiology (2001)
Dysphagia from esophageal tuberculosis in a patient with undiagnosed HIV infection
Authors: Rajat Garg, Sean Carter, Mohammed Barawi
Journal: Endoscopy (2017)

A 57-year-old woman from Ethiopia presented with a 1-month history of dysphagia and odynophagia, with associated decreased appetite and unintentional weight loss. The patient had a remote history of treated pulmonary tuberculosis.
Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications
Authors: Njira Lugogo, Dave Francisco, Kenneth J. Addison, Akarsh Manne, William Pederson, Jennifer L. Ingram, Cynthia L. Green, Benjamin T. Suratt, James J. Lee, Mary E. Sunday, Monica Kraft, Julie G. Ledford
Journal: Journal of Allergy and Clinical Immunology (2017)
Phase II clinical trial of atezolizumab (A) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with PD1-directed therapy.
Authors: Saveri Bhattacharya, Cindy Yun, Katja Schulze, Tullia C. Bruno, Brenda F Kurland, Mark A. Socinski, Liza Cosca Villaruz
Journal: Journal of Clinical Oncology (2017)

TPS9105 Background: While inhibition of the PD1 axis is associated with improved response rates vs cytotoxic therapy in pts with previously treated NSCLC, the majority of pts will not benefit from objective response. Anti-PD1 and PD-L1 antibodies block distinct inhibitory pathways, possibly resulting in different clinical outcomes. While anti-PD1 antibodies block PD1 binding to PD-L1 and PD-L2, they do not affect the inhibitory signal of the PD-L1/B7.1 interaction. This trial is critical to establishing the clinical activity of sequencing PD-L1 inhibition in pts previously treated with PD1 directed and identifying candidate biomarkers of response and resistance to PD1/PD-L1 directed therapies. Methods: In this phase II clinical trial, pts with advanced NSCLC with stable or progressive disease on anti-PD1 therapy (nivolumab or pembrolizumab) will be treated with A1200 mg day 1 of a 21-day cycle until disease progression, unacceptable toxicity or death. The kinetics of response to anti-PD1 therapy can be variable and in some cases characterized by pseudo-progression. In order to account for variable response kinetics to PD1 therapy, pts will be enrolled in 3 parallel cohorts based on best overall response (BOR) to PD1 therapy (stable disease; progressive disease; complete or partial response followed by progressive disease). The primary objective is BOR to A. Secondary endpoints include duration of response, progression free survival, overall survival, and safety. 37 pts will be enrolled per cohort. A Simon 2-stage design will be employed with a stopping rule for futility if 0 of the first 11 evaluable patients within a cohort have a confirmed objective response in Stage 1. A promising result would be if ≥3 responses are seen at the conclusion of stage 2. This design has 80% power to detect a true response rate of 15% in each cohort (null rate 2%; alpha 0.05). Mandatory biopsies at time of enrollment, archival tumor pre-PD1 directed therapy, and optional biopsy at the time of progression on A will be collected for exploratory studies of immune biomarkers of response and resistance. Clinical trial information: NCT03014648.
Obesity and survival in the neoadjuvant breast cancer setting: Role of tumor subtype and race.
Authors: Ying Liu, Benjamin Peter Catanese, Anurag Saraf, Shing Lee, Yuan Zhang, Eileen Connolly, Kevin Kalinsky
Journal: Journal of Clinical Oncology (2017)

e12136 Background: Obesity may adversely influence survival in breast cancer; however, studies are conflicting and limited in the neoadjuvant setting. Results may also vary by tumor subtype and race/ethnicity. Our study seeks to examine associations between obesity and survival in women receiving neoadjuvant chemotherapy (NAC) and the role of tumor subtype and race/ethnicity. Methods: In a retrospective review of women with operable invasive breast cancer administered Adriamycin/Taxane-based NAC at a single intuition from 2004-2016, we identified n = 273 women with completed BMI data at diagnosis. Obesity was defined as body mass index (BMI) &gt; = 30. We assessed associations between obesity and progression-free survival (PFS), using STEEP criteria, and overall survival (OS), using all-cause mortality, both overall and stratified by tumor subtype in three groups: Hormone Receptor Positive (HR+)/HER2- (n = 135), HER2+ regardless of hormonal status (n = 94), and Triple Negative Breast Cancer (TNBC) (n = 44), examining race/ethnicity (Non-Hispanic White, Black and Hispanic) in each subtype. Results: There were 60 events and 33 deaths observed. Overall, obesity was associated with worse PFS (HR1.71 95% CI 1.03-2.85, p = 0.04) and a trend towards worse OS (HR 1.70 95% CI 0.86-3.37, p = 0.13). In HR+/HER2- disease, there was an interaction between obesity and hormonal therapy. In those receiving only tamoxifen (n = 35), obesity was associated with worse PFS (HR 2.96 95% CI 1.02-8.6, p = 0.047) and OS (HR 14.3 95% CI 1.67-123.1, p = 0.015). In those receiving an aromatase inhibitor (AI) (n = 96), there was no association between obesity and survival, p &gt; 0.05. In TNBC, obesity was associated with worse PFS (HR 2.62 95% CI 1.03-6.66, p = 0.043) and OS (HR 3.00 95% CI 0.95-9.51, p = 0.062). In HER2+ disease, obesity was associated with worse PFS (HR 3.37 95% CI 0.97-11.72, p = 0.056) but not OS (HR 1.35 95% CI 0.22-8.19, p = 0.75). Race/ethnicity was not significantly associated with survival in any tumor subtype, and there were no interactions between race/ethnicity and obesity with survival. Conclusions: Obesity negatively impacts survival in all tumor subtypes, including TNBC, and may be influenced by hormonal therapy class in HR+/HER2- disease.
A Twin Centre Study of Ex Vivo Sentinel Lymph Node Mapping in Colorectal Carcinoma. Introducing a Workable Technique Into Practice
Authors: FM Smith, JC Coffey, N Khasri, E Galvin, M Walsh, A El Sayed, OJ O'Connor, C Malone, N Parfrey, E Gaffney, R Stephens, MJ Kennedy, JV Reynolds, WO Kirwan, HP Redmond
Journal: Endoscopy (2004)

Background The development of systemic disease after curative surgery for colorectal cancer approaches 30%. This may represent understaging. Sentinel lymph node mapping identifies lymph nodes at high risk of harbouring metastatic disease.
Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer
Authors: A.-S. Hamy, J.-Y. Pierga, A. Sabaila, E. Laas, H. Bonsang-Kitzis, C. Laurent, A. Vincent-Salomon, P. Cottu, F. Lerebours, R. Rouzier, M. Lae, F. Reyal
Journal: Annals of Oncology (2017)
Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial–Mesenchymal Transition
Authors: Bo Pang, Nan Wu, Rongwei Guan, Lin Pang, Xinlei Li, Su Li, Liudi Tang, Ying Guo, Jialei Chen, Donglin Sun, Haiming Sun, Jialin Dai, Jing Bai, Guohua Ji, Peng Liu, An Liu, Qiushi Wang, Sheng Xiao, Songbin Fu, Yan Jin
Journal: Clinical Cancer Research (2017)

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P < 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P = 0.002), lymph node metastasis (P = 0.004), and advanced clinical stage (P = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion, and proliferation in vitro Further study found that RCC2 induced epithelial-mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9.Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK-JNK signaling. Clin Cancer Res; 23(18); 5598-610. ©2017 AACR.
Effect of Oral Clarythromycin on Gall Bladder Motility in Subjects with Gall Stone Disease
Authors: S Sengupta, P Modak, N McCawley, Ljd O'Donnell
Journal: Endoscopy (2004)

Introduction: Motilin receptor stimulation has been shown to have a prokinetic effect on gall bladder motility in human beings (1). Clarythromycin is a semi-synthetic macrolide antibiotic widely used in clinical practice for various infections and H. Pylori eradication.
Guidelines of the European Society of Gastrointestinal Endoscopy (E.S.G.E.) Endoscopic Ultrasonography. Part II: Retroperitoneum and large bowel, Training.
Authors: Michael Bau Mortensen, G Caletti, J. Devière, P Fockens, WR Lees, Svein Ødegaard, T Rösch, Jonathan Souquet, Peter Vilmann
Journal: Endoscopy (1996)
[<sup>18</sup>F]AA-7: PET imaging in patients with suspected glioma.
Authors: Satoshi Nozaki, Tomoko Oshita, Yuka Nakatani, Yumi Sasano, Kenichiro Yamamoto, W.Ewan Hume, Yasuhiro Wada, Akira Ishii, Masaaki Tanaka, Susumu Shiomi, Naohiro Tsuyuguchi, Kazuya Kodama, Yasuyoshi Watanabe
Journal: Journal of Clinical Oncology (2015)

11066 Background: Positron emission tomography (PET) imaging with [11C]methionine provides valuable information about amino acid metabolism in brain tumors. In surgical resection or radiotherapy of gliomas, precisely detecting the normal brain tissue–tumor boundary is critically important. However, as [11C]methionine accumulates not only in tumor tissues but also in normal and inflamed tissues, it cannot detect precisely the normal brain tissue–tumor boundary. Hence, the purpose of this study was to develop a tumor-specific PET tracer, targeting the amino acid transporter LAT1, to assess the safety, biodistribution, and dosimetric properties of the novel PET radiopharmaceutical agent, and to preliminarily evaluate its application in the diagnosis of glioma. Methods: We have developed the novel LAT1-specific tracer, [18F]AA-7. In preclinical studies, PET imaging with [18F]AA-7 was performed in mice bearing LNZ308 human glioblastoma cell line and also in two mice models of inflammation (turpentine oil-induced myositis model and collagen-induced arthritis model mice). In a clinical study, dosimetry estimations for [18F]AA-7 in healthy volunteers were determined. Patients with glioma received 185 MBq of [18F]AA-7 and underwent PET scan for 45 minutes after the injection. [11C]methionine and [18F]FDG were used as control tracers in both preclinical and clinical studies. Results: In preclinical studies, [18F]AA-7 was highly accumulated in LAT1 positive tumors as compared with [11C]methionine[tumor to muscle ratio: 3.3±0.2 vs 2.1±0.4]. Moreover, although [18F]FDG was also highly accumulated in inflamed regions, noticeable accumulation of [18F]AA-7 was not observed in the two mice models of inflammation. In a clinical study, three healthy volunteers and five patients were enrolled in the “first-in-human” trial. All subjects had no significant problem. Upon visual examination, PET imaging using [18F]AA-7 resulted in extremely clear images in patients with suspected glioblastoma. Conclusions: [18F]AA-7 may be useful as a novel PET tracer for LAT1-positive tumor imaging and imaging for the efficacy evaluation of therapies, which has low accumulation in inflamed tissues. It may be suitable for PET imaging in patients with suspected glioblastoma. Clinical trial information: UMIN000015271.