tbuckley/cabot-search huggingface dataset:
TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer
Authors: Jonathan M. Cooper, Yi-Hung Ou, Elizabeth A. McMillan, Rachel M. Vaden, Aubhishek Zaman, Brian O. Bodemann, Gurbani Makkar, Bruce A. Posner, Michael A. White
Journal: Cancer Research (2017)

Abstract Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely dependent on TBK1-mediated support of AKT/mTORC1 pathway activation for survival. Cancer Res; 77(18); 5077–94. ©2017 AACR.
Predictive factors of distant recurrence after surgery in patients with clinical stage IA lung adenocarcinoma.
Authors: Yuta Ibuki, Yoshihiro Miyata, Tomoharu Yoshiya, Takahiro Mimae, Yasuhiro Tsutani, Morihito Okada
Journal: Journal of Clinical Oncology (2013)

e18563 Background:The tumor recurrence after complete surgical resection occurs even in patients with clinical stage IA lung adenocarcinoma. The predictive factors of the distant recurrence have not been determined yet in such early stage lung adenocarcinoma patients. Methods:A total of 610 patients with clinical stage IA lung adenocarcinoma who underwent complete resection in multi-institutions were retrospectively analyzed . The correlation between clinicopathological factors andthe incidence of distant recurrence was examined. Results:Thirty six patients with distant recurrence had significant inferior overall survival. In the multivariate Cox regression analysis, solid tumor size on high resolution computed tomography (HRCT) and maximum standardized uptake (SUVmax) on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) were found to be independent predictors of distant recurrence. According to receiver operating characteristic analysis, 1.6cm or more of solid tumor size and 3.3 or more of SUVmax were indicated to be an optimal criteria to detect a high risk group for distant recurrence. In fact, distant recurrence and local recurrence were more frequently observed in patients whose solid tumor size and SUVmax met the criteria than the unmet patients (24 of 104 (20.2%) patients v.s. 12 of 506 patients (2.4%)). Conclusions:Solid tumor size on HRCT and SUVmax on FDG-PET/CT were indicated to be predictive factors of distant recurrence for the patients with clinical stage IA lung adenocarcinoma. It is highly possible that neoadjuvant chemotherapy is useful for such a high risk group.
Financing transformative health systems towards achievement of the health Sustainable Development Goals: a model for projected resource needs in 67 low-income and middle-income countries
Authors: Karin Stenberg, Odd Hanssen, Tessa Tan-Torres Edejer, Melanie Bertram, Callum Brindley, Andreia Meshreky, James E Rosen, John Stover, Paul Verboom, Rachel Sanders, Agnès Soucat
Journal: The Lancet Global Health (2017)

The ambitious development agenda of the Sustainable Development Goals (SDGs) requires substantial investments across several sectors, including for SDG 3 (healthy lives and wellbeing). No estimates of the additional resources needed to strengthen comprehensive health service delivery towards the attainment of SDG 3 and universal health coverage in low-income and middle-income countries have been published.
C9orf72 expansion disrupts ATM-mediated chromosomal break repair
Authors: Callum Walker, Saul Herranz-Martin, Evangelia Karyka, Chunyan Liao, Katherine Lewis, Waheba Elsayed, Vera Lukashchuk, Shih-Chieh Chiang, Swagat Ray, Padraig J Mulcahy, Mateusz Jurga, Ioannis Tsagakis, Tommaso Iannitti, Jayanth Chandran, Ian Coldicott, Kurt J De Vos, Mohamed K Hassan, Adrian Higginbottom, Pamela J Shaw, Guillaume M Hautbergue, Mimoun Azzouz, Sherif F El-Khamisy
Journal: Nature Neuroscience (2017)
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial
Authors: Michele Maio, Arnaud Scherpereel, Luana Calabrò, Joachim Aerts, Susana Cedres Perez, Alessandra Bearz, Kristiaan Nackaerts, Dean A Fennell, Dariusz Kowalski, Anne S Tsao, Paul Taylor, Federica Grosso, Scott J Antonia, Anna K Nowak, Maria Taboada, Martina Puglisi, Paul K Stockman, Hedy L Kindler
Journal: The Lancet Oncology (2017)
Tailored neoadjuvant epirubicin and cyclophosphamide (EC) and nanoparticle albumin-bound paclitaxel (<i>nab</i>-P) in breast cancer.
Authors: Mustafa Khasraw, Violet Rudo Mukaro, Linda West, Karen White, Elisabeth Rippy, Conrad Brandt, Robert Tobler, Caitlin Clare Murphy, Ian M. Collins, Sally E. Baron-Hay, David M. Ashley, Sujata Patil
Journal: Journal of Clinical Oncology (2016)

e12515 Background: We evaluated the feasibility and the likelihood of achieving high response rates by tailoring neoadjuvant therapy based on individual patient and tumor characteristics. Triple negative (TNBC) and HER2+ pts were treated with chemotherapy. Hormone Receptor (HR)+ HER2- pts were treated based on the Oncotype DX Breast Recurrence Score (RS) result. Methods: Between 4/2013 and 1/2015, 40 pts with stage II (T > 2cm) or III were enrolled: 15 HER2+, 15 TNBC and 10 with HR + HER2- breast cancer with RS ≥25. HR+ HER2-tumors with RS <25 were treated in an exploratory cohort. The primary cohort (n=40) was treated with preoperative epirubicin 90mg/m2 and cyclophosphamide 600mg/m2 Q3 weeks x 4, followed by nab-P (125mg/m2days 1, 8, 15 Q4 weeks) for 12 weeks, with the addition of trastuzumab in HER2+ pts. The primary endpoint was pCR in breast (ypT0/ypTis). A single stage binomial design was planned to discriminate between overall pCR rates of 30 and 50% with a type I error of 6% and 87% power. Secondary endpoints included pCR in breast and lymph nodes (LN), toxicity, PFS, and translational endpoints using pre- and post-chemotherapy MRIs and tissue biomarker analysis. An independent data safety board assessed trialsafety. Clinicaltrials.gov: NCT01830244. Results: Median age was 50 yrs (34 – 76). Clinical stages were T2 (67.5%), T3 (25%), T4 (7.5%), N0 (32.5%), N1 (40%), N2 (22.5%) and N3 (5%). LN involvement was confirmed with biopsy in 20 of 27 pts with N1 – N3. Breast conservation rate was 48% (n=19). Overall pCR rate in the breast was 55% (n=22). pCR rate in subsets is shown below pCR %(n): See table. Grade 3/4 Adverse Events (AEs): febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhea (2%), pneumothorax (2%). Common grade 1/2 AEs: alopecia (95%), fatigue (68%), nausea (57%), neutropenia (57%) and neuropathy in (50%). Conclusions: This EC and nab-P regimen resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy including patient selection by OncotypeDX is feasible and warrants further investigation. Clinical trial information: NCT01830244. All (40) HER2+ (15) TNBC (15) HR+ HER2- RS ≥25 (10) Breast 55 (22) 80 (12) 46 (7) 30 (3) Breast & LN 48 (19) 80 (12) 40 (6) 10 (1)
Abstract 163: Regulation of Adult Cardiomyocyte Proliferation and Repair by Tbx20
Authors: Katherine E Yutzey, Minzhe Guo, Fu-Li Xiang
Journal: Circulation Research (2015)

Background: In the adult heart, there is increasing evidence that cardiomyocytes can proliferate, but these rates are exceedingly low and are not sufficient for myocardial repair after injury. In the embryonic heart, the T-box transcription factor Tbx20 is required for cardiomyocyte proliferation, and Tbx20 overexpression (Tbx20OE) promotes fetal characteristics in adult cardiomyocytes when initiated before birth in mice. We hypothesize that Tbx20OE, when induced in adult cardiomyocytes, promotes proliferation and improves cardiac repair after injury. Methods and Results: Mice were generated with tamoxifen-inducible Tbx20OE specifically in differentiated cardiomyocytes driven by αMHCMerCreMer. Tbx20OE initiated in adult cardiomyocytes leads to increased numbers of mononucleated proliferating cardiomyocytes, increased expression of cyclins, and increased total numbers of cardiomyocytes. No changes in cardiac function or heart weight/body weight ratios were observed, although the average size of cardiomyocytes with Tbx20OE is smaller than controls. In addition cardiac proliferative pathways, including AKT, Yap1, and IGF1, are activated, while cell cycle inhibitors, including Meis1 and p21, are decreased. In order to determine if Tbx20 promotes cardiac repair after injury, Tbx20OE was induced 3 days post-myocardial infarction (MI). In Tbx20OE mice subjected to MI, cardiac function was significantly improved, the infarct scar size was smaller, and increased pHH3+ cardiomyocytes were observed. Likewise, capillary density and expression of VegfA and bFGF are increased in the injured myocardium with Tbx20OE. Ongoing studies will determine direct regulatory interactions of Tbx20 with genes and regulatory pathways that promote cardiomyocyte proliferation and repair in adults. Conclusions: Tbx20OE in adult CM activates cell proliferation also improves cardiac function and repair in mice when induced post-MI.
Low rates of symptomatic venous thromboembolism in patients with gastrointestinal cancer: an Iranian study.
Authors: Mohammad Reza Mortazavizadeh, Yasaman Ayoughi, Nasrollah Bashardoost, Pedram Fadavi
Journal: Journal of Clinical Oncology (2016)

e13105 Background: Venous thromboembolism (VTE) which is mostly presented by deep venous thrombosis (DVT) and Pulmonary Embolism (PE) is associated with considerable morbidity and mortality in patients with cancer and according to the reports the gastrointestinal (GI) cancers have the highest rates of VTE among other malignancies. But since little is known about VTE associated with GI cancer among the populations in the Middle East, we aimed to determine the relative frequency of symptomatic VTE in Iranian patients with GI cancer. Methods: The files of patients with GI cancers in the cancer clinic center were investigated from 2010 to 2015 for symptomatic VTE in a retrospective study.In this study all of the patients received chemotherapy. The data included the patient's characteristics, site of cancer, time of treatment initiation, type of VTE, the time of developing symptomatic VTE and the stage which VTE occurred. Symptoms of DVT or PE or other type of venous thrombosis were sought and they were confirmed by Doppler ultrasonography and CT angiography . Results: A total of 614 consecutive GI cancer patients were included in this study and all of them received chemotherapy.22 patients (3.6%) were found to have experienced symptomatic VTE(CI 95%:2.1% to 5.1%) which included: 19 with DVT and 3 patients with PE .Other types of VTE were not seen. Of 22 patients with VTE, 17 of them have occurred after chemotherapy (77%) and within 6.17±5.17 month (range: 1to19 months) after starting chemotherapy. 4 of the patients experienced VTE at the time of diagnosis. one patient suffered from DVT after surgery.VTE occurred in different stages of disease as follows: Stage III (45%), stage IV (36.3%) and stage II (18.1%). We found that the relative frequency of VTE in GI cancer in both sex is almost equal and not dependent on age and there were no statistically significant difference in cancer types. Conclusions: The rate of symptomatic VTE in patients with GI cancer In Iran is relatively lower than other studies done in the west. Therefore, it seems the rate of VTE differs in different ethnic groups. More investigation should be done to find out the etiology which could be useful in controlling and treatment of VTE in different populations.
Visualizing Nerve Injury in a Neuropathic Pain Model with [<sup>18</sup>F]FTC-146 PET/MRI
Authors: Bin Shen, Deepak Behera, Michelle L. James, Samantha T. Reyes, Lauren Andrews, Peter W. Cipriano, Michael Klukinov, Amanda Brosius Lutz, Timur Mavlyutov, Jarrett Rosenberg, Arnold E. Ruoho, Christopher R. McCurdy, Sanjiv S. Gambhir, David C. Yeomans, Sandip Biswal, Frederick T. Chin
Journal: Theranostics (2017)

The ability to locate nerve injury and ensuing neuroinflammation would have tremendous clinical value for improving both the diagnosis and subsequent management of patients suffering from pain, weakness, and other neurologic phenomena associated with peripheral nerve injury. Although several non-invasive techniques exist for assessing the clinical manifestations and morphological aspects of nerve injury, they often fail to provide accurate diagnoses due to limited specificity and/or sensitivity. Herein, we describe a new imaging strategy for visualizing a molecular biomarker of nerve injury/neuroinflammation, i.e., the sigma-1 receptor (S1R), in a rat model of nerve injury and neuropathic pain. The two-fold higher increase of S1Rs was shown in the injured compared to the uninjured nerve by Western blotting analyses. With our novel S1R-selective radioligand, [18F]FTC-146 (6-(3-[18F]fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one), and positron emission tomography-magnetic resonance imaging (PET/MRI), we could accurately locate the site of nerve injury created in the rat model. We verified the accuracy of this technique by ex vivo autoradiography and immunostaining, which demonstrated a strong correlation between accumulation of [18F]FTC-146 and S1R staining. Finally, pain relief could also be achieved by blocking S1Rs in the neuroma with local administration of non-radioactive [19F]FTC-146. In summary, [18F]FTC-146 S1R PET/MR imaging has the potential to impact how we diagnose, manage and treat patients with nerve injury, and thus warrants further investigation.
Presence of a Translocation Is Associated with Short Time to Treatment from Diagnosis in IGHV Mutated Chronic Lymphocytic Leukemia (CLL) Patients
Authors: Nyla A. Heerema, Qiuhong Zhao, Amy S. Ruppert, Heather Breidenbach, Jeffrey Jones, Leslie A. Andritsos, Jennifer A. Woyach, Farrukh T. Awan, Meixiao Long, Amber Gordon, Caitlin Coombes, John C. Byrd, Natarajan Muthusamy
Journal: Blood (2016)
Self‐Normalized Detection of ANXA3 from Untreated Urine of Prostate Cancer Patients without Digital Rectal Examination
Authors: Minhong Jeun, Sungwook Park, Yongdeok Kim, Jaewon Choi, Sang Hoon Song, In Gab Jeong, Choung‐Soo Kim, Kwan Hyi Lee
Journal: Advanced Healthcare Materials (2017)

A noninvasive quantitative assay that is capable of identifying prostate cancer biomarkers in untreated urine is an attractive diagnosis tool, but this method is subject to various obstacles. Difficulties presented by untreated urine include varying salt concentrations, and pH levels that may be different even though they are from the same patient. Untreated urine also presents interference from other biomolecules and possesses a fewer number of cancer biomarkers than can be found in serum. As a result, urine preconditioning processes and digital rectal examination (DRE) to increase biomarker secretion are mandatory in current urine assays. To address these challenges, an ion‐responsive urine sensor (IRUS) that measures differential electrical signals is proposed as a self‐normalized detection method. The proposed IRUS is based on a FET biosensor with a disposable sensing gate and has the capability to detect the prostate cancer antigen ANXA3 in untreated patient urine. The IRUS can detect ANXA3 at &lt;1 fg mL −1 with high reliability. In addition, it is found that ANXA3 levels in urine show clinically significant correlation with real tumor volumes. This paper provides a guideline in developing a clinically ready accurate noninvasive platform, which is capable of predicting prostate cancer using untreated urine without DRE.
Establishing and prioritizing research questions for the prevention, diagnosis and treatment of hair loss (excluding alopecia areata): the Hair Loss Priority Setting Partnership
Authors: A. Macbeth, J. Tomlinson, A. Messenger, K. Moore-Millar, C. Michaelides, A. Shipman, J. Kassim, J. Brockley, W. Szczecinska, P. Farrant, R. Robinson, J. Rodgers, J. Chambers, S. Upadhyaya, M. Harries
Journal: British Journal of Dermatology (2017)

Hair and scalp problems are common. Unfortunately, many uncertainties exist around the most effective management and treatment strategies for these disorders.To identify uncertainties in hair-loss management, prevention, diagnosis and treatment that are important to both people with hair loss and healthcare professionals.A Hair Loss Priority Setting Partnership was established between patients, their carers and relatives, and healthcare professionals to identify the most important uncertainties in hair loss. The methodology of the James Lind Alliance was followed to ensure a balanced, inclusive and transparent process.In total, 2747 treatment uncertainties were submitted by 912 participants; following exclusions 884 uncertainties relating to hair loss (excluding alopecia areata) were analysed. Questions were combined into 'indicative uncertainties' following a structured format. A series of ranking exercises further reduced this list to a top 25 that was taken to a final prioritization workshop where the top 10 priorities were agreed.We present the top 10 research priorities for hair loss (excluding alopecia areata) to guide researchers and funding bodies to support studies important to both patients and clinicians.
Abstract 024: MicroRNAs and Anesthetic Cardioprotection in Diabetes
Authors: Zeljko J Bosnjak, Jessica Olson, Alison Kriegel, Xiaowen Bai, Mingyu Liang
Journal: Circulation Research (2013)

Introduction: MicroRNAs are endogenous small RNA molecules that regulate a wide range of cellular functions primarily through reduction of target protein expression. Several microRNAs have been shown to play important roles in cardiac injury, and also contribute to the development of diabetic complications and cardiac preconditioning. We utilized a model of the patient-specific induced pluripotent stem cells (iPSCs) differentiated into the cardiac lineage in order to delineate the environmental and cellular mechanisms responsible for overturning anesthetic cardioprotection in diabetes. We hypothesized that miR-21 contributes to cardioprotection conferred by anesthetics in human cardiomyocytes and that diabetic conditions compromise this protection in part via suppression of miR-21. Methods: We have developed and validated a clinically relevant model of cardioprotection using human cardiomyocytes differentiated from the iPSCs derived from non-diabetic individuals (N-CM) and patients with type 2 diabetes mellitus (T2-CM). Results: Our results indicate that cardiomyocytes derived from type 2 diabetes-specific stem cells recapitulate the phenotypic findings from type 2 diabetic patients. For instance, T2-CM exhibited a suppression of protein kinase B (Akt) and activation of glycogen synthase kinase-3β, compared to N-CM; indicating that this pathway is compromised in cardiomyocytes derived from diabetic individuals. In addition, we examined whether isoflurane could delay oxidative stress-induced mitochondrial permeability transition pore (mPTP) opening in T2-CM and found that the effects of isoflurane were significantly attenuated as compared to N-CM. Finally, isoflurane increased miR-21 abundance in N-CM, but not in T2-CM. Summary: Diabetes and hyperglycemia substantially increase perioperative cardiovascular risk, with few mitigating strategies. Our data indicate an important role of miR-21 in isoflurane-induced cardioprotection and its impairment by diabetic conditions that may suggest new therapeutic targets for reducing perioperative cardiovascular morbidity and mortality in high-risk patients.
Herpes zoster in psoriasis patients treated with tofacitinib
Authors: Kevin L. Winthrop, Mark Lebwohl, Arnon D. Cohen, Jeffrey M. Weinberg, Stephen K. Tyring, Scott T. Rottinghaus, Pankaj Gupta, Kaori Ito, Huaming Tan, Mandeep Kaur, Alexander Egeberg, Lotus Mallbris, Hernan Valdez
Journal: Journal of the American Academy of Dermatology (2017)
High Peripheral Blood Stem Cell (PBSC) CD34+ Cell Dose Increases the Risk of Chronic Gvhd after Human Leukocyte Antigen (HLA) Matched Sibling Transplantation
Authors: Ezzideen Barjes Alrawi, Erica D. Warlick, Qing Cao, Mukta Arora, Shernan G. Holtan, Tim Krepski, Michael R. Verneris, John Wagner, Daniel J. Weisdorf, Claudio G Brunstein
Journal: Blood (2016)
Erratum: A nodal- and ALK4-independent signaling pathway activated by cripto-1 through glypican-1 and c-Src, (Cancer Research (March 15, 2003) (1192-1197))
Authors: Catarina Bianco, Luigi Strizzi, Aasia Rehman, Nicola Normanno, Christian Wechselberger, Youping Sun, Nadia Khan, Morihisa Hirota, Heather Adkins, Kevin Williams, Richard U. Margolis, Michele Sanicola, David S. Salomon
Journal: Cancer Research (2003)
A first-in-patient phase I study of BGB324, a selective Axl kinase inhibitor in patients with refractory/relapsed AML and high-risk MDS.
Authors: Sonja Loges, Bjorn Torre Gjertsen, Michael Heuser, I Ben-Batalla, David Micklem, Chromik Jorg, Maxim Kebenko, Walter M. Fiedler, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2016)

2561 Background: The RTK Axl represents an independent prognostic factor and therapeutic target in AML. BGB324 is an orally available selective potent Axl inhibitor, which has antileukemic activity in preclinical models of AML. Methods: A standard 3 + 3 dose escalation study was performed to identify the maximum tolerated dose of BGB324 in patients with previously treated AML or high risk MDS. BGB324 was administered as an oral loading dose on days one and two followed by a reduced daily maintenance. Three dose levels were explored 400/100mg, 600/200mg and 900/300mg Results: To date, 13 patients with AML and 3 patients with MDS were treated in the first three dose levels. 6 patients remain on treatment and 11 are evaluable. Therapy has been well-tolerated and the MTD has not yet been reached. The majority of adverse events reported have been Grade 1 and 2. The most common related adverse events are diarrhea and fatigue. One patient with pre-existing cardiac conduction abnormalities discontinued study treatment because of prolonged QTc prolongation leading to an expansion of the first dose cohort to six patients. The use of a loading dose achieved steady state between three and six days which was maintained throughout treatment. One AML patient has an ongoing CRi > 5 months, one patient achieved clearance of circulating blasts accompanied by peripheral blood count recovery > 3 months and three AML patients experienced disease stabilisation for more than four months. The status of patients with MDS remained unchanged. Evidence of target inhibition in leukemic blasts was demonstrated by almost complete inhibition of Axl phosphorylation accompanied by reduction in phosphoErk and phosphoAkt signalling at day 21 of treatment. Conclusions: BGB324 can be safely administered for prolonged periods at doses that abrogate AXL signalling. Treatment with BGB324 exhibits anti-leukemic activity. Clinical trial information: NCT02488408.