tbuckley/cabot-search huggingface dataset:
Glypican‐3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment
Authors: Fubo Zhou, Wenting Shang, Xiaoling Yu, Jie Tian
Journal: Medicinal Research Reviews (2017)

Liver cancer is the second leading cause of cancer-related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican-3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.
THE DEVELOPMENT OF INJURY PREVENTION EDUCATIONAL TOOLS FOR EVALUATION IN CHILDREN AND ADOLESCENTS IN SCHOOL AND COMMUNITY SETTINGS
Authors: Maya Djerboua, Carla van den Berg, Sarah A. Richmond, Megan McKinlay, Kyla White, Brent Hagel, Carolyn Emery
Journal: British Journal of Sports Medicine (2017)

Background Educational resources are important tools in the implementation of sport injury prevention strategies to help foster uptake of information in a community setting; however, there is limited information on how these tools are developed. Objective To develop two injury prevention educational tools targeting children and adolescents for evaluation in school and community settings. Design Qualitative. Setting Schools and ski/snowboard facilities in Calgary, Canada. Participants Key informants, including: 1) Community stakeholders from school and ski/snowboard settings, 2) Students ages 9–14 years, and 3) Ski/snowboard instructors, safety patrols and physical education (PE) specialists. Interventions Semi-structured focus groups and surveys were conducted with key stakeholders to explore pre-understandings, relevant content, delivery methods, and format of the tools. Consultations with community partners, PE specialists and ski/snowboard instructors and patrols helped further inform content and format during the development process. Main Outcome Measurements Videos and posters were developed based on feedback and discussions with key informants. These tools were designed as educational resources for teacher and student evaluation in two injury prevention studies. Results Videos were the main tools developed for the school-based delivery; including content about a neuromuscular training program and ski/snowboard safety strategies targeting injury prevention in youth sport. Focus group participants and informants emphasized the importance of understanding the target audience and adapting content and delivery approaches that increase the likelihood of successful uptake of key messages. This included communicating information in a clear and concise manner and utilizing visual and auditory cues to accommodate multiple learning styles. A health behaviour framework (i.e., Health Action Process Approach) was used to inform tool development. Conclusions Engaging informants supported the development of sport injury prevention educational tools. These tools are being utilized in studies evaluating their effectiveness in increasing knowledge, changing behaviour and reducing the risk of sport-related injury in school and community settings.
Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells
Authors: Aarti D. Rohira, Fei Yan, Lei Wang, Jin Wang, Suoling Zhou, Andrew Lu, Yang Yu, Jianming Xu, David M. Lonard, Bert W. O'Malley
Journal: Cancer Research (2017)

Tumor-initiating cells (TIC) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation, and metastasis. Here we report that SRC-3 supports the TIC/CSC state and induces an epithelial-to-mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers. We also show that inhibition of SRC-3 and SRC-1 with SI-2, a second-generation SRC-3/SRC-1 small-molecule inhibitor, targets the CSC/TIC population both
A new technique for difficult biliary cannulation using endobiliary forceps in a patient with a periampullary diverticulum
Authors: Kook Kim, Tae Kim
Journal: Endoscopy (2017)

An 83-year-old man attended the emergency room complaining of abdominal pain for 1 month. He had a history of having undergone cholecystectomy and had ongoing chronic kidney disease. His appearance was suggestive of chronic illness and there was tenderness on palpation of the right upper quadrant of his abdomen. On admission, the results of his liver function tests and blood chemistry were as follows: aspartate aminotransferase 31 IU/L, alanine aminotransferase 13 IU/L, total bilirubin 1.0 mg/dL, alkaline phosphatase 59 IU/L, γ-glutamyl transferase 12 IU/L, white blood cell count 4600 /mm3 (reference 3000 – 9000 /mm3), hemoglobin 8.2 g/dL, creatinine 3.42 mg/dL (reference 0.6 – 1.5 mg/dL), and albumin 2.5 g/dL. A non-enhanced abdominal computed tomography (CT) scan demonstrated a round calcified lesion of about 15 mm in size in the distal common bile duct (CBD) ([Fig. 1]).
Abstract 417: Adenosine Diphosphate Ribosyl Cyclase via PI3K-Akt and FOXO3a Up-regulating MMP-9 to Enhance Vascular Smooth Muscle Cell Proliferation and Migration in Mice
Authors: Yuming Li, Haitao Li, Xinfang Wang, Junya Wang, Zhongqiu Li
Journal: Circulation Research (2015)

The current study was designed to explore the mechanisms of vascular smooth muscle cell (VSMC) proliferation and migration induced by adenosine diphosphate ribosyl cyclase(ADPRC). In this study, 32 Male ApoE-/- mice(6 weeks old, 18-22g)on a C57BL/6J background were divided into four groups, which received normal chow (n=8, NC group), high-fat Western-type diet (n=8, 0.25% cholesterol, 21% fat,HFD group), high-fat Western-type diet,infusion of 2,2′-dihydroxyazobenzene(DHAB, a ADPRC inhibitor, 2mg/kg/day, n=8, HFD-DHAB group) intraperitoneally or high-fat Western-type diet,infusion of LY294002(a Inhibitor of Akt, 5mg/kg/d, n=8, HFD-LY group) intraperitoneally, for 10 weeks. 8 male C57BL/6J mice served as control. After 10 weeks, mice were anesthetized with chloral hydrate, aorta was removed and immediately frozen in liquid nitrogen. Aortic atherosclerotic lesions, VSMC proliferation and migration were assessed by histomorphological observation, smooth muscle actin-α(α-SMA)and proliferating cell nuclear antigen (PCNA) examination. ADPRC expression and alterations of Akt, FOXO3a, phospho-FOXO3a and MMP-9 were determined by RT-PCR, Western Blot, Immunohistochemistry or Immunofluorescence. The results showed that, in aortic atherosclerotic lesions derived from atherosclerotic mice of HFD group, an increased VSMC proliferation and migration, reflected by the up-regulation of α-SMA and PCNA expression, were observed followed by increased expression of ADPRC, Akt, FOXO3a, phospho-FOXO3a and MMP-9. The enhanced expression of ADPRC and followed alterations of FOXO3a, phospho-FOXO3a, MMP-9 as well as α-SMA, PCNA, VSMC proliferation and migration were absent in NC group and C57BL/6J control mice. Treatment with DHAB or LY294002 reversed VSMC proliferation, migration and expression of Akt, FOXO3a, phospho-FOXO3a and MMP-9 in HFD-DHAB and HFD-LY group. These data shows that high-fat Western-type diet induced ADPRC may via PI3K-Akt to phosphorylate FOXO3a up-regulating MMP-9 to enhance vascular smooth muscle cell proliferation and migration in mice.
A high-affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors
Authors: Adeela Kamal, John Sensintaffar, Patricia Karjian, Lin Zhang, Marcus Boehm, Lawrence C. Fritz, Francis J. Burrows
Journal: Cancer Research (2004)

5628  Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins including HER-2, Akt, Raf-1, Bcr-Abl, and mutated p53. The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) binds Hsp90 and induces proteasomal degradation of Hsp90 ‘client’ proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells, and 17-AAG is currently in Phase I clinical trials. However, the molecular basis of the tumor selectivity of Hsp90 inhibitors is unknown. The selective retention of 17-AAG in subcutaneous tumor masses in vivo suggests the existence of a drug ‘sink’ in tumor cells. Here we report that Hsp90 derived from tumor cells and clinical cancer biopsies has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells and tissues. Furthermore, the cytotoxic activity of 17-AAG correlates closely with the binding affinity of the drug to Hsp90 isolated from different cells. This binding affinity change is induced by association of Hsp90 with it’s co-chaperone proteins since tumor Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. Additional experiments addressing the relative contribution of cell cycling, oncoprotein overexpression and stress to the activation of Hsp90 will also be presented. We propose a model of Hsp90-dependent malignant progression in which, as tumor cells gradually accumulate mutant and overexpressed signaling proteins, Hsp90 becomes engaged in active chaperoning and stabilization of oncoproteins, and adopts a novel high-affinity form induced by bound co-chaperone proteins. Interestingly, dependence on the activated, high affinity chaperone could make Hsp90 an ’Achilles heel’ of tumor cells, driving the selective accumulation and bioactivity of pharmacological Hsp90 inhibitors, and making tumor Hsp90 a unique cancer target.
Abstract 429: MicroRNA Control of the Pacemaker Channel and Training-induced Bradycardia
Authors: Alicia D’Souza, Eleanor Gill, Charlotte Cox, Halina Dobrzynski, Elizabeth Cartwright, Delvac Oceandy, Mark R Boyett
Journal: Circulation Research (2015)

Background: Athletes are prone to bradyarrythmias and have a higher-than-normal incidence of pacemaker implantation but the underlying mechanisms are poorly understood. In previous work we demonstrated a training-induced electrical remodelling of the sinoatrial node (SAN), including a down regulation of the key pacemaker channel HCN4 that carries the pacemaker current I f . Here we investigated post-transcriptional regulation of HCN4 by microRNAs (miRNAs) in the trained SN. Methods and Results: Mice subjected to 60-min swimming twice daily for 28 days (TM) were compared to parallel sedentary mice (SM).TM were bradycardic (cycle length in vivo : SM, 81±1.3 ms; TM, 102±3 ms; n=6, p &lt;0.05). The cycle length of the isolated, denervated SAN (intrinsic heart rate) was also prolonged by exercise training (SM, 110±3 ms; TM, 150±5 ms; n=7, p &lt;0.05). Deep sequencing for miRNAs on SAN punch biopsies revealed 10 differentially expressed miRNAs in TM vs SM (FDR adjusted P &lt;0.05); 8 miRNAs were upregulated, 2 were downregulated. These findings were further confirmed by real-time PCR. We used the computation prediction tools Targetscan and Ingenuity Pathway Analysis to identify miR-423-5p and miR-486-3p as putative miRNAs participating in the post-transcriptional repression of HCN4 in the trained SAN. Both miRNAs had conserved seed sequences in the HCN4 3’UTR. To validate whether these miRNAs directly recognise the 3’UTR of HCN4, they were co-transfected with a construct containing HCN4 3’UTR fused downstream to a luciferase coding sequence in H9c2 cells. Transient transfection of precursor miR-423-5p and miR-486-3p decreased HCN4 3’UTR luciferase reporter activity in H9C2 cells by 47% and 22% respectively, compared with unaltered luciferase activity on co-transfection with control miR or miR-27a. Conclusions: This is the first report of miRNA dysregulation in the trained SAN. We describe a novel molecular mechanism whereby an altered miRNA profile in the trained SAN promotes HCN4 downregulation and altered sinus automaticity. Data suggest miR-423-5p as a potential therapeutic target for bradyarrythmias in the athlete.
Arterio-Venous Fistula Is an Applicable Vascular Access for Erythracytapheresis in Patients with Sickle Cell Disease
Authors: Marianne Delville, Sandra Manceau, Nassim Ait Abdallah, Jan Stolba, Sameh Awad, Thibaud Damy, Barnabas Gellen, Laurent Sabbah, Karima Debbache, Vincent Audard, Jean-Louis Beaumont, Cecile Arnaud, Christelle Chantalat-Auger, Françoise Driss, François Lefrere, Marina Cavazzana, Gilbert Franco, Frédéric Galacteros, Jean-Antoine Ribeil, Justine Gellen-Dautremer
Journal: Blood (2016)
Subsequent Malignant Neoplasms Among Children and Adolescents with Hodgkin Lymphoma Treated with Response-Adapted Therapy: A Report from the Children's Oncology Group Study AHOD0031
Authors: Lisa Giulino-Roth, Qinglin Pei, Allen Buxton, Suzanne Wolden, Louis S. Constine, Kara M. Kelly, Cindy L. Schwartz, Debra L. Friedman
Journal: Blood (2016)
<i>Strongyloides stercoralis</i> Hyperinfection
Authors: Heidi H McDonald, Milton Moore
Journal: New England Journal of Medicine (2017)

A 47-year-old man who had lived in Laos and was taking prednisone for dermatomyositis presented with hemoptysis, rash, abdominal pain, and melena. He was found to have Strongyloides stercoralis hyperinfection syndrome.
Pharmacokinetics in Children with Sickle Cell Anemia Following Single Dose Versus Chronic Treatment with Hydroxyurea
Authors: Joana Marie Mack, Pawel Wiczling, Joseph Moen, Guolian Kang, Robert I. Liem, Julie A. Panepinto, Gregory Kearns, Kathleen A Neville, Jeremie H. Estepp
Journal: Blood (2016)
Perspectives on the Overall Risks of Living With Hypertrophic Cardiomyopathy
Authors: Barry J. Maron, Martin S. Maron, Ethan J. Rowin
Journal: Circulation (2017)

ypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, unique in many respects among cardiovascular conditions, including its extreme clinical heterogeneity.Through the years, HCM has acquired the unfortunate reputation as an unrelenting disease with a highly unfavorable and generally grim prognosis, and largely without effective treatment strategies or acceptable expectation for longevity and quality of life. 1 Many patients with HCM, based on evaluation in general cardiology practices, have come to mistakenly believe that their diagnosis is among the least favorable that could confront them. Perspectives on the Overall Risks of Living With Hypertrophic Cardiomyopathy
Longitudinal changes in patient-reported symptoms and physical function during taxane-based chemotherapy in breast cancer patients.
Authors: Scott M. Monfort, Xueliang Jeff Pan, Robyn Patrick, Janani Singaravelu, Rachel M. Layman, Ewa Mrozek, Bhuvaneswari Ramaswamy, Raquel E. Reinbolt, Robert Wesolowski, Michelle Joy Naughton, Charles L. Shapiro, Charles L. Loprinzi, Ajit M.W. Chaudhari, Maryam B. Lustberg
Journal: Journal of Clinical Oncology (2016)

10098 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several commonly used chemotherapy drugs including taxanes, vinca alkaloids, and platinum compounds. Development of CIPN is highly variable, both in self-reported symptoms and functional consequences, and can be severe enough to alter dose intensity. The purpose of this pilot study was to gain insight into the natural history of both patient-reported and objective functional symptoms in breast cancer patients undergoing taxane-based chemotherapy. Methods: Thirty-two breast cancer patients (31 female/ 1 male; 47.6 ± 11.2 yr; n = 16 stage II/ n = 16 stage III) were enrolled. Patients completed self-reports of symptoms and function (e.g., EORTC QLQ-CIPN20) and objective measures of physical function (i.e., balance and gait testing) in an outpatient oncology clinic at five timepoints: (1) prior to starting chemotherapy to provide a baseline, (2-4) before starting subsequent chemotherapy cycles, and (5) 1-3 months after receiving their last taxane infusion. The balance task consisted of quietly standing on a balance plate with eyes closed. Gait testing consisted of 10 meter overground walking. All data were recorded by trained clinical personnel. Results: Significant negative changes in both patient-reported outcomes and objective functional measures were observed. Decreased balance (i.e., increased center of pressure dispersion quantified by 95% confidence ellipse areas) was observed as early as after the first chemotherapy cycle [45% increase, p = 0.01] and progressed with cumulative exposure [87% increase, p = 0.002]. Patients also demonstrated slower walking speeds as they progressed through treatment [4% decrease in speed, p = 0.01]. These functional deficits were mirrored with increased patient-reported symptom severity for all EORTC QLQ-CIPN20 subscales [all p < 0.05]. Conclusions: This is the first study to longitudinally assess patient-reported symptoms concurrently with balance and gait testing in patients undergoing taxane therapy. Taxane treatment was associated with the development of clinically relevant problems in both CIPN symptoms and patient function.
Randomized phase III trial of induction chemotherapy (ICT) with docetaxel-cisplatin-5fluorouracil (DCF) followed by cisplatin-radiotherapy (CRT) or cetuximab-radiotherapy (CetRT) in patients (pts) with locally advanced unresectable head and neck cancer (LAUHNC).
Authors: Ricardo Hitt, Ricard Mesia, Juan Jose Grau, Lara Iglesias, Elvira Del Barco, Alicia Lozano, Javier Martinez Trufero, Carlos Garcia Giron, Ana Lopez Martin, Juan Jesus Cruz hernandez
Journal: Journal of Clinical Oncology (2016)

6001 Background: CetRT has not been compared with CRT after ICT in phase III. Objective: To compare the impact on overall survival of CRT vs. CetRT after ICT in a Phase III randomized controlled clinical trial with a non-inferiority design of CetRT compared to CRT. Response Rate (RR), loco-regional control (LRC) and toxicity in both arms were considered secondary objectives. Methods: Pts with LAUHNC, ECOG 0-1, 18-72 years old, measurable disease, and with adequate renal and liver function, received standard DCF with G-CSF. After at least 2 cycles (range 2-3), pts with objective response or stable disease were randomized (stratified by tumor location, 1:1) between cisplatin 100 mg/m2 days 1, 22, 43) plus radiotherapy (dose 68-72 Gy, in 35 fractions) (arm A) or cetuximab (400mg d1, 250mg/m2 weekly concurrent with RT) plus the same radiotherapy scheme (arm B). Non-inferiority will be assumed if the upper limit of the one-sided 95% CI of the hazard ratio for OS (CetRT/CRT) is below 1.3. Analyses were done by intention to treat. Results: 530 pts were enrolled and 407 randomized (arm A: 205; arm B: 202). Median age 56 years , 89% male, ECOG 1: 70%, oropharynx and hypopharynx: 64%, T3/T4: 81%, N2/N3: 76%. During ICT the major causes of discontinuation were progressive disease or toxicity (24%). Median number of DCF cycles was 3 (range 0-3). RR during ICT was 71%. Toxicity G3/4 was observed in 40% of pts. After randomization the median number of cisplatin cycles was 3 (range 1-3), median number of cetuximab cycles was 8 (range 1-15) and median dose of radiotherapy was 70Gy (range 62-72 Gy). After CRT and CetRT, RRs were 72% and 78%, respectively. Toxicity (G3/4 RTOG) during CRT and CetRT were 36% and 32%, respectively. With a median follow up of 36 months LRC were 56% in arm A vs. 52% in arm B ( hazard ratio (HR), 1.13; 95% CI , 0.84 to 1.51 ) p value = 0.4 Conclusions: This is the first randomized Phase III trial that compare CRT vs. CetRT after ICT in pts with LAUHNC. The RR, toxicity and LRC were similar in both arms. With a long follow up, data of survival will be present in the meeting. Clinical trial information: NCT00716391.
Silencing of retinoic acid signaling to test for the presence of early signs of malignancy in morphologically “normal” breast epithelial cells
Authors: Stefano Rossetti, Gaia Bistulfi, Richard Cheney, Nicoletta Sacchi
Journal: Clinical Cancer Research (2007)

A63  In the last decade, advances in molecular and cell biology technologies have made it possible to explore rate limiting factors that make human breast epithelial cells lose their harmonious morphology and escape growth constraints, thereby converting normal breast epithelial cells into cancerous cells. It is now well understood that cancer is intrinsically intertwined with normal development. The postnatal development of normal human breast relies on finely regulated developmental signaling pathways. Vitamin A, in the form of its bioactive derivative retinoic acid (RA), governs fundamental signaling pathways of postnatal mammary gland development. We have recently demonstrated that an aberrant RA signaling leads to a non-random “domino epigenetic silencing” (marked by aberrant hypermethylation) of two genes: RAR beta 2, a RA-receptor with tumor growth suppression function, and CRBP1, encoding for a protein transporting Vitamin A in the cell and pivotal for maintaining the apicobasal polarization of breast epithelial cells. We established that the acquisition of RA-resistance precedes the loss of breast epithelial apicobasal polarity and the ability of breast epithelial cells to form ductal-like hollow acini when grown in three-dimensional culture (Bistulfi et al., Cancer Res. 66(21):10308-14, 2006). The uncoupling of the concerted succession of silencing events delineating distinct breast epithelial transforming phenotypes makes the combined analysis of both RAR beta 2 and CRBP1 methylation a specific tool for stratifying distinct stages of early tumorigenesis in breast tissue with a seemingly normal morphology.  This work was supported by a Roswell Park Alliance Foundation Award (NS), a DOD Predoctoral Award (GB), and the Susan Komen Foundation (SR).