tbuckley/cabot-search huggingface dataset:
Identifying an early indicator of drug efficacy in patients (pts) with metastatic colorectal cancer (mCRC): A prospective evaluation of circulating tumor cells (CTC), 18F-fluorodeoxyglucose positron-emission tomography (PET), and the RECIST criteria.
Authors: Brigette Ma, Ann Dorothy King, LI Leung, Annette Poon, Ki Wang, Herbert H. F. Loong, Rosalie Ho, Frankie Mo, Wing Ming Ho, Charles Chan, Anthony T. C. Chan, Cesar SC Wong
Journal: Journal of Clinical Oncology (2014)

3582 Background: The early determination of drug response is a keystone in oncology, and CTC is a promising biomarker in mCRC. This study investigated the prognostic significance of a novel dual-endpoint of ‘PET and CTC response’ at 4 weeks (wk), and of the conventional RECIST response at 10 wks post-1stline chemotherapy (chemo). Methods: All pts had a whole-body (WB) PET-CT (contrast) and CTC analysis (7.5ml blood) at baseline, a plain PET-CT and CTC analysis at 4 wks, and a WB-CT at 10 wks after starting chemo. CTCs were isolated using the cancer cell enrichment and detection kit (Milenyi Biotech). A positive CTC is defined as having: a positive red staining, round-to-oval morphology, size = or > 2 times that of lymphocyte. Evaluable lesions must have a SUVmax = or > 2 on PET and be measurable based on RECIST (version 1.0 and 1.1). PET response is defined as = or > 30% drop in the sum of SUVmax of target lesions, and CTC response is defined as ‘any level of drop’, or a ‘CTC < 3 cells’ at 4 wks. Results: 70 pts have been recruited. The mean age was 63.9 yrs, 70% had oxaliplatin-based chemo. At a median follow-up of 13.6 months, 38 pts have died. At baseline, 1 pt did not have PET and CTC. At 10wks, 7 pts did not have the PET done. In a multivariate analysis, CTC level < 3 cells at 4 wks (p=0.048, odds ratio, OR = 0.106, 95% CI=0.011-0.985) was an independent predictor of OS. RECIST response (both versions, p < 0.05, OR = 0.021 to 0.179) predicted PFS. Conclusions: In this early analysis, CTC level at 4 wks and RECIST-response at 10 wks are associated with survival in pts with mCRC. The prognostic significance of dual ‘PET and CTC response’ at 4 wks will be reported. The optimal cut-off for a drop in SUVmax and CTC will be explored. Clinical trial information: NCT01163305.
Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification
Authors: Julien Calderaro, Gabrielle Couchy, Sandrine Imbeaud, Giuliana Amaddeo, Eric Letouzé, Jean-Frédéric Blanc, Christophe Laurent, Yacine Hajji, Daniel Azoulay, Paulette Bioulac-Sage, Jean-Charles Nault, Jessica Zucman-Rossi
Journal: Journal of Hepatology (2017)
Diagnostic EGFR testing with ctDNA versus tumour in patients with advanced non-small cell lung cancer (NSCLC): The Royal Marsden experience
Authors: R. Kumar, D.P. Walder, J. Bhosle, T.A. Yap, M.E.R. O'Brien, S. Popat, L. Thompson, S. Macmahon, J. Palma, D. Gonzalez de Castro
Journal: Annals of Oncology (2017)
Factors that influence the improvement of serum albumin during interferon-free sofosbuvir/ledipasvir therapy for Japanese patients with chronic hepatitis C virus infection
Authors: A. Kawano, E. Ogawa, N. Furusyo, H. Nomura, K. Dohmen, N. Higashi, K. Takahashi, K. Azuma, T. Satoh, M. Nakamuta, T. Koyanagi, S. Shimoda, M. Kato, E. Kajiwara, J. Hayashi
Journal: Journal of Hepatology (2017)
Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients
Authors: Keri A. Streby, James I. Geller, Mark A. Currier, Patrick S. Warren, John M. Racadio, Alexander J. Towbin, Michele R. Vaughan, Melinda Triplet, Kristy Ott-Napier, Devon J. Dishman, Lori R. Backus, Beth Stockman, Marianne Brunner, Kathleen Simpson, Robert Spavin, Joe Conner, Timothy P. Cripe
Journal: Clinical Cancer Research (2017)

Abstract Purpose: HSV1716 is an oncolytic herpes simplex virus-1 (HSV-1) studied in adults via injection into the brain and superficial tumors. To determine the safety of administering HSV1716 to pediatric patients with cancer, we conducted a phase I trial of image-guided injection in young patients with relapsed or refractory extracranial cancers. Experimental Design: We delivered a single dose of 105 to 107 infectious units of HSV1716 via computed tomography–guided intratumoral injection and measured tumor responses by imaging. Patients were eligible for up to three more doses if they achieved stable disease. We monitored HSV-1 serum titers and shedding by PCR and culture. Results: We administered a single dose of HSV1716 to eight patients and two doses to one patient. We did not observe any dose-limiting toxicities. Adverse events attributed to virus included low-grade fever, chills, and mild cytopenias. Six of eight HSV-1 seronegative patients at baseline showed seroconversion on day 28. Six of nine patients had detectable HSV-1 genomes by PCR in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had transient focal increases in metabolic activity on 18fluorine-deoxyglucose PET, consistent with inflammatory reactions. In one case, the same geographic region that flared later appeared necrotic on imaging. No patient had an objective response to HSV1716. Conclusions: Intratumoral HSV1716 is safe and well-tolerated without shedding in children and young adults with late-stage, aggressive cancer. Viremia consistent with virus replication and transient inflammatory reactions hold promise for future HSV1716 studies. Clin Cancer Res; 23(14); 3566–74. ©2017 AACR.
Frequent deterioration in autoimmune hepatitis with acute presentation is not associated with acute AIH but acute exacerbation that could be differentiated from acute AIH by surrogate markers for liver fibrosis
Authors: J.-H. Kang, K. Tanaka, T. Matsui, Y. Yamamoto, R. Utsunomiya, K. Tsuji, Y. Yosino, Y. Kodama, Y. Sakurai, A. Takiyama, T. Shinohara, H. Maguchi
Journal: Journal of Hepatology (2017)
Sofosbuvir based therapy for recurrent hepatitis C post liver transplantation: an Egyptian experience
Authors: A. Yosry, M.I. Mehrez, N. Zayed, W. Elakel, M.T. Kaddah, E.M. Hasan, A.O. Abdelaziz, G. Esmat, M.A. EL-Serafy, W. Doss
Journal: Journal of Hepatology (2017)
Treatment with SOF/VEL or SOF/VEL/VOX is well tolerated and results in high SVR12 in genotype 1–6 HCV infected patients with minimal fibrosis: a retrospective analysis of the ASTRAL and POLARIS clinical studies
Authors: E. Lawitz, M. Bourlière, L. Han, J. Mcnally, L.M. Stamm, D.M. Brainard, G.M. Subramanian, S.L. Flamm, K.R. Reddy
Journal: Journal of Hepatology (2017)
Timing and extension of lymphadenectomy in medullary thyroid carcinoma: A case series from a single institution
Authors: Andrea Polistena, Alessandro Sanguinetti, Roberta Lucchini, Sergio Galasse, Massimo Monacelli, Stefano Avenia, Andrea Boccolini, Louis Banka Johnson, Nicola Avenia
Journal: International Journal of Surgery (2017)
Combining reactive triblock copolymers with functional cross-linkers: A versatile pathway to disulfide stabilized-polyplex libraries and their application as pDNA vaccines
Authors: Philipp Heller, Dominika Hobernik, Ulrich Lächelt, Meike Schinnerer, Benjamin Weber, Manfred Schmidt, Ernst Wagner, Matthias Bros, Matthias Barz
Journal: Journal of Controlled Release (2017)
Variants in TM6SF2 and PCSK7 are risk factors for the development of cirrhosis in people with genetic haemochromatosis
Authors: S. Buch, M.J. Way, F. Stickel, E. Ryan, H. Zoller, W.J.H. Griffiths, A. McQuillin, J. Zwerina, J.D. Ryan, S. Gallati, T. Berg, C. Datz, D. Gotthardt, S. Stewart, J. Hampe, M.Y. Morgan
Journal: Journal of Hepatology (2017)
The presence of two or more baseline NS5A resistance associated substitutions jeopardizes DAA treatment success in HCV patients
Authors: I.C. Garcia, A. Arias, L. Benítez-Gutiérrez, G. Lledó, R. Garcia, S. Requena, M. Cuesta, L. Otero, V. Cuervas-Mons, C. de Mendoza
Journal: Journal of Hepatology (2017)
The association of nonalcoholic fatty liver disease with genetic polymorphisms: a multicenter study
Authors: A. Uygun, K. Ozturk, H. Demirci, A. Oztuna, F. Eren, S. Kozan, Y. Yilmaz, O. Kurt, T. Turker, S. Vatansever, E. Alper, B. Unsal
Journal: Journal of Hepatology (2017)
No impact of RASs on the high efficacy of SOF/VEL/VOX for 12 weeks in DAA-experienced patients: an integrated resistance analysis of the POLARIS-1 and POLARIS-4 studies
Authors: C. Sarrazin, C.L. Cooper, M.P. Manns, R.K. Reddy, K. Kowdley, H. Dvory-Sobol, E. Svarovskia, R. Martin, B.P. Doehle, G. Camus, L.M. Stamm, R.H. Hyland, D.M. Brainard, H. Mo, S.C. Gordon, M. Bourlière, S. Zeuzem, S.L. Flamm
Journal: Journal of Hepatology (2017)
Multifunctional liposomes delay phenotype progression and prevent memory impairment in a presymptomatic stage mouse model of Alzheimer disease
Authors: Simona Mancini, Claudia Balducci, Edoardo Micotti, Daniele Tolomeo, Gianluigi Forloni, Massimo Masserini, Francesca Re
Journal: Journal of Controlled Release (2017)
Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses
Authors: Toshiro Saito, Takeshi Uchiumi, Mikako Yagi, Rie Amamoto, Daiki Setoyama, Yuichi Matsushima, Dongchon Kang
Journal: Cardiovascular Research (2017)

Mitochondria are important organelles, dedicated to energy production. Mitochondrial p32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of p32/C1qbp in vivo is poorly understood because of embryonic lethality in the systemic p32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial p32/C1qbp in the heart. We investigated the role of p32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against p32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of p32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by p32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific p32-deficient mice. The mice died beginning at 12 months and their median lifespan was ∼14 months. Cardiac mitochondria in the p32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in p32-deficient compared with control myocytes, AMPKɑ was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the p32-deficient hearts. These findings support a key role for mitochondrial p32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.
Health Care Service and Outcomes Among an Estimated 6.7 Million Ambulatory Care Diabetic Foot Cases in the U.S.
Authors: Grant H. Skrepnek, Joseph L. Mills, Lawrence A. Lavery, David G. Armstrong
Journal: Diabetes Care (2017)

OBJECTIVE To evaluate ambulatory clinical cases of diabetic foot ulcers (DFUs) and diabetic foot infections (DFIs) in the U.S. from 2007 to 2013 and to assess outcomes of emergency department or inpatient (ED/IP) admission, number of clinic visits per year, and physician time spent per visit. RESEARCH DESIGN AND METHODS A cross-sectional historical cohort analysis was conducted by using the nationally representative Centers for Disease Control and Prevention National Ambulatory Medical Care Survey data from 2007 to 2013, including patients age ≥18 years with diabetes and either DFIs or DFUs. Study outcomes were analyzed by using generalized linear models controlling for key demographics and chronic conditions. RESULTS Across the estimated 5.6 billion ambulatory care visits between 2007 and 2013, 784.8 million involved diabetes and ∼6.7 million (0.8%) were for DFUs (0.3%) or DFIs (0.5%). Relative to other ambulatory clinical cases, multivariable analyses indicated that DFUs were associated with a 3.4 times higher odds of direct ED/IP admission (CI 1.01–11.28; P = 0.049), 2.1 times higher odds of referral to another physician (CI 1.14–3.71; P = 0.017), 1.9 times more visits in the past 12 months (CI 1.41–2.42; P &amp;lt; 0.001), and 1.4 times longer time spent per visit with the physician (CI 1.03–1.87; P = 0.033). DFIs were independently associated with a 6.7 times higher odds of direct ED referral or IP admission (CI 2.25–19.51; P &amp;lt; 0.001) and 1.5 times more visits in the past 12 months (CI 1.14–1.90; P = 0.003). CONCLUSIONS This investigation of an estimated 6.7 million diabetic foot cases indicates markedly greater risks for both ED/IP admissions and number of outpatient visits, with DFUs also associated with a higher odds of referrals to other physicians and longer physician visit times.
HBV/HDV co-infection microRNA profile: downregulation of anti-inflammatory and upregulation of pro-apoptotic and viral replication mircoRNAs is associated with HDV RNA replication and HBsAg levels
Authors: I. Carey, D. Shang, M. Bruce, M. Horner, M. Subramanian, A. Gaggar, K. Agarwal
Journal: Journal of Hepatology (2017)
Biomarkers to predict the clinical efficacy of bevacizumab in advanced colorectal cancer: <i>KRAS</i> mutational status of circulating tumor cells.
Authors: Marco Danova, Giuditta Comolli, Martina Torchio, Valerio Gristina, Alessandro Stefano Bertolini, Giuliano Mazzini
Journal: Journal of Clinical Oncology (2014)

e22030 Background: Despite the clinical effects of Bevacizumab (B) in unselected pts with metastatic colorectal cancer (mCRC), the possibility to target the treatment toward specific pt subgroups would improve therapeutic efficacy and cost-effectiveness. The search for non-invasive biomarkers of response to B is of great interest. The number of CTCs and the mutational status of KRAS in primary tumor, have been identified as independent prognostic factors in pts treated with B-based therapy. Methods: This study is focused to a new analytical platform developed in our laboratory that combines the technology of magnetic microbead labelling with the advantages of conventional microscopy for samples very low number of cells. The system is based on a simple, low-cost method, capable of an efficient and selective separation of CTCs from peripheral blood (PB), without pre-labelling or processing samples. This label-free technology is able to release and recover viable CTCs that can be directly transferred into the assay for KRAS mutational analysis. Sensitivity was demonstrated by spike-in experiments with two cell lines with varying levels of capture antigen expression. Results: We focused on EpCAM +ve, cytokeratins +ve and CD45 –ve cells and we identified viable cells diluted in the PB with a range of 4-7 CTCs/ml and approximately 55% purity. Spike-in recovery rates of 74%, and 85% for SNU-C2B and SW-480 cells, with low and high levels of EGFR expression, respectively, were obtained. In a series of samples (N= 15), mCRC pts presenting more than 4 CTCs/ml of PB were 94%.The assay for whole genome amplification used showed KRAS mutations in 6 of these pts that all displayed CTC KRAS mutational status overimposable to that of the previously acquired tissue biopsy data. Conclusions: We have shown the feasibility of analyzing pure CTCs, using a label-free technology able to preserve their viability / proliferation capability and a molecular assay. The approach is being applied to a prospective series of mCRC pts for verifying the prognostic and/or predictive value of the KRAS mutational status of CTCs during B-based therapy.
The I148M PNPLA3 variant is a novel key player modulating the proinflammatory and profibrogenic phenotype of human hepatic stellate cells
Authors: F.V. Bruschi, T. Claudel, M. Tardelli, A. Caligiuri, T.M. Stulnig, F. Marra, M. Trauner
Journal: Journal of Hepatology (2017)
Parasites in raw and undercooked fish can be cause of abdominal pain, doctors warn
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Asking patients with idiopathic abdominal pain whether they have recently eaten sushi may help establish a diagnosis, doctors have advised, after finding that such a patient had been infected with a parasite found in raw and undercooked fish.

Eating raw or undercooked fish or seafood is increasingly popular in Western countries, said …
Designing a web application for personalized medicine trials.
Authors: Stuart Watt, Wei Jiao, Andrew M. K. Brown, Teresa Petrocelli, Ben Tran, Tong Zhang, Janet Dancey, Lillian L. Siu, Lincoln D. Stein, Vincent Ferretti
Journal: Journal of Clinical Oncology (2012)

e13107 Background: Clinical genomics uses information from a patient's genome in clinical decision-making, an example of personalized medicine. The OICR/UHN Genomics Cohort Study is assessing the feasibility and developing standard operating procedures for clinical genomics in late stage cancer patients to enable larger trials. Tumor DNA from consenting patients is sequenced across 19 genes to identify actionable mutations and inform use of targeted therapeutic agents. Informatics systems are critical as the study involves 40 staff in 5 cancer centres, 2 laboratories, 3 genomics technologies, and spans screening, consent, obtaining/processing biopsy samples, genomic analysis, clinical laboratory verification, and reporting for decision-making. Methods: We used a process-centered method to develop a web system to manage study activities. Initially it tracked patients, samples, genomic results, decisions and reports across the cohort, monitored progress and sent reminders, working alongside an electronic data capture (EDC) system for the trial's clinical and genomic results. We later added a system to read, store, and analyze the genomics data, and a knowledge base of mutations’ tumor frequency (from the COSMIC database) annotated with clinical significance and drug sensitivity to generate reports for clinicians. Results: The web tracker proved highly adaptive. The design method allowed procedural refinements mid-study, including changes in sample preparation, sample sources, and differences in nomenclature across technologies. As the study procedures stabilized, the system provided deeper support for clinical decision making, enabling the generation of draft reports for verification by an expert panel prior to forwarding to the treating physician. The web tracker complemented the EDC system with its fixed modules for collection of clinical data and genomic results. Conclusions: The system effectively complemented clinical trial software. An agile development process enabled procedures to be refined as feasibility issues were found and resolved, and enabled flexible analysis of mutation data. Our design approach helped stabilize effective procedures for a clinical genomics service, and establish means to assess its performance.
Effect of novel AKT inhibitor ARQ 751 as single agent and its combination with sorafenib on hepatocellular carcinoma in a cirrhotic rat model
Authors: K. Keerthi, Z.M. Jilkova, G.S. Roth, G. Abbadessa, Y. Yu, P. Marche, T. Decaens
Journal: Journal of Hepatology (2017)
Abstract 173: The Role of Bax and Bak in Autophagic Cell Death
Authors: Jason Karch, Tobias G Schips, Matthew J Brody, Onur Kanisicak, Michelle A Sargent, Jeffery D Molkentin
Journal: Circulation Research (2015)

In times of energy depletion, a cell will attempt to maintain metabolic homeostasis and viability by degrading and recycling organelles and intracellular components and proteins in a process referred to as autophagy. However, if the energy depletion persists, the cell will be overwhelmed by the autophagic process and will succumb to autophagic cell death. This form of cell death has been implicated in cardiac remodeling during heart failure and damage during ischemic injury. Two proteins that have been previously shown to play a role in virtually every form of regulated cell death, including autophagy, are Bax and Bak. These effectors are responsible for cytochrome-c release during apoptosis and effect mitochondrial permeability transition pore opening during regulated necrosis. Although the expression of either Bax or Bak is required for autophagic cell death to occur, the role of Bax/Bak in this type of cell death is poorly understood, although the lysosome appears to be centrally involved. Here we show that Bax/Bak DKO MEFs subjected to several days of serum starvation contain intact lysosomes compared to WT MEFs. Furthermore, the acidity of the lysosomes in starved DKO MEFs is preserved compared with starved WT MEFs. Bax and Bak are both found in isolated lysosomal preparations and Bax targeted to the lysosome can completely restore autophagic cell death in DKO MEFs. Finally, although Bax oligomerization is required for apoptosis, it is not necessary for autophagic cell death, as DKO MEFs expressing an oligomerization defective mutant of Bax are still susceptible to this form of death, as monomeric Bax can still increase membrane permeability. In conclusion our results suggest that lysosomal membrane permeability through Bax or Bak is required for autophagic cell death to occur and without Bax or Bak the lysosomes remain intact where they can function as an energy source during times of nutrient deprivation.
Efficacy of combination chemotherapy with itraconazole for treating metastatic pancreatic cancer in the second-line setting.
Authors: Kayo Inoue, Hiroshi Tsubamoto, Takashi Sonoda, Shinichi Ikuta, Satoshi Tani, Naoki Yamanaka
Journal: Journal of Clinical Oncology (2015)

e15255 Background: The treatment of progressive pancreatic cancer after front-line chemotherapy is under investigation. Pretreated tumors express cancer stem cell markers and P-glycoprotein. Itraconazole, a common antifungal agent, is a potent inhibitor of the Hedgehog pathway, P-glycoprotein, and angiogenesis. We aimed to evaluate the efficacy and feasibility of chemotherapy with itraconazole for treating progressive pancreatic cancer. Methods: We retrospectively reviewed the medical charts of histologically diagnosed pancreatic cancer patients who had received one or more lines of chemotherapy and subsequent chemotherapy with itraconazole. The efficacy of itraconazole was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1 by considering the survival after chemotherapy with itraconazole. Results: Between 2008 and 2013, we enrolled 38 recurrent patients. All the patients were referred to our institution from tertiary care hospitals; they received docetaxel (35 mg/m2), gemcitabine (1,000 mg/m2), and carboplatin (area under the curve, 4 mg·min−1·mL−1) on day 1 and oral itraconazole solution (400 mg) on days −2 to 2 (i.e. the docetaxel, gemcitabine, and carboplatin [DGC] plus itraconazole regimen). The regimen was repeated every 2 weeks. One complete response and 13 partial responses were observed, with a response rate of 37% (95% confidence interval [CI]: 48–78%). Eight (21%) patients experienced febrile neutropenia after receiving the DGC plus itraconazole regimen. No patients required platelet transfusion. Before disease progression, the regimen was switched to irinotecan and itraconazole containing regimen among 35 patients. The median overall survival was 11.4 months (95% CI: 8.5–21.2 months). Conclusions: Combination chemotherapy with itraconazole is promising for prolonging overall survival with acceptable toxicities in the second-line setting of pancreatic cancer.