tbuckley/cabot-search huggingface dataset:
Abstract 5538A: Cell size-specific intracellular delivery
Authors: May Tun Saung, Armon Sharei, Viktor Adalsteinsson, Andrew Liss, Nahyun Cho, Tushar Kamath, Camilo Ruiz, Jesse Kirkpatrick, Robert Langer, Christopher Love, Klavs Jensen
Journal: Cancer Research (2015)

Abstract Among the many methods of intracellular delivery, cell size-selective delivery is particularly applicable to cancer research and therapeutics where tumor cells tend to be larger than blood cells and selective manipulation of a single cell-type while minimally affecting the other cells in a heterogeneous mixture is important. In this study, cell size-selective delivery is achieved using a novel microfluidic device with 75 parallel channels through which cells are pushed under nitrogen pressure. The cells undergo deformation as they transit through the channels, which results in temporary disruption of the cell membrane to facilitate delivery of material into the cytoplasm. For each cell size, there is a specific channel width for which optimal cell viability and fluorophore delivery is achieved, with smaller cells requiring narrower channels. When two cells of different sizes are mixed in solution, the channel width for optimal cell viability and fluorophore delivery for each cell type remains the same, and larger cells can achieve fluorophore delivery at a significantly higher percentage than smaller cells at the former's optimal channel width. One possible application for this technology is tagging circulating tumor cells, and we have been able to selectively deliver fluorophores into tumor cells when spiked into whole human blood with 91% specificity. We were also able to isolate pancreatic tumors cells from a patient's blood sample that matched the genotype of the patient's primary pancreatic tumor. Intracellular delivery of materials has become increasingly important as we delve deeper into understanding cellular processes and developing targeted therapies, and with this device, selective delivery can be achieved in a vector-free environment and without dependence on cell-surface receptors. Citation Format: May Tun Saung, Armon Sharei, Viktor Adalsteinsson, Andrew Liss, Nahyun Cho, Tushar Kamath, Camilo Ruiz, Jesse Kirkpatrick, Robert Langer, Christopher Love, Klavs Jensen. Cell size-specific intracellular delivery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5538A. doi:10.1158/1538-7445.AM2015-5538A
A seeding based cellular assay of tauopathy
Authors: Yin Xu, Heidi Martini-Stoica, Hui Zheng
Journal: Molecular Neurodegeneration (2016)

Tauopathy is characterized by neurofibrillary tangles composed of insoluble hyperphosphorylated tau protein. Currently, cellular models that mimic neurofibrillary tangles in vitro are lacking. Previous studies indicate that neurofibrillary tangles form via a prion replication mechanism. In the present work, we establish a seeding based cellular model according to the prion hypothesis. We show that cellular soluble tau can be converted to insoluble tau by seeds from the brain lysate of rTg4510 mice or synthetically generated preformed tau fibrils (PFFs). The cellular insoluble tau exhibits classic features of neurofibrillary tangles. Using genetic and pharmacological methods, we demonstrate that inhibition of autophagy increases whereas enhancement of autophagy reduces insoluble tau in our seeding based cellular model. The insoluble tau can be detected and quantified by thioflavin-S staining, thus allowing us to adapt our cellular model to a high-content image-based screening platform. Our seeding based cellular model reproduces neurofibrillary tangle pathology in vitro and serves as a useful tool for studying tauopathy and identifying tau modulators.
PWE-399 Improving the enhanced recovery programs in laparoscopic colectomy: liposomal bupivacaine may not be the answer
Authors: C Peeples, S Chadi, R Akiba, C Reategui, G Dasilva, DR Sands, EG Weiss, SD Wexner
Journal: Gut (2015)

<h3>Introduction</h3> Enhanced recovery programs (ERP) are standard of care in colorectal surgery. Avoidance of opioid analgesia and associated postoperative adverse events (AEs) lead to shortened hospitalisation and lower costs. The addition of long-acting liposomal bupivacaine as part of multimodality pain control may decrease reliance on opioids. This study aimed to evaluate the effect of liposomal bupivacaine infiltration on total amount of opioid use, incidence of AEs and length of stay (LOS) after minimally invasive (MIS) sigmoid coloctomy. <h3>Method</h3> A single-centre retrospective review was performed in patients undergoing a MIS sigmoid resection from 2012–2014. Patients in the intervention group received 266mg of liposomal bupivacaine in the surgical incision by a single surgeon and were matched to controls for age, gender, BMI, procedure and extraction site. Primary outcome was total opioid use in the first 72 h. Secondary outcomes included LOS, time to first flatus and bowel movement, and incidence of AEs (ileus and urinary retention). Confounding variables (i.e. ketorolac use) were determined <i>a priori</i>and were accounted for. Univariate analyses included a t-test for continuous variables and a Mann-Whitney U test for non-parametric variables. Multivariable regression identified the role the intervention had in predicting the primary outcome with adjustment of confounding variables. <h3>Results</h3> 70 patients (43% female; mean age 60 (±13) years) were included. The intervention and controls groups included 35 patients each. Diagnoses included diverticulitis (72%), colonic malignancy (14%), benign neoplasm (10%) and inflammatory bowel disease (4%). The median number of port sites was 4 (3–5), where 39% of patients had a midline extraction site vs. 61% with a Pfannenstiel. Total incision length was 9.5cm in 63% of patients. No difference in total opioid use was identified between groups (61mg vs. 70mg; p = 0.51) on univariate analysis. A sensitivity analysis was used to account for extremes in opioid use by removing the outermost 10<sup>th</sup>percentiles of opioid use; no difference was confirmed (59mg vs. 60mg; p = 0.98). LOS was similar in both groups (median 5 days), with no difference in AEs. There was no significant difference in time to first flatus or bowel movement (p = 0.23 and p = 0.35, respectively). A multivariate logistic regression adjusting for ketorolac and acetaminophen use demonstrated that liposomal bupivacaine did not predict total opioid use (OR 0.56–3.73; p = 0.446). <h3>Conclusion</h3> When added to an aggressive ERP, liposomal bupivacaine does not decrease the amount of total opioid consumption, the incidence of AEs or the LOS in patients undergoing MIS sigmoid resection. <h3>Disclosure of interest</h3> None Declared.
TCTAP A-121 Adjunctive Loading Dose of Cilostazol in Preventing Periprocedural Myocardial Infarction
Authors: Kang-Yin Chen, Ling-Xia Xu, Guangping Li, Tong Liu, Xin-Tian Zheng, Yanmin Xu, Zhanquan Jiao
Journal: Journal of the American College of Cardiology (2016)
A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer’s disease
Authors: Jia Luo, Sue H. Lee, Lawren VandeVrede, Zhihui Qin, Manel Ben Aissa, John Larson, Andrew F. Teich, Ottavio Arancio, Yohan D’Souza, Ahmed Elharram, Kevin Koster, Leon M. Tai, Mary Jo LaDu, Brian M. Bennett, Gregory R. J. Thatcher
Journal: Molecular Neurodegeneration (2016)

Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer's disease (AD) therapeutic strategies. The mixed pathology reported in a large population of AD patients demands a multifunctional drug approach. Since activation of cAMP response element binding protein (CREB) plays a crucial role in synaptic strengthening and memory formation, we retooled a clinical drug with known neuroprotective and anti-inflammatory activity to activate CREB, and validated this novel multifunctional drug, NMZ, in 4 different mouse models of AD. NMZ was tested in three mouse models of familial AD and one model of sporadic AD. In 3 × Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with robust cognitive deficits. NMZ treatment lowered neurotoxic forms of Aβ in both APP/PS1 and 3 × Tg transgenic mice while also restoring neuronal plasticity biomarkers in the 3 × Tg mice. In EFAD mice, incorporation of the major genetic AD risk factor, hAPOE4, did not mute the beneficial drug effects. In a novel sporadic mouse model that manifests AD-like pathology caused by accelerated oxidative stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function. The multifunctional approach, embodied by NMZ, was successful in mouse models of AD incorporating Aβ pathology (APP/PS1), tau pathology (3xTg), and APOE4, the major human genetic risk factor for AD (EFAD). The efficacy observed in a novel model of sporadic AD (Aldh2 −/− ) demonstrates that the therapeutic approach is not limited to rare, familial AD genetic mutations. The multifunctional drug, NMZ, was not designed directly to target Aβ and tau pathology; however, the attenuation of this hallmark pathology suggests the approach to be a highly promising, disease-modifying strategy for AD and mixed pathology dementia.
The Paradigm of the Paradox: Women, Pregnant Women, and the Unequal Burdens of the Zika Virus Pandemic
Authors: Lisa H. Harris, Neil S. Silverman, Mary Faith Marshall
Journal: The American Journal of Bioethics (2016)

The Zika pandemic provides biomedical scientists, clinicians, public health advocates, and governments a unique opportunity to advance reproductive justice by addressing the paradoxes outlined in this essay. The circumstances in which pregnancies occur are morally relevant to women’s reproductive life decisions, to the provision of reproductive health care, and to the development of reproductive health policy. Whether the Zika pandemic might foster context-driven reproductive pandemic planning and response is yet to be determined. Maintaining the status quo will surely increase a range of global health disparities and further stratify reproduction, producing predictable and preventable outcomes in which some people receive the necessary care and resources to achieve family building while others are neglected. Women and men should be able to count on biomedical researchers to answer the questions that need answering without undue influence from political agendas. Women should be able to continue pregnancies and count on public health assistance and help for children with Zika-related disabilities, or prevent or end a Zika-affected pregnancy. Pandemic responses that don’t further these ends are morally unacceptable.
Histone Methylation and STAT‐3 Differentially Regulate Interleukin‐6–Induced Matrix Metalloproteinase Gene Activation in Rheumatoid Arthritis Synovial Fibroblasts
Authors: Yasuto Araki, Takuma Tsuzuki Wada, Yoshimi Aizaki, Kojiro Sato, Kazuhiro Yokota, Kenta Fujimoto, Yoon‐Taek Kim, Hiromi Oda, Riki Kurokawa, Toshihide Mimura
Journal: Arthritis & Rheumatology (2015)

Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs.MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6.The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs.Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.
CREB engages C/EBPδ to initiate leukemogenesis
Authors: C Tregnago, E Manara, M Zampini, V Bisio, C Borga, S Bresolin, S Aveic, G Germano, G Basso, M Pigazzi
Journal: Leukemia (2016)

cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. We generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased CCAAT-enhancer-binding protein-δ (C/EBPδ) levels to cause myeloid differentiation arrest, and the silencing of CREB-C/EBPδ axis restored myeloid terminal differentiation. Then, C/EBPδ overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveils the aberrant activation of CREB-C/EBPδ axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement.
The ITA.LI.CA Staging System: A Novel Staging System for Hepatocellular Carcinoma
Authors: Neehar D. Parikh, Amit G. Singal
Journal: PLoS Medicine (2016)

Hepatocellular carcinoma (HCC) is an increasingly common and highly morbid malignancy.Appropriate tumor staging is crucial to inform prognosis and guide treatment decisions in clinical practice; however, staging for HCC can be complex because of many patient-level factors that can impact prognosis and treatment eligibility.HCC is a unique malignancy in that it typically occurs in the setting of underlying organ dysfunction (i.e., cirrhosis), so most staging systems take both tumor burden and the degree of underlying liver dysfunction into account for prognostication.The most commonly used staging systems for HCC include the Barcelona Clinic Liver Cancer (BCLC) system [1], the Hong Kong Liver Cancer (HKLC) system [2], the Cancer of the Liver Italian Program (CLIP) system [3], the Japan Integrated Staging (JIS) system [4], and the Model to Estimate Survival in Ambulatory HCC patients (MESIAH) (Table 1) [5].However, there has been a lack of consensus regarding the optimal staging system, and none is universally accepted.Most existing systems were derived from single-center data, lack prospective or external validation, and lack granularity in intermediate-and advanced-stage patients.In this issue of PLOS Medicine, Alessandro Vitale and colleagues detail the derivation and validation of a novel staging system for HCC, the ITA.LI.CA system [6].The ITA.LI.CA system attempts to address many deficiencies of prior staging systems and demonstrates better discriminant ability for predicting survival than existing HCC staging systems in both internal and external validation cohorts.The ITA.LI.CA system was derived from a prospective multicenter database of over 5,000 HCC patients from Italy.The majority of patients in the cohort had hepatitis C infection, nearly all (97%) had good performance status, and three-fourths had well-compensated cirrhosis.External validation was performed using data from a Taiwanese cohort of over 2,600 patients, with the primary etiology of liver disease for patients in this cohort being chronic hepatitis B infection.Using a priori variable selection based on prior staging systems and a literature review, the authors derived a model that uses a prognostic score based upon tumor burden (categories of 0, A, B1-3, and C), functional status, Child-Pugh score, and alpha fetoprotein (AFP) concentration (1,000 or >1,000 ng/ml).The model had better discriminant ability than any of the existing staging systems in the training, internal validation, and external validation cohorts (c-statistic values being 0.72, 0.71, and 0.78, respectively).The BCLC staging system is currently the most widely accepted staging system and has been endorsed by the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) [7,8].Though some aspects of the ITA.LI.CA system are rooted in the BCLC, it is distinct in several important ways: first, in
Recurrent KIT D816V Mutation in Atypical Chronic Myeloid Leukemia
Authors: Sara Redaelli, Rocco Piazza, Alessandra Pirola, Vera Magistroni, Susanne Schnittger, Manja Meggendorfer, Nicholas C.P. Cross, Delphine Rea, Carlo Gambacorti-Passerini
Journal: Blood (2014)
Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma
Authors: V González-Calle, J Dávila, F Escalante, A G de Coca, C Aguilera, R López, A Bárez, J M Alonso, R Hernández, J M Hernández, P de la Fuente, N Puig, E M Ocio, N C Gutiérrez, R García-Sanz, M V Mateos
Journal: Leukemia (2016)
Complicated Renal-Artery Stenosis
Authors: H. C. Stansel
Journal: New England Journal of Medicine (1964)

THE appreciation of renal-artery lesions as a cause of systemic hypertension began with the work of Goldblatt et al.1 in 1934. This experimental finding was immediately implicated in human hypertension with overenthusiasm and eventual disillusionment by many workers in the field. Although many nephrectomies were performed for presumably unilateral renal-artery disease only an occasional cure of systemic hypertension was reported.It now appears that the primary reason for the high failure rate of nephrectomy in these early reports was the inability to make an accurate diagnosis of renal-artery disease. The development of aortography described originally by dos Santos and his . . .
Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma (AHCC): results of a phase II study
Authors: J. Taieb, T. Mansourbakht, M. Ducreux, L. Bonyhay, T. De Baere, M. Delgado, T. Poynard, V. Boige
Journal: Journal of Clinical Oncology (2004)

4086 Background: New therapies are needed to improve the prognosis of patients (pts) with AHCC. The rationale to develop the gemcitabine / oxaliplatin combination in AHCC is based on: (i) the synergy between these two drugs, (ii) the clinical activity of these drugs in HCC according to preliminary phase II results, (iii) the lack of renal or hepatic toxicity of oxaliplatin in cirrhotic pts. Recently, we conducted a pilot study to evaluate two distinct bimonthly schedules of gemcitabine plus oxaliplatin in advanced HCC. We have therefore selected the most promising schedule to perform a phase II trial in non pre-treated AHCC patients. Methods: 30 pts with non pre-treated AHCC were prospectively enrolled. They received gemcitabine 1000 mg/m2 d1 and oxaliplatin 100 mg/m2 d2 (GEMOX). Treatment was repeated every two weeks until disease progression or limiting toxicity. Eligibility criteria were: pathologically proven advanced HCC or alpha-fetoprotein (AFP) levels over 250 ng/ml associated with a radiological liver tumor, PS (ECOG) 0–2, age ≥ 18, measurable disease, adequate hematological and renal functions, compensated Child A or B cirrhosis, and written informed consent. Results: Twenty six patients are currently evaluable for toxicity and efficacy. Their characteristics, treatment toxicity and clinical activity are summarized in the following table. No Toxic death occurred. Hematological grade 3–4 toxicities consisted in thrombocytopenia (18%), anemia (18%) and neutropenia (30%), without any febrile neutropenia or bleeding event. No grade3–4 non hematological toxicity was observed. Grade 1 and 2 neurotoxicity (specific scale) was observed in 14 and 6 pts, respectively. Four objective responses were observed, one leading to a surgical resection of the tumor. Conclusions: gemcitabine plus oxaliplatin seems to be an active regimen with manageable toxicity in non pre-treated AHCC patients. No significant financial relationships to disclose.
‘FIFA 11 for Health’ for Europe. 1: effect on health knowledge and well-being of 10- to 12-year-old Danish school children
Authors: Colin W Fuller, Christina Ørntoft, Malte Nejst Larsen, Anne-Marie Elbe, Laila Ottesen, Astrid Junge, Jiri Dvorak, Peter Krustrup
Journal: British Journal of Sports Medicine (2016)

Aim To modify the ‘FIFA 11 for Health’ programme to the European situation, and to assess its effects on health knowledge and well-being in Danish school children. Method A two-cohort study with seven intervention and two control schools. Of the 546 Danish children (boys 269; girls 277) of mean age 11.1 (±0.4) years from five city and four country-side schools, 402 undertook the ‘FIFA 11 for Health’ programme and 144 acted as controls. As part of each school's PE curriculum, seven intervention schools received a 45 min Play Football period (football skills and 3 vs 3 games) and a 45 min Play Fair period (health issues and football drills) on a weekly-basis for 11 weeks. Control participants continued with their regular school PE activities. Participants completed preintervention and postintervention health knowledge and well-being questionnaires. Results Overall, health knowledge increase was significantly (p&lt;0.05) greater for the intervention group (11.9%) than the control group (2.6%). Significant (p&lt;0.05) between-group differences were obtained for 8 of 10 health topics (6.1–20.2%) related to physical activity, nutrition, hygiene and well-being. The social dimension of the well-being questionnaire was significantly (p&lt;0.05) improved in the intervention group compared to the control group, but there were no significant between-group effects for the physical, emotional and school dimensions. Positive reporting about the programme was given by 72.4% of the children and only 4.8% reported negatively. Conclusions The ‘FIFA 11 for Health’ programme modified for Europe demonstrated positive effects on children's health knowledge and social dimension of well-being, thereby providing evidence that the football-based health education programme can be used effectively within a European school's curriculum to increase physical activity, well-being and health knowledge.