tbuckley/cabot-search huggingface dataset:
Abstract LB-007: Intracellular delivery of SOCS3 suppresses pancreatic cancer progression
Authors: Kuysook Lee, Seulmee Shin, Yunseo Hwang, Youngsil Choi, Daewoong Jo
Journal: Cancer Research (2018)

Abstract Background JAK/STAT signaling, regulated by SOCS family proteins, plays a role in the progression of the inflammation, growth and metastasis of pancreatic adenocarcinoma. SOCS3 suppresses JAK kinase activity and degrades the activated cytokine receptor complex, and its loss contributes to pancreatic cancer development. We have developed advanced macromolecule transduction domains (aMTDs) to deliver recombinant proteins into to cells and tissues. In principle, aMTD enabled SOCS3 could provide an effective treatment for pancreatic tumors that depends on JAK/STAT signaling for growth or survival. Objective The present study utilized aMTD sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutic against pancreatic cancer. Method Improved cell-permeable SOCS3 proteins, with and without a 12-amino acid aMTD sequence, were expressed at high yields in E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. Results The iCP-SOCS3 exhibited high solubility, cell-/tissue-permeability and biological activity in pancreatic cancer cell lines (BxPC3, HPAC and PANC-1) with decreased endogenous SOCS3 levels, hyperactived JAK/STAT signaling and hypermethylated socs3 promoter region. The iCP-SOCS3 suppressed cancer-associated phenotypes (i.e., up to 90% inhibition of cell viability, 52% induction of apoptosis, 14.8% inhibition of cell cycle progression, 54% inhibition of migration and 61.5% inhibition of invasion) in pancreatic cancer cells dependent on elevated JAK/STAT signaling, whereas, these effects were not observed in non-cancer cells (H6c7, pancreatic duct epithelial cell) or with proteins lacking the aMTD sequence. In contrast, gemcitabine, a conventional pancreatic cancer therapeutic, showed undesirable cytotoxic effects including decreased cell viability and induced apoptosis in non-cancer cells. Furthermore, iCP-SOCS3 (30 mg/kg) induced tumor regression (-168% at day 18) in PANC-1 CDX model. In BxPC-3 orthotopic CDX model, iCP-SOCS3 suppressed tumor growth by 98% which was significantly higher compared to the suppressed tumor growth induced by gemcitabine (77%). Correlating to the tumor suppression, iCP-SOCS3 significantly decreased the secretion of TNF-α and the expression of p-STAT1, p-STAT3 and VEGF in tumor tissues. Conclusion These results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of SOCS3 with iCP-SOCS3 may provide a novel protein therapy against pancreatic cancer. Citation Format: Kuysook Lee, Seulmee Shin, Yunseo Hwang, Youngsil Choi, Daewoong Jo. Intracellular delivery of SOCS3 suppresses pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-007.
Systematic literature review and indirect treatment comparisons (ITC) of glasdegib (GLAS) plus low dose ara-c (LDAC) versus a hypomethylating agent (HMA) for previously untreated acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy (NIC).
Authors: Anna Forsythe, Bhakti Arondekar, Gabriel Tremblay, Geoffrey Chan, Yun Su
Journal: Journal of Clinical Oncology (2017)

e18526 Background: In a randomized phase 2 study, GLAS, an oral, smoothened inhibitor, combined with LDAC, showed significantly better overall survival (OS) vs LDAC alone in previously untreated AML NIC patients. HMAs azacitidine (AZA) and decitabine (DEC) are considered current standard of care in this population. An ITC was conducted to compare OS for GLAS+LDAC vs. AZA and DEC, respectively. Methods: Embase, MEDLINE, Cochrane database, and conference abstracts (ASCO, ESMO and ASH) were systematically searched through 12/2016 for relevant RCTs of GLAS, AZA and DEC in AML patients ineligible for IC. Classical frequentist ITC using the Bucher method was used to indirectly compare OS hazards ratios with 95% confidence intervals (CI) using LDAC as the common comparator. Results: Four studies met inclusion criteria: AZA Fenaux 2010, N (treatment/ comparator) = 14/20, AZA Dombret 2015, N = 241/158, DEC: Kantarjian 2012, N = 242/243, and GLAS+LDAC: Cortes 2016, N = 88/44. Upon review of baseline characteristics, Fenaux 2010 was excluded based on major population differences (% bone marrow blasts). Three studies contributed data to ITC based on comparable populations: age, cytogenic risk and OS of comparator were similar among studies: age 75/73/76 years old, poor cytogenic risk 34%/37%/39%, OS of the comparator 6.4/5.0/4.3 months in AZA/DEC/GLAS+LDAC, respectively. In the ITC, GLAS+LDAC showed significantly better OS HR vs. AZA and DEC (0.51 and 0.56 respectively) (Table). Conclusions: Using ITC, treatment with GLAS+LDAC yielded significantly better OS HR than AZA and DEC in previously untreated AML patients ineligible for treatment with IC. Limitations include mixed IC &amp; NIC population for the AZA trial, and mixed comparator arm of both LDAC and BSC for the DEC trial. Analyses using patient-level data matching baseline characteristics across studies may enable more robust ITC. [Table: see text]
Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders
Authors: M. Juhani Junttila, Lauri Holmström, Katri Pylkäs, Tuomo Mantere, Kari Kaikkonen, Katja Porvari, Marja-Leena Kortelainen, Lasse Pakanen, Risto Kerkelä, Robert J. Myerburg, Heikki V. Huikuri
Journal: Circulation (2018)

Background: Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. Methods: Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency &lt;0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. Results: Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy–associated genes, and 11 in dilated cardiomyopathy–associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel–encoding genes. Conclusions: A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease–associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.
Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production
Authors: Zhizhang Wang, Weijie Yin, Lizhen Zhu, Jia Li, Yikun Yao, Feifei Chen, Mengmeng Sun, Jiayuan Zhang, Nan Shen, Yan Song, Xing Chang
Journal: Immunity (2018)
‘What should I prescribe?’: time to improve reporting of resistance training programmes to ensure accurate translation and implementation
Authors: Sinéad Holden, Christian J Barton
Journal: British Journal of Sports Medicine (2018)

There is no doubt that exercise is efficacious for treating and preventing multiple chronic conditions. Evidence supports exercise prescription for treating at least 26 different chronic conditions ,1 cumulatively affecting 117 million people. The question is, how to prescribe exercise to ensure patients benefit optimally? How much (or little) is enough?

Different exercises types (such as aerobic activities, resistance training and balance/proprioceptive exercises) serve different purposes and can all be effective. However, not all activities are equally effective for different parameters of health, function or performance. The desired outcomes and prescription parameters will vary depending on the exercise modality, as will the physiological mechanisms and responses underpinning the exercise prescription. This underscores the need to consider specific prescription and doses relative to exercise modalities in research interventions.

As an example, many clinical practice guidelines for musculoskeletal conditions recommend resistance training (e.g., National Institute for Health and Care Excellence guidelines for osteoarthritis),2 but lack specific details on how/what to prescribe. The literature is difficult to synthesise, as …
Azithromycin enhances anticancer activity of TRAIL by inhibiting autophagy and up‐regulating the protein levels of DR4/5 in colon cancer cells in vitro and in vivo
Authors: Xinran Qiao, Xiaofei Wang, Yue Shang, Yi Li, Shu‐zhen Chen
Journal: Cancer Communications (2018)

Abstract Background Azithromycin is a member of macrolide antibiotics, and has been reported to inhibit the proliferation of cancer cells. However, the underlying mechanisms are not been fully elucidated. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) selectively targets tumor cells without damaging healthy cells. In the present study, we examined whether azithromycin is synergistic with TRAIL, and if so, the underlying mechanisms in colon cancers. Methods HCT‐116, SW480, SW620 and DiFi cells were treated with azithromycin, purified TRAIL, or their combination. A sulforhoddamine B assay was used to examine cell survival. Apoptosis was examined using annexin V‐FITC/PI staining, and autophagy was observed by acridine orange staining. Western blot analysis was used to detect protein expression levels. In mechanistic experiments, siRNAs were used to knockdown death receptors (DR4, DR5) and LC‐3B. The anticancer effect of azithromycin and TRAIL was also examined in BALB/c nude mice carrying HCT‐116 xenografts. Results Azithromycin decreased the proliferation of HCT‐116 and SW480 cells in a dose‐dependent manner. Combination of azithromycin and TRAIL inhibited tumor growth in a manner that could not be explained by additive effects. Azithromycin increased the expressions of DR4, DR5, p62 and LC‐3B proteins and potentiated induction of apoptosis by TRAIL. Knockdown of DR4 and DR5 with siRNAs increased cell survival rate and decreased the expression of cleaved‐PARP induced by the combination of azithromycin and TRAIL. LC‐3B siRNA and CQ potentiated the anti‐proliferation activity of TRAIL alone, and increased the expressions of DR4 and DR5. Conclusion The synergistic antitumor effect of azithromycin and TRAIL mainly relies on the up‐regulations of DR4 and DR5, which in turn result from LC‐3B‐involved autophagy inhibition.
Abstract 14769: Specific Epigenetic Changes Associated With the Dysfunctional Profile in CD34+ Cells Exposed to High Glucose Concentration
Authors: Valentina Bianchessi, Vera Vigorelli, Giulio Pompilio, Maria Cristina Vinci
Journal: Circulation (2016)

Introduction: CD34+ cells dysfunction in diabetic patients contributes to the pathogenesis of diabetic vascular complications that persist and progress even in patients with good long-term glycemic...
Abstract 5119: In vivo characterization of the Duffy Antigen Receptor for Chemokines (DARC) in the breast cancer microenvironment
Authors: Rachel Martini, Nancy Manley, Melissa Davis
Journal: Cancer Research (2018)

Abstract Chemokines are small inflammatory molecules that, in combination with their receptors, recruit lymphocytes to influence immune and inflammatory responses. This work specifically follows an atypical chemokine receptor, known as the Duffy Antigen Receptor for Chemokines (DARC). DARC is a non-signaling receptor able to bind both the CC and CXC chemokine classes, and mainly functions to regulate homeostatic levels of chemokines in circulation, and aid in chemokine transcytosis from sites of inflammation to mediate immune response. DARC serves as a portal of entry for the malaria-causing parasite Plasmodium vivax. In Sub-Saharan Africa, where malaria is endemic, a regulatory variant arose removing DARC expression from red blood cells (RBCs). This mutation, known as the Duffy-Null allele, was highly beneficial in this population, as removal of DARC from RBCs conferred immunity to Duffy-Null individuals. The Duffy-Null allele quickly rose to fixation in this population, and today recent decedents of Sub-Saharan Africans carry this allele. In the context of breast cancer (BCa) we are particularly interested in how Duffy-Null status impacts the tumor microenvironment. In clinic, we observe that pre-menopausal women of African descent have higher incidence rates of BCa, and that regardless of age, these women are disproportionately diagnosed with the most aggressive molecular subtype of BCa, triple-negative BCa. Knowing the important role that DARC plays in immune response, and that the Duffy-Null allele is prevalent in this population of women, we aim to investigate how Duffy-Null status impacts the tumor microenvironment in vivo through establishment of mouse models that depict Duffy-Null status in the BCa environment. To do this, we are using the C3(1)-TAg BCa transgenic mouse, alongside a DARC-KO mouse to characterize cancer progression and aggressiveness in BCa transgenic mice with varying global DARC expression. At 6 and 12 week time points, mice were sacrificed and the following information was obtained: total number of tumors, tumor location, tumor size and weight, and hematoxylin and eosin staining of tumor sections. Removal of DARC could lead to an excess of chemokines in the tumor microenvironment, promoting processes of tumor progression and metastasis, leading to the more aggressing tumor phenotypes we observe in women of African descent in clinic. Citation Format: Rachel Martini, Nancy Manley, Melissa Davis. In vivo characterization of the Duffy Antigen Receptor for Chemokines (DARC) in the breast cancer microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5119.
Abstract 353: Using cancer-associated variants to dissect functions of SETD8
Authors: Yongxia Zhu, Lihui Wang, Chamara Senevirathne, Shi Chen, Fabio Pittella Silva, Minkui Luo
Journal: Cancer Research (2018)

Abstract Protein lysine methyltransferases (PKMTs) play important roles in carcinogenesis through methylation of histone and non-histone substrates. SETD8 is the sole human methyltransferase for the monomethylation of histone H4 Lys20 (H4K20me1). Besides histone substrates, SETD8 modifies multiple non-histone substrates including proliferating cell nuclear antigen (PCNA), Numb, and p53. The biological functions related to the methyltransferase activity of SETD8 have been implicated in many essential biological processes including DNA replication, DNA damage response, cell cycle regulation, and transcription modulation. The SET domain of SETD8 is required to catalyze the methylation in substrates using the cofactor S-adenosyl-L-methionine (SAM). The C-terminal region post the SET domain (cSET) contains both the cofactor and protein substrate-binding sites. Recent genomics data from samples of cancer patients have revealed distinct variants in the SET domain of SETD8. Missense mutations, such as, E289Q, R292L, V315I, and H347Q were found in multiple types of cancers. To help dissect the roles of SETD8, we proposed the identification and characterization of SETD8 variants with partial loss-of-function phenotypes. Our data showed that overexpression of the SETD8 mutants increased the migration and tumor sphere formation of breast cancer cells without affecting H4K20me1. In vitro biochemical assay also confirmed that the SETD8 mutants lose the methyltransferase activity on H4K20 substrate. The RNA-seq data in the context of SETD8 mutant indicated that the c-Myc pathway was upregulated without affecting c-Myc expression. With the technology of Bioorthogonal Profiling of Protein Methylation (BPPM), we have found that SETD8 can methylate cancer-associated transcription factors in a cellular context. Collectively, these findings suggest that native SETD8 can act on cancer driving-associated transcription factors and its mutant maintains this methyltransferase activity but spare H4K20 methylation for cancer malignancy. Acknowledgements: This project was supported by 1R01GM120570. Citation Format: Yongxia Zhu, Lihui Wang, Chamara Senevirathne, Shi Chen, Fabio Pittella Silva, Minkui Luo. Using cancer-associated variants to dissect functions of SETD8 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 353.
Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study
Authors: Dong Hoon Lee, NaNa Keum, Frank B Hu, E John Orav, Eric B Rimm, Walter C Willett, Edward L Giovannucci
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To investigate the association of predicted lean body mass, fat mass, and body mass index (BMI) with all cause and cause specific mortality in men. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> Health professionals in the United States <h3>Participants</h3> 38 006 men (aged 40-75 years) from the Health Professionals Follow-up Study, followed up for death (1987-2012). <h3>Main outcome measures</h3> All cause and cause specific mortality. <h3>Results</h3> Using validated anthropometric prediction equations previously developed from the National Health and Nutrition Examination Survey, lean body mass and fat mass were estimated for all participants. During a mean of 21.4 years of follow-up, 12 356 deaths were identified. A J shaped association was consistently observed between BMI and all cause mortality. Multivariable adjusted Cox models including predicted fat mass and lean body mass showed a strong positive monotonic association between predicted fat mass and all cause mortality. Compared with those in the lowest fifth of predicted fat mass, men in the highest fifth had a hazard ratio of 1.35 (95% confidence interval 1.26 to 1.46) for mortality from all causes. In contrast, a U shaped association was found between predicted lean body mass and all cause mortality. Compared with those in the lowest fifth of predicted lean body mass, men in the second to fourth fifths had 8-10% lower risk of mortality from all causes. In the restricted cubic spline models, the risk of all cause mortality was relatively flat until 21 kg of predicted fat mass and increased rapidly afterwards, with a hazard ratio of 1.22 (1.18 to 1.26) per standard deviation. For predicted lean body mass, a large reduction of the risk was seen within the lower range until 56 kg, with a hazard ratio of 0.87 (0.82 to 0.92) per standard deviation, which increased thereafter (P for non-linearity &lt;0.001). For cause specific mortality, men in the highest fifth of predicted fat mass had hazard ratios of 1.67 (1.47 to 1.89) for cardiovascular disease, 1.24 (1.09 to 1.43) for cancer, and 1.26 (0.97 to 1.64) for respiratory disease. On the other hand, a U shaped association was found between predicted lean body mass and mortality from cardiovascular disease and cancer. However, a strong inverse association existed between predicted lean body mass and mortality from respiratory disease (P for trend &lt;0.001). <h3>Conclusions</h3> The shape of the association between BMI and mortality was determined by the relation between two body components (lean body mass and fat mass) and mortality. This finding suggests that the "obesity paradox" controversy may be largely explained by low lean body mass, rather than low fat mass, in the lower range of BMI.
Technology-Enabled Assessment of Functional Health
Authors: Diane J. Cook, Maureen Schmitter-Edgecombe, Linus Jonsson, Anne V. Morant
Journal: IEEE Reviews in Biomedical Engineering (2018)

The maturation of pervasive computing technologies has dramatically altered the face of healthcare. With the introduction of mobile devices, body area networks, and embedded computing systems, care providers can use continuous, ecologically valid information to overcome geographic and temporal barriers and thus provide more effective and timely health assessments. In this paper, we review recent technological developments that can be harnessed to replicate, enhance, or create methods for assessment of functional performance. Enabling technologies in wearable sensors, ambient sensors, mobile technologies, and virtual reality make it possible to quantify real-time functional performance and changes in cognitive health. These technologies, their uses for functional health assessment, and their challenges for adoption are presented in this paper.
Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm 2018
Authors: Guido Finazzi, Valerio De Stefano, Tiziano Barbui
Journal: Blood Cancer Journal (2018)

Myeloproliferative neoplasms (MPNs) are a leading cause of splanchnic vein thrombosis (SVT). SVT is observed in all MPNs and frequently affects young patients. Therapy should be addressed to three main goals: preventing thrombosis recurrence, managing the underlying MPN, and supporting liver dysfunction. Life-long oral anticoagulation with vitamin K antagonists is the cornerstone of the antithrombotic treatment. However, recurrences of SVT or other thrombosis may occur in 15-20% of patients. Direct oral anticoagulants can represent an alternative and preliminary data encourage comparative studies. Survival of patients with SVT in MPN is primarily influenced by the natural history of the underlying neoplasms, rather than the SVT event. An aggressive management is recommended and a treatment algorithm based on the different MPN subtypes is proposed. Hydroxyurea is the cytoreductive drug of choice in polycythemia vera and essential thrombocythemia, whereas ruxolitinib is indicated in intermediate and high-risk patients with myelofibrosis and in PV patients resistant or intolerant to hydroxyurea. The management of SVT in MPNs requires a multidisciplinary approach that may include a hematologist, a gastroenterologist, an interventional radiologist, and a surgeon. In the case of clinical deterioration despite pharmacological therapy, patients with SVT should be considered for invasive procedures or liver transplantation.