tbuckley/cabot-search huggingface dataset:
Silk‐Based Bioinks for 3D Bioprinting
Authors: Shikha Chawla, Swati Midha, Aarushi Sharma, Sourabh Ghosh
Journal: Advanced Healthcare Materials (2018)

Abstract 3D bioprinting field is making remarkable progress; however, the development of critical sized engineered tissue construct is still a farfetched goal. Silk fibroin offers a promising choice for bioink material. Nature has imparted several unique structural features in silk protein to ensure spinnability by silkworms or spider. Researchers have modified the structure–property relationship by reverse engineering to further improve shear thinning behavior, high printability, cytocompatible gelation, and high structural fidelity. In this review, it is attempted to summarize the recent advancements made in the field of 3D bioprinting in context of two major sources of silk fibroin: silkworm silk and spider silk (native and recombinant). The challenges faced by current approaches in processing silk bioinks, cellular signaling pathways modulated by silk chemistry and secondary conformations, gaps in knowledge, and future directions acquired for pushing the field further toward clinic are further elaborated.
Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel
Authors: Rui Xie, Jingyu Xu, Yufeng Xiao, Jilin Wu, Hanxing Wan, Bo Tang, Jingjing Liu, Yahan Fan, Suming Wang, Yuyun Wu, Tobias Xiao Dong, Michael X. Zhu, John M. Carethers, Hui Dong, Shiming Yang
Journal: Cancer Research (2017)

Abstract Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here, we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/β-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499–512. ©2017 AACR.
Cost-effectiveness of zoledronic (ZOL) acid plus endocrine therapy (ET) in premenopausal women with early breast cancer (EBC) from a Canadian perspective
Authors: K. E. Ougari, C. Taneja, O. Sofrygin, S. Kaura, T. Delea
Journal: Journal of Clinical Oncology (2009)

557 Background: The Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG-12) examined the efficacy of 3 years (yrs) of treatment with goserelin in combination with ET (anastrozole or tamoxifen) with or without ZOL 4 mg q6 mos in 1,803 premenopausal women with EBC (median age 45 yrs). After a median follow-up of 47.8 mos (max 84 mos), risk of disease-free survival (DFS) events was reduced by 36% (HR = 0.64; p = 0.01) in patients (pts) who received ZOL (ZOL+ET) compared with those who did not (ET). Methods: A Markov model was used to estimate the cost per quality adjusted life years (QALYs) gained of 3 years treatment duration of ZOL+ET versus ET-only in premenopausal women with EBC based on results of the ABCSG-12. A Canadian healthcare system perspective and a lifetime timeframe were used. Outcomes and cost of breast cancer recurrence were based on recent published studies. Results were generated under 2 scenarios regarding duration of benefit (reduction in risk of recurrence) with ZOL: (1) Benefits persist to maximum follow-up in ABCSG-12 (trial benefit); (2) Benefits persist until death (lifetime benefit). Results: The cost of 3 years of ZOL (medication and administration) is 4 191 $CDN. Under the lifetime benefit scenario, 73% of these costs are offset by savings in the cost of recurrences. Under the trial benefit scenario, 12% are offset. QALYs gained are 1.63 yrs and 0.52 yrs under the lifetime and trial benefit scenarios respectively; cost-effectiveness is 1 122 $CDN and 3 675 $CDN per QALY gained respectively, which is well below the 50 000 $CDN per QALY threshold frequently used to assess whether therapies are cost-effective. Conclusions: The combination of ZOL + ET is a cost-effective use of healthcare resources from a Canadian healthcare system perspective. [Table: see text]
Abstract 16182: Jay D. Coffman Early Career Investigator Award: Large-scale Targeted Sequencing of Genomic Regions Associated With Coronary Heart Disease Uncovers Evidence for Polygenic Overlap With Peripheral Arterial Disease
Authors: Maya S Safarova, Erin E Austin, Daniel J Schaid, Iftikhar J Kullo
Journal: Circulation (2016)

Introduction:  Although both coronary heart disease (CHD) and peripheral arterial disease (PAD) result from atherosclerosis, relatively few genetic susceptibility variants for PAD have been discovered so far in contrast to CHD.   Hypothesis:  We hypothesized that genes harboring variants conferring susceptibility to CHD in genome-wide association studies are also associated with PAD.   Methods:  We performed targeted sequencing of 41 CHD susceptibility genomic regions (coding regions and 2/1 kb upstream/downstream) in 1826 PAD cases and 1725 controls. PAD cases (69±11 years, 61% men) had a resting/post-exercise ankle-brachial index (ABI) ≤0.9 or ≥1.4 and/or history of lower extremity revascularization, and no history of CHD at the time of recruitment. Controls (60±11 years, 55% men) had a normal ABI and no history of PAD or CHD. Sequencing was performed on an Illumina HiSeq 2000 (average read depth ≥30x). A gene-based global association analysis was done using the adaptive weighted sum of powered score test (aSPUw), followed by variant-level analyses using penalized regression models and fine mapping.   Results:  Six genes, i.e.  ABO, KCNK5, MRAS, PCSK9, SORT1 , and  CXCL12 , met a gene-level based threshold of significance ( P  P  6 ) of PAD with low-frequency variants (minor allele frequency 1-5%), followed by common and rare variants, respectively. A total of 352 genetic variants identified with penalized regression most parsimoniously explained the observed association with PAD for the 6 genomic regions, of which 18 were novel putatively impactful risk variants.   Conclusions:  This large-scale targeted sequencing study of genomic regions associated with CHD uncovers evidence for polygenic overlap with PAD and provides insights into pleiotropy between these two subtypes of atherosclerotic vascular disease and the relevant biological pathways. Further functional studies are required to uncover the biological roles of identified genes and variants with PAD.
Antigen-Independent, Autonomous B-Cell Receptor Signaling As a Dominant Candidate Oncogenic Mechanism in ABC DLBCL
Authors: Marvyn T. Koning, Rudolf Übelhart, Arjen H.G. Cleven, Willem H. Zoutman, Sander A.J. van der Zeeuw, Philip Kluin, Marieke Griffioen, Cornelis P. Tensen, Maarten H. Vermeer, Rein Willemze, Szymon M. Kielbasa, Marcelo A. Navarrete, Hassan Jumaa, Hendrik Veelken
Journal: Blood (2016)
Radiomic subtyping improves disease stratification beyond key molecular, clinical, and standard imaging characteristics in patients with glioblastoma
Authors: Philipp Kickingereder, Ulf Neuberger, David Bonekamp, Paula L Piechotta, Michael Götz, Antje Wick, Martin Sill, Annekathrin Kratz, Russell T Shinohara, David T W Jones, Alexander Radbruch, John Muschelli, Andreas Unterberg, Jürgen Debus, Heinz-Peter Schlemmer, Christel Herold-Mende, Stefan Pfister, Andreas von Deimling, Wolfgang Wick, David Capper, Klaus H Maier-Hein, Martin Bendszus
Journal: Neuro-Oncology (2017)

The purpose of this study was to analyze the potential of radiomics for disease stratification beyond key molecular, clinical, and standard imaging features in patients with glioblastoma.
Monitoring Treatment Response and Metastatic Relapse in Advanced Bladder Cancer by Liquid Biopsy Analysis
Authors: Karin Birkenkamp-Demtröder, Emil Christensen, Iver Nordentoft, Michael Knudsen, Ann Taber, Søren Høyer, Philippe Lamy, Mads Agerbæk, Jørgen Bjerggaard Jensen, Lars Dyrskjøt
Journal: European Urology (2017)
Hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy
Authors: Christoforos Tsantoulas, Sergio Laínez, Sara Wong, Ishita Mehta, Bruno Vilar, Peter A. McNaughton
Journal: Science Translational Medicine (2017)

Blocking HCN2 ion channel activity in peripheral nociceptive neurons alleviates the pain hypersensitivity associated with diabetic neuropathy.
Regulation of Chromatin Assembly and Cell Transformation by Formaldehyde Exposure in Human Cells
Authors: Danqi Chen, Lei Fang, Shenglin Mei, Hongjie Li, Xia Xu, Thomas L. Des Marais, Kun Lu, X. Shirley Liu, Chunyuan Jin
Journal: Environmental Health Perspectives (2017)

Background: Formaldehyde (FA) is an environmental and occupational chemical carcinogen. Recent studies have shown that exogenous FA causes only a modest increase in DNA adduct formation compared with the amount of adducts formed by endogenous FA, raising the possibility that epigenetic mechanisms may contribute to FA-mediated carcinogenicity. Objectives: We investigated the effects of FA exposure on histone modifications and chromatin assembly. We also examined the role of defective chromatin assembly in FA-mediated transcription and cell transformation. Methods: Cellular fractionation and Western blot analysis were used to measure the levels of histone modifications in human bronchial epithelial BEAS-2B cells and human nasal RPMI2650 cells in the presence of FA. Chromatin immunoprecipitation (ChIP) and micrococcal nuclease (MNase) digest assays were performed to examine the changes in chromatin assembly and accessibility after FA exposure. RNA sequencing (RNA-seq) and real-time polymerase chain reaction (PCR) were used to examine transcriptional dysregulation. Finally, anchorage-independent cell growth ability was tested by soft agar assay following FA exposure. Results: Exposure to FA dramatically decreased the acetylation of the N-terminal tails of cytosolic histones. These modifications are important for histone nuclear import and subsequent chromatin assembly. Histone proteins were depleted in both the chromatin fraction and at most of the genomic loci tested following FA exposure, suggesting that FA compromises chromatin assembly. Moreover, FA increased chromatin accessibility and altered the expression of hundreds of cancer-related genes. Knockdown of the histone H3.3 gene (an H3 variant), which mimics inhibition of chromatin assembly, facilitated FA-mediated anchorage-independent cell growth. Conclusions: We propose that the inhibition of chromatin assembly represents a novel mechanism of cell transformation induced by the environmental and occupational chemical carcinogen FA. https://doi.org/10.1289/EHP1275
Subclinical Pulmonary Edema Is Associated With Reduced Exercise Capacity in HFpEF and HFrEF
Authors: Richard B. Thompson, Joseph J. Pagano, Kelvin Chow, Viktor Sekowski, Ian Paterson, Justin Ezekowitz, Todd Anderson, Jason R.B. Dyck, Mark J. Haykowsky
Journal: Journal of the American College of Cardiology (2017)
Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-α
Authors: Xiao-Wei Dou, Yuan-Ke Liang, Hao-Yu Lin, Xiao-Long Wei, Yong-Qu Zhang, Jing-Wen Bai, Chun-Fa Chen, Min Chen, Cai-Wen Du, Yao-Chen Li, Jie Tian, Kwan Man, Guo-Jun Zhang
Journal: Theranostics (2017)

The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor α expression (ERα).Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer.ERα signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer.In this study, we demonstrate that Notch3 positively associates with ERα in both breast cancer cell lines and human breast cancer tissues.We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ERα negative breast cancer cells re-activated ERα, while knock-down of Notch3 reduced ERα transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERα.Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERα promoter and activates ERα expression.Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay.Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo.Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo.Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ERα positive breast cancer patients.Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERα expression in breast cancer.These findings delineate the role of a Notch3/ERα axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERα negative or low-expressing breast cancers to hormone therapy.
Over 15% of atrial fibrillation patients are not prescribed any antithrombotic agent for stroke prevention by GPs
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Antithrombotic treatment for stroke prevention in patients with non-valvular atrial fibrillation is improving, but nearly 20% still receive antiplatelet agents alone and over 15% no antithrombotic agents at all, a study published in BMJ Open has found.1

The study was based on five cross sectional analyses of general practice data in the UK Clinical Practice Research Datalink. Patients were included if they had a diagnosis of non-valvular atrial fibrillation and were eligible for anticoagulation under European Society …
Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naïve &amp; experienced metastatic melanoma patients.
Authors: Abraham C.F. Leung, Shivaani Kummar, Sanjiv S. Agarwala, John J. Nemunaitis, Rene Gonzalez, Joseph J. Drabick, Emmett V. Schmidt, Elliot Chartash, Biao Xing, Graeme Currie, Robert Janssen, Antoni Ribas
Journal: Journal of Clinical Oncology (2017)

9550 Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 (NCT02521870), assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH &gt; 1 ULN 27%, ≥ 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (≥20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade ≥ 3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. Additional follow up data through May 15, 2017 will be presented. Clinical trial information: NCT02521870.
Stroma-free long-term growth of primary acute myeloid leukemia (AML) cells.
Authors: Jing Chen, Glorymar Ibanez Sanchez, Paul Calder, Mark G. Frattini
Journal: Journal of Clinical Oncology (2017)

e18535 Background: To individualize therapy for relapsed/refractory AML patients, optimal in-vitro culture conditions to support primary leukemic cells are essential for drug sensitivity testing. Our lab has validated a high throughput chemosensitivity assay with primary AML cells maintained by growth factors (cytokines); however, growth factors have not been shown to support long-term assays of primary AML cells. Stromal cells of the tumor microenvironment are crucial to maintain normal hematopoiesis and leukemic cells and have been shown to support long term in-vitro expansion of primary AML cells. However, there is little information characterizing these growth conditions. The aim of this study was to compare long-term proliferation and phenotypes of primary AML cells with growth factors or stromal support to best determine their utility as a platform for drug sensitivity testing in functional assays. Methods: Patient-derived AML cells were cultured in 96-well plates in: 1) cell culture medium only 2) Human HS5 or HS27 stromal cells 3) HS5 or HS27 stroma-conditioned media or 4) cytokine cocktail. Viability readout by Guava ViaCount and leukemic cell surface phenotypes by fluorescently-conjugated antibodies were performed weekly over 3 weeks. Results: Primary AML cells cultured with only cytokines maintained proliferation at 3 weeks. In comparison, AML cells cultured in HS5 stroma-conditioned medium also maintained proliferation at a similar rate at 3 weeks, while co-culture with HS5 stromal cells demonstrated significantly higher proliferation. Leukemic immunophenotypes were maintained for all growth conditions over 3 weeks. Conclusions: Contrary to known data, primary AML cells with cytokines continued to expand at 3 weeks, at a similar rate to HS5 stroma-conditioned medium, a finding that has not been reported. Consistent with previous studies, we confirmed that stromal cells such as HS5 can provide long-term in-vitro expansion of primary AML cells, which cannot be substituted by stroma-conditioned medium. The ability to maintain long-term expansion of primary AML cells by both cytokines and stromal cells sets up a platform for a direct comparison of high throughput drug sensitivity testing under these growth conditions.
Cardiac Atlas of the Preterm Heart: Cardiovascular Magnetic Resonance Reveals Unique Variation in 3D Left Ventricular Geometry in Young Adulthood
Authors: Adam J Lewandowski, Pablo Lamata, Daniel Augustine, Merzaka Lazdam, Esther F Davis, Jane Francis, Kenny McCormick, Andrew Wilkinson, Atul Singhal, Alan Lucas, Nic Smith, Stefan Neubauer, Paul Leeson
Journal: Circulation (2012)

Background - Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development. In animal studies this results in an adversely re...
<i>dcmqi</i>: An Open Source Library for Standardized Communication of Quantitative Image Analysis Results Using DICOM
Authors: Christian Herz, Jean-Christophe Fillion-Robin, Michael Onken, Jörg Riesmeier, Andras Lasso, Csaba Pinter, Gabor Fichtinger, Steve Pieper, David Clunie, Ron Kikinis, Andriy Fedorov
Journal: Cancer Research (2017)

Abstract Quantitative analysis of clinical image data is an active area of research that holds promise for precision medicine, early assessment of treatment response, and objective characterization of the disease. Interoperability, data sharing, and the ability to mine the resulting data are of increasing importance, given the explosive growth in the number of quantitative analysis methods being proposed. The Digital Imaging and Communications in Medicine (DICOM) standard is widely adopted for image and metadata in radiology. dcmqi (DICOM for Quantitative Imaging) is a free, open source library that implements conversion of the data stored in commonly used research formats into the standard DICOM representation. dcmqi source code is distributed under BSD-style license. It is freely available as a precompiled binary package for every major operating system, as a Docker image, and as an extension to 3D Slicer. Installation and usage instructions are provided in the GitHub repository at https://github.com/qiicr/dcmqi. Cancer Res; 77(21); e87–90. ©2017 AACR.
Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA–MUF Interaction with ANXA2 and miR-34a
Authors: Xinlong Yan, Dongdong Zhang, Wei Wu, Shuheng Wu, Jingfeng Qian, Yajing Hao, Fang Yan, Pingping Zhu, Jiayi Wu, Guanling Huang, Yinghui Huang, Jianjun Luo, Xinhui Liu, Benyu Liu, Xiaomin Chen, Ying Du, Runsheng Chen, Zusen Fan
Journal: Cancer Research (2017)

Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704-16. ©2017 AACR.