tbuckley/cabot-search huggingface dataset:
Tumor-Educated Platelets as a Noninvasive Biomarker Source for Cancer Detection and Progression Monitoring
Authors: Myron G. Best, Pieter Wesseling, Thomas Wurdinger
Journal: Cancer Research (2018)

Liquid biopsies represent a potential revolution in cancer diagnostics as a noninvasive method for detecting and monitoring diseases, complementary to or even replacing current tissue biopsy approaches. Several blood-based biosources and biomolecules, such as cell-free DNA and RNA, proteins, circulating tumor cells, and extracellular vesicles, have been explored for molecular test development. We recently discovered the potential of tumor-educated blood platelets (TEP) as a noninvasive biomarker trove for RNA biomarker panels. TEPs are involved in the progression and spread of several solid tumors, and spliced TEP RNA surrogate signatures can provide specific information on the presence, location, and molecular characteristics of cancers. So far, TEP samples from patients with different tumor types, including lung, brain, and breast cancers, have been tested, and it has been shown that TEPs from patients with cancer are distinct from those with inflammatory and other noncancerous diseases. It remains to be investigated how platelets are "educated," which mechanisms cause intraplatelet RNA splicing, and whether the relative contribution of specific platelet subpopulations changes in patients with cancer. Ultimately, TEP RNA may complement currently used biosources and biomolecules employed for liquid biopsy diagnosis, potentially enhancing the detection of cancer in an early stage and facilitating noninvasive disease monitoring. Cancer Res; 78(13); 3407-12. ©2018 AACR.
LGG-49. MOLECULAR ALTERATIONS IN PREGNANT ADOLESCENT AND YOUNG ADULT WOMEN WITH GLIOMA
Authors: Julie Bennett, Scott Ryall, Michal Zapotocky, Ana Guerreiro Stucklin, Kohei Fukuoka, Sunit Das, Warren Mason, James Perry, Arjun Sahgal, Kenneth Aldape, Julia Keith, David Munoz, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2018)

Brain tumors account for 10% of tumors in adolescents and young adults (AYA), with gliomas being most common. This age overlaps with peak fertility in women. Previous case series suggested a link between progression/transformation of gliomas during pregnancy. Molecular alterations in this group is unknown. We sought to identify a cohort of AYA women, describe tumor behavior during pregnancy and define molecular alterations. An institutional review was conducted identifying women 15-39.9 years with glioma and pregnancy at initial diagnosis or during treatment. Tumor specimens were tested for common molecular alterations. Of 217 female patients identified, 8 were diagnosed with glioma during pregnancy (1 pilocytic astrocytoma, 1 diffuse astrocytoma, 4 oligodendrogliomas, 2 anaplastic astrocytomas and 1 glioblastoma multiforme). Of these, 6 tumors underwent molecular testing: 2 with loss of heterozygosity of 1p/19q (oligodendrogliomas), 1 with IDH-1 mutation (DA) and 3 with no alterations found (PA, AA, GBM). Importantly, no tumors harbored common MAPK pathway alterations. Median gestational age was 32 weeks (range 8-38), with one patient undergoing therapeutic abortion prior to treatment for tumor. Three additional patients had malignant transformation during pregnancy (2 DA transformed to GBM, 1 DA transformed to AA), with one IDH-1 mutation identified (DA to GBM) and one with no alteration found. Molecular alterations in this population corresponded to those typically seen in adult tumors, with no pediatric-type alterations found. Malignant transformation is a possibility and patients should be counselled on this risk. Therapeutic abortion should be considered in extreme situations.
Dietary Recommendations for Adults With Psoriasis or Psoriatic Arthritis From the Medical Board of the National Psoriasis Foundation
Authors: Adam R. Ford, Michael Siegel, Jerry Bagel, Kelly M. Cordoro, Amit Garg, Alice Gottlieb, Lawrence J. Green, Johann E. Gudjonsson, John Koo, Mark Lebwohl, Wilson Liao, Arthur M. Mandelin, Joseph A. Markenson, Nehal Mehta, Joseph F. Merola, Ronald Prussick, Caitriona Ryan, Sergio Schwartzman, Evan L. Siegel, Abby S. Van Voorhees, Jashin J. Wu, April W. Armstrong
Journal: JAMA Dermatology (2018)

Psoriasis is a chronic, inflammatory skin disease and has significant associated morbidity and effect on quality of life. It is important to determine whether dietary interventions help reduce disease severity in patients with psoriatic diseases.To make evidence-based dietary recommendations for adults with psoriasis and/or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation.We used literature from prior systematic reviews as well as additional primary literature from the MEDLINE database from January 1, 2014, to August 31, 2017, that evaluated the impact of diet on psoriasis. We included observational and interventional studies of patients with psoriasis or psoriatic arthritis. The quality of included studies was assessed using the Newcastle-Ottawa scale for observational studies and the Cochrane Risk of Bias Tool for interventional studies. We made evidence-based dietary recommendations, which were voted on by the National Psoriasis Foundation Medical Board.We identified 55 studies meeting the inclusion criteria for this review. These studies represent 77 557 unique participants of which 4534 have psoriasis. Based on the literature, we strongly recommend dietary weight reduction with a hypocaloric diet in overweight and obese patients with psoriasis. We weakly recommend a gluten-free diet only in patients who test positive for serologic markers of gluten sensitivity. Based on low-quality data, select foods, nutrients, and dietary patterns may affect psoriasis. For patients with psoriatic arthritis, we weakly recommend vitamin D supplementation and dietary weight reduction with a hypocaloric diet in overweight and obese patients. Dietary interventions should always be used in conjunction with standard medical therapies for psoriasis and psoriatic arthritis.Adults with psoriasis and/or psoriatic arthritis can supplement their standard medical therapies with dietary interventions to reduce disease severity. These dietary recommendations from the National Psoriasis Foundation Medical Board will help guide clinicians regarding the utility of dietary interventions in adults with psoriatic diseases.
Surgical management of pancreatic tumors in children
Authors: A. Lukashenko, Y. Ostapenko, O. Kolesnik, N. Chorna
Journal: Annals of Oncology (2018)

Introduction: Pancreatic tumors in children are relatively uncommon. The data of their presentation accrues mostly through institutional case series. The very limited experience along with the broad histological heterogeneity have made it difficult to identify possible prognostic factors and develop treatment protocols. The aim of the presented research was to improve surgical treatment of pancreatic tumors in children. Methods: Retrospective review of medical records and pathology reports of children who were undergone surgery at National Cancer Institute was conducted from 1990 to 2017. Over the whole period there were 19 patients under the age of 18 with surgical treatment due to pancreatic tumors. Results: Radical (R0) surgical resection was achieved in 18 patients (94,7%). In 12 (63,1%) cases distal pancreatic resection were performed accordingly to localization of the tumor in pancreatic body or tail. Pancreatoduodenectomy (PD) was performed in 4 (21%) cases. Organ-preserving approach was used for 3 patients: enucleations of tumor of pancreatic tail in 1 case (5,2%), spleen preserving distal pancreatectomy in 2 (10,5%) cases. There was no postoperative mortality, but postoperative complications occurred in 2 patients (10,5%) and was treated conservatively. The median follow-up was 126 months (range 16-292 months). No patients were observed with postoperative pancreatic exocrine or endocrine insufficiencies. All patients are still alive so far. Conclusion: Conclusion: Pancreatic tumors in children have more favorable outcomes in comparison with adults. Surgical treatment is the prominent method for young patients under the age of 18 with pancreatic tumors. Pancreatic resection of pancreatic tumors in children should performed in high-experience surgical center.
Bariatric Surgery and Hypertension
Authors: Jøran Hjelmesæth, Gunn Signe Jakobsen, Njord Nordstrand
Journal: JAMA (2018)

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Affinity Maturation Drives Epitope Spreading and Generation of Proinflammatory Anti–Citrullinated Protein Antibodies in Rheumatoid Arthritis
Authors: Serra E. Elliott, Sarah Kongpachith, Nithya Lingampalli, Julia Z. Adamska, Bryan J. Cannon, Rong Mao, Lisa K. Blum, William H. Robinson
Journal: Arthritis & Rheumatology (2018)

Objective Rheumatoid arthritis ( RA ) is characterized by the presence of anti–citrullinated protein antibodies ( ACPA s); nevertheless, the origin, specificity, and functional properties of ACPA s remain poorly understood. The aim of this study was to characterize the evolution of ACPA s by sequencing the plasmablast antibody repertoire at serial time points in patients with established RA . Methods Blood samples were obtained at up to 4 serial time points from 8 individuals with established RA who were positive for ACPA s by the anti–cyclic citrullinated peptide test. CD 19+ CD 3−IgD− CD 14− CD 20− CD 27+ CD 38++ plasmablasts were isolated by single‐cell sorting and costained with citrullinated peptide tetramers to identify ACPA ‐expressing plasmablasts. Cell‐specific oligonucleotide barcodes were utilized, followed by large‐scale sequencing and bioinformatics analysis, to obtain error‐corrected, paired heavy‐ and light‐chain antibody gene sequences for each B cell. Results Bioinformatics analysis revealed 170 persistent plasmablast lineages in the RA blood, of which 19% included multiple isotypes. Among IgG‐ and IgA‐expressing plasmablasts, significantly more IgA‐expressing than IgG‐expressing persistent lineages were observed ( P &lt; 0.01). Shared complementarity‐determining region 3 sequence motifs were identified across subjects. A subset of the plasmablast lineages included members derived from later time points with divergent somatic hypermutations that encoded antibodies that bind an expanded set of citrullinated antigens. Furthermore, these recombinant, differentially mutated plasmablast antibodies formed immune complexes that stimulated higher macrophage production of tumor necrosis factor (TNF) compared to antibodies representing earlier time point–derived lineage members that were less mutated. Conclusion These findings demonstrate that established RA is characterized by a persistent IgA ACPA response that exhibits ongoing affinity maturation. This observation suggests the presence of a persistent mucosal antigen that continually promotes the production of IgA plasmablasts and their affinity maturation and epitope spreading, thus leading to the generation of ACPA s that bind additional citrullinated antigens and more potently stimulate macrophage production of TNF .
TBIO-25. CHOROID PLEXUS PAPILLOMAS IN FAMILIES WITH DICER1 MUTATION ASSOCIATED DISEASE
Authors: Barbara Rivera, Anne-Sophie Chong, Christian Thomas, Sommayeh Fahiminiya, Doug Strother, John Priest, Martin Hasselblatt, William Foulkes
Journal: Neuro-Oncology (2018)

Choroid plexus tumors are rare intraventricular neoplasms, which can be divided into choroid plexus papillomas (CPP, WHO grade I), atypical choroid plexus papillomas (aCPP, WHO grade II) and malignant choroid plexus carcinomas (CPC, WHO grade III). While CPC are often associated with TP53 germline mutations, only little is known on the etiology of sporadic and rare familial CPP. Recently, the report of a child concurrently harboring aCPP and pleuropulmonary blastoma, a childhood neoplasia strongly associated with DICER1 mutations, was published. Similarly, in a second kindred affected by familial goiter (also a DICER1 associated disorder), a child harboring CPP and goiter was encountered. In order to identify underlying genetic alterations and molecular mechanisms, these families were further examined. In both families, no DICER1 germline alterations could be detected. Examination of the pleuropulmonary blastoma of the first child yielded two different somatic DICER1 mutations and there was no indication of a mosaic DICER1 mutation on digital droplet PCR assay performed on blood, normal lung, two different pleuropulmonary blastoma samples and the CPP. Results from whole exome sequencing, which was performed on DNA from peripheral blood leukocytes and tumor samples in comparison to 24 archival sporadic choroid plexus tumors are pending. Our results are expected to shed light on the etiology of CPP in these families, but may also have implications for sporadic CPP.
Development of carrier-free nanocrystals of poorly water-soluble drugs by exploring metastable zone of nucleation
Authors: Xiaoting Ren, Jianping Qi, Wei Wu, Zongning Yin, Tonglei Li, Yi Lu
Journal: Acta Pharmaceutica Sinica B (2018)

There has been increasing interest in research and development of nanocrystals for the delivery of poorly water-soluble drugs that can be directly produced from solution. Compared with traditional carrier-based or encapsulation designs, drug nanocrystals circumvent possible side-effects due to carrier polymers and poor stability issues associated with encapsulation. The production of carrier-free nanocrystals requires careful control of nucleation and thus a thorough understanding of the relevant solution's metastable zone. A solution may stay supersaturated without forming any nuclei and become metastable. The maximal degree of supersaturation is known as the metastable zone width. When nucleation is triggered directly from the metastable zone, it helps to produce homogeneous nuclei leading to uniform nanocrystals. Herein, we report a study in which the solubility and metastable limit of paclitaxel (PTX) in ethanol aqueous solution were measured at 40 °C. A wide range of metastable compositions were studied to prepare carrier-free PTX nanocrystals with particle size smaller than 250 nm and PDI less than 0.25. Compared with the raw material, dissolution rate of PTX nanocrystals was significantly increased. The study enables production of high-quality drug nanocrystals for treating patients.
Drebrin regulates angiotensin II-induced aortic remodelling
Authors: Lisheng Zhang, Jiao-Hui Wu, Tai-Qin Huang, Igor Nepliouev, Leigh Brian, Zhushan Zhang, Virginia Wertman, Nathan P Rudemiller, Timothy J McMahon, Sudha K Shenoy, Francis J Miller, Steven D Crowley, Neil J Freedman, Jonathan A Stiber
Journal: Cardiovascular Research (2018)

The actin-binding protein Drebrin is up-regulated in response to arterial injury and reduces smooth muscle cell (SMC) migration and proliferation through its interaction with the actin cytoskeleton. We, therefore, tested the hypothesis that SMC Drebrin inhibits angiotensin II-induced remodelling of the proximal aorta.Angiotensin II was administered via osmotic minipumps at 1000 ng/kg/min continuously for 28 days in SM22-Cre+/Dbnflox/flox (SMC-Dbn-/-) and control mice. Blood pressure responses to angiotensin II were assessed by telemetry. After angiotensin II infusion, we assessed remodelling in the proximal ascending aorta by echocardiography and planimetry of histological cross sections. Although the degree of hypertension was equivalent in SMC-Dbn-/- and control mice, SMC-Dbn-/- mice nonetheless exhibited 60% more proximal aortic medial thickening and two-fold more outward aortic remodelling than control mice in response to angiotensin II. Proximal aortas demonstrated greater cellular proliferation and matrix deposition in SMC-Dbn-/- mice than in control mice, as evidenced by a higher prevalence of proliferating cell nuclear antigen-positive nuclei and higher levels of collagen I. Compared with control mouse aortas, SMC-Dbn-/- aortas demonstrated greater angiotensin II-induced NADPH oxidase activation and inflammation, evidenced by higher levels of Ser-536-phosphorylated NFκB p65 subunits and higher levels of vascular cell adhesion molecule-1, matrix metalloproteinase-9, and adventitial macrophages.We conclude that SMC Drebrin deficiency augments angiotensin II-induced inflammation and adverse aortic remodelling.
EPEN-33. STUDY OF ANTI-HER2 CAR T CELLS IN THE IMMUNOSUPPRESSIVE EPENDYMOMA TUMOR MICROENVIRONMENT
Authors: Anandani Nellan, Andrea Griesinger, Davis Witt, Andrew Donson, Vladimir Amani, Nicholas K Foreman
Journal: Neuro-Oncology (2018)

Ependymoma (EPN) is a brain tumor that is chemotherapy insensitive. Surgery can remove grossly visible tumor in most EPN cases but, even when combined with radiation, there is a 10-year relapse rate of over 70%. Chimeric antigen receptor (CAR) T cell therapy has been very effective in the clinic treating patients with hematologic malignancies, but progress in solid tumors has lagged. Microarray analysis of pediatric EPN samples revealed HER2 as an important target. A second-generation anti-HER2 CAR-T cell containing the CD3-zeta and 4-1BB signaling motifs will be studied against two patient derived, high-risk EPN cell lines (811 and 928). Co-culture assays will be performed to determine specific cytokine release indicative of CAR-T cell activation upon antigen recognition. Cytolytic assays to determine EPN cell killing by CAR-T cells will be done using continuous monitoring through the IncuCyte allowing for direct evaluation of both cytotoxicity and localization of CAR-T cells to tumor cells. An orthotopic intraventricular xenograft model will be employed to validate these findings. Finally, experiments to determine the effect of the immunosuppressive EPN tumor environment on CAR-T cells will be performed. HER2 CAR-T cells secreted increased cytokine levels (IFN-γ, IL-2, TNFα) in the presence of 811 and 928 tumor cells compared to control T cells. HER2-BBz-CAR T cells demonstrated significant killing of 928 and 811 (p<0.0001), even at low E:T ratios. HER2 CAR-T cells demonstrate antigen recognition of EPN cell lines and confers specific killing activity against HER2-positive EPN cell lines. Further studies are ongoing.
TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress
Authors: John L Jones, Deborah Peana, Adam B Veteto, Michelle D Lambert, Zahra Nourian, Natalia G Karasseva, Michael A Hill, Brian R Lindman, Christopher P Baines, Maike Krenz, Timothy L Domeier
Journal: Cardiovascular Research (2018)

Abstract Aims Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia–reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. Methods and results TRPV4 protein expression increased in cardiomyocytes of Aged (24–27 months) mice compared with Young (3–6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 μmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4−/−) mice. In Aged, pharmacological inhibition of TRPV4 (1 μmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Conclusions Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.
Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
Authors: Xinyi Guo, Yuanyuan Zhang, Liangtao Zheng, Chunhong Zheng, Jintao Song, Qiming Zhang, Boxi Kang, Zhouzerui Liu, Liang Jin, Rui Xing, Ranran Gao, Lei Zhang, Minghui Dong, Xueda Hu, Xianwen Ren, Dennis Kirchhoff, Helge Gottfried Roider, Tiansheng Yan, Zemin Zhang
Journal: Nature Medicine (2018)