tbuckley/cabot-search huggingface dataset:
Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson’s disease
Authors: Qian-Qian Chen, Caroline Haikal, Wen Li, Ming-Tao Li, Zhan-You Wang, Jia-Yi Li
Journal: Translational Neurodegeneration (2018)

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, neuropathologically characterized by misfolded protein aggregation, called Lewy bodies and Lewy neurites. PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease. In order to study PD pathology in the colon, we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype α-synuclein (α-syn) fused with the green fluorescent protein (GFP), under the endogenous mouse α-syn promoter. We observed an age-dependent progressive expression and accumulation of α-syn-GFP in the enteric neurons of Meissner's (submucosal) and Auerbach's (myenteric) plexuses of the colon. Additionally, the phosphorylation of α-syn at serine 129 also increased with age and the aggregation of α-syn-GFP coincided with the appearance of motor deficits at 9 months of age. Furthermore, α-syn (-GFP) distinctly co-localized with different subtypes of neurons, as identified by immunohistochemical labeling of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin. Our results show the development of α-syn pathology in the enteric neurons of the colon in a PD mouse model, which coincide with the appearance of motor deficits. Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.
MBRS-02. PERSONALIZED IMMUNOTHERAPY WITH TRANSLATABLE RNA NANOPARTICLES TARGETING MEDULLOBLASTOMA
Authors: Elias Sayour, Hector Mendez-Gomez, Adam Grippin, Gabriel De Leon, Brian Stover, Catherine Flores, Christina Pham, Duane Mitchell
Journal: Neuro-Oncology (2018)

While recurrent medulloblastoma (MB) remains almost uniformly fatal, our group has shown a trend (p=0.07) toward improved survival in patients receiving autologous tumor-RNA pulsed dendritic cells (DCs) coupled with ex vivo expanded total RNA activated T-cells. However, the advancement of autologous cellular therapeutics remains encumbered by significant cost, complexity and time to generation. To circumvent these challenges, we developed a novel treatment platform, which leverages the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor-derived RNA for near-immediate induction of systemic immunity against MB. We identified a clinically translatable NP formulation for the delivery of RNA to antigen presenting cells for induction of anti-tumor T-cell immunity. When administered intravenously, RNA-NPs increased expression of co-stimulatory molecules on CD11c+ cells throughout reticuloendothelial organs and within the tumor microenvironment; this phenotype was dependent on type I interferon. Targeted inhibition of type I interferon signaling (via INFAR1-mAbs) abrogated anti-tumor immunity mediated by RNA-NPs. We enhanced the immunogenicity of this platform by simply combining mRNAs encoding for immunomodulatory molecules (i.e. HCV-PAMPs, GM-CSF) or by combining RNA-NPs with immune checkpoint inhibitors. Addition of checkpoint inhibitors to RNA-NPs mediated synergistic anti-tumor activity in settings where PD-1 or PD-L1 inhibition alone did not confer therapeutic benefit. In a pre-clinical cellular immunotherapy model targeting an anaplastic murine MB, RNA NPs superseded DCs in mediating anti-tumor activity. Based on these findings, we are exploring the preclinical safety, efficacy and immunologic effects of RNA-NPs targeting malignant brain tumors in canines (UF-IACUC#:201609430) before first in-human evaluation.
Gut microbial community diversity is associated with systemic vascular endothelial growth factor A levels among colorectal cancer patients
Authors: A. Holowatyj, W. Stephens, C. Warby, K. Buhrke, B. Gigic, T. Lin, J. Boehm, N. Habermann, E. Herpel, J. Ose, M. Schneider, P. Schrotz-King, P. Schirmacher, A. Ulrich, A. Toriola, J. Round, C. Ulrich
Journal: Annals of Oncology (2018)

Introduction: Dysbiosis in the gut microbiota and activation of the angiogenic switch in the tumor microenvironment contribute to colorectal carcinogenesis. Methods: Analyses of baseline fecal samples via 16S rRNA gene sequencing, and evaluation of angiogenic stimulators, vascular endothelial growth factor (VEGF) A and D, in patient sera among n=125 patients diagnosed with colorectal cancer in the ColoCare Study were used to explore the link between the gut microbiome and systemic biomarkers of angiogenesis. Results: Baseline clinicopathologic and demographic characteristics were evaluated. Relative contributions of taxonomic groups identified through 16S sequencing were examined. Diverse microbial taxa, including previously cancer-associated microbes, were detected in fecal biospecimens. A significant association of gut microbial community diversity was observed by circulating VEGFA (Bray-Curtis metric: R2=0.94; false discovery rate [FDR] q-value=0.007; weighted Unifrac: R2=0.95, FDR q-value=0.026) but not by VEGFD (Bray-Curtis metric: R2=0.81, FDR q-value=0.77; weighted Unifrac: R2=0.80, FDR q-value=0.8) levels. Differences in systemic VEGFA or VEGFD levels were not directly correlated with individual taxa. Conclusion: These findings suggest that microbial community level function is important for driving the association between gut microbial community diversity and circulating VEGFA biomarker levels. Together, profiling of the microbial taxa and systemic angiogenesis biomarkers among colorectal cancer patients demonstrates that circulating levels of angiogenic stimulator VEGFA may reflect changes in the microbial ecosystem of the human gut that influence colorectal carcinogenesis.
SWRK-05. CELEBRATE LIFE, HONOR COURAGE: BRAIN TUMOR SPECIFIC BEREAVEMENT PROGRAMMING
Authors: Melissa Mark, Bridget Kikta, Aimee Thompson, Wanda Meriwether, Mandy Bley, Sue Jelinek, Maryam Fouladi, Lionel Chow
Journal: Neuro-Oncology (2018)

There has been increasing research focused on supporting bereaved families within pediatric oncology. Children with brain tumors and their families report feeling isolated from other oncology patients. To better support the bereaved families in our neuro-oncology (N/O) program, we developed a brain tumor bereavement program. We held a focus group with nine bereaved family members, whose children had brain tumors treated at our institution. Common themes elicited included a desire for positive messaging and providing opportunities to network with other bereaved families. In pre-event surveys 88% of the N/O team responded they would be willing to attend a bereavement program for families. The program was held on the hospital campus. It was unstructured, except for brief opening remarks and a slide show presenting patient pictures accompanied by staff memories of the child. 45 bereaved family members attended representing 15 patients. 10 N/O team members attended. Most team members cited a scheduling conflict for not attending, but some expressed discomfort. Follow up surveys from N/O team members (16) and families (6) were overall positive. One respondent did not attend because the event was on the hospital campus while two people reported that they enjoyed being able to write notes to staff. Several parents reported during the event the importance of hearing specific staff memories of their child. Parents of deceased children with brain tumors prefer diagnosis specific bereavement programming, have a strong desire to connect with other bereaved parents, and want opportunities to thank staff that cared for their children.
GERM-17. CHARACTERISTICS OF SUCCESSFULLY SALVAGED PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM (CNS) NON-GERMINOMATOUS GERM CELL TUMORS (NGGCTs)
Authors: Mohammad H Abu Arja, Mohamed S AbdelBaki, Jonathan L Finlay
Journal: Neuro-Oncology (2018)

Outcomes of patients with relapsed CNS NGGCTs are extremely poor compared to patients with relapsed germinomas. The rarity of these tumors and paucity of prospective clinical trials make it difficult to establish a standard treatment approach. A review of clinical trials that included patients with relapsed CNS NGGCTs was performed. Seventy-four patients reported in one prospective clinical trial and three retrospective studies were identified; only 14 patients were reported as long-term survivors (19%). Of the 14 survivors, eight relapsed within 24 months of initial diagnosis; five of 14 survivors had elevated serum/ cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) at primary diagnosis; none had elevated serum/CSF AFP at relapse. Of the 14 survivors, seven had elevated serum/CSF beta-human chorionic gonadotropin (HCGβ) at initial diagnosis or relapse. Eleven received radiotherapy at some time following relapse (craniospinal irradiation=9, focal radiotherapy=2). Twelve received high-dose chemotherapy (HDCx) followed by autologous hematopoietic cell rescue (AuHCR); of six with data, all achieved complete or continuing complete (two after surgical resection) remission (CR) prior to HDCx. Post-transplant, eleven out of twelve (one with stable disease) continued without residual or recurrent disease. Serum/ CSF AFP status at relapse, achieving CR prior and post-HDCx, receiving radiotherapy and HDC may have more prognostic value compared to the time of relapse, tumor markers at initial diagnosis and achieving GTR prior to consolidation therapy. Future trials need to better stratify relapsed patients on the basis of AFP status prior to relapse and receiving radiotherapy and HDCx.
Survival and prognostic factors of non metastatic rectal adenocarcinoma: Analytic multifactor review of 91 cases
Authors: K. Darif, Z. Benbrahim, M. Benhami, I. Ahalli, R. Boujarnija, H. Erraichi, R. Elhazzaz, H. Ouahbi, L. Amaadour, K. Oualla, F. El M'rabet, S. Arifi, N. Mellas
Journal: Annals of Oncology (2018)

Introduction: Rectal cancers are the second most common cancers in human and major public health problems worldwide. Prognostic factors have a pivotal role in clinical oncology. They are helpful in the selection of treatment; provide insights into the disease process and the therapeutic response. This study attempts to observe the survival of rectal adenocarcinoma and to find prognostic factors and other variables potentially associated with outcome of operated rectal adenocarcinoma. Methods: It's a retrospective study based on 91 patients with operated rectal adenocarcinoma collected at the Medical Oncology Department of Hassan II University Hospital for a period of 4 years between January 2014 and June 2017. Various prognostic factors had been identified through univariate (Kaplan-Meier) then multivariate (Cox) analyze, namely: age, sex, tumor localization, degree of differentiation, stage, tumor recurrence, ACE level, neoadjuvant therapy and adjuvant chemotherapy. Results: The mean age was 59 years (± 14.14) with extremes "24-86". These were 40% men and 60% women. At endoscopic examination the tumor was located: in the middle rectum in 30.8%; 36.3% in the lower rectum and 33% in the upper rectum. Histologically, the biopsy showed that liberkunian adenocarcinoma was well differentiated in 56%, moderately differentiated in 42% and in 2% poorly differentiated. The carcinoembryonic antigen revealed a rate greater than 5 ng/ml in 25% of patients. Neo-adjuvant treatment with concomitant radiochemotherapy was performed in 61.5% and radiotherapy for 24%. Histopathological examination classified the patients according to the TNM classification with: 7% of patients in stage I, 30% in stage II, 54% in stage III and 9% in stage IV. After surgery 78 patients (86%) received adjuvant chemotherapy. Average overall survival was 25 months. In addition, 23% of patients had a recurrence, median-free survival was 29-month. Adjuvant therapy was the only prognostic factor influencing survival: mean survival in the group receiving adjuvant chemotherapy was 32 months vs 14 months in the surveillance group with a very significant difference (p = 0.006). Conclusion: In our series adjuvant therapy was an important prognostic factor influencing overall survival, our results correlate with those in the literature.
HGG-01. RADIATION INCREASES PRE-CLINICAL EFFICACY OF OLIG2 INHIBITOR CT-179 IN PEDIATRIC GBM
Authors: Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank Braun, Mari Kogiso, Sarah Injac, Mary Sobieski, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Xiao-Nan Li
Journal: Neuro-Oncology (2018)

Oligodendrocyte Lineage Transcription Factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells. We evaluated the pre-clinical efficacy of the OLIG2 inhibitor CT-179 in patient-derived orthotopic xenograft (PDOX) models of pediatric glioblastoma (pGBM). Cells from 8 pGBM models were treated with single agent CT-179 (0-10 µM) as well as CT-179 (0-1 µM) plus radiation (XRT) (0-8 Gy). For in vivo drug testing, 105 pGBM cells were implanted into mice. After 1 week, treatment was initiated with vehicle, CT-179 (200 mg/kg via gavage every 4 days), XRT (2 Gy/day x 5 days), and combination CT-179/XRT. CT-179 inhibited cell viability in a time- and dose-dependent manner in all 8 pGBM tumors (IC50 0.03-10 µM). XRT potentiated the effects of CT-179 at low/moderate drug doses (0.03-1 µM). In vivo treatment was complicated by murine weight loss. Single agent CT-179 did not increase pGBM PDOX survival compared to vehicle (p=0.973) or XRT (p=0.262). However, the combination of CT-179 and XRT trended toward improved animal survival compared to vehicle (p=0.086). CT-179 and XRT combination treatment was significantly more effective at prolonging murine survival than single agent CT-179 (p<0.001). The OLIG2 inhibitor CT-179 demonstrated in vitro efficacy against numerous pGBM samples and a trend toward improved survival when combined with XRT in vivo in an aggressive PDOX model of pGBM. Further in vivo combinatorial testing in additional GBM models is planned through the Pediatric Pre-clinical Testing Consortium with drug administered every 5 days to prevent murine weight loss.
Towards a complex systems approach in sports injury research: simulating running-related injury development with agent-based modelling
Authors: Adam Hulme, Jason Thompson, Rasmus Oestergaard Nielsen, Gemma J M Read, Paul M Salmon
Journal: British Journal of Sports Medicine (2018)

Objectives There have been recent calls for the application of the complex systems approach in sports injury research. However, beyond theoretical description and static models of complexity, little progress has been made towards formalising this approach in way that is practical to sports injury scientists and clinicians. Therefore, our objective was to use a computational modelling method and develop a dynamic simulation in sports injury research. Methods Agent-based modelling (ABM) was used to model the occurrence of sports injury in a synthetic athlete population. The ABM was developed based on sports injury causal frameworks and was applied in the context of distance running-related injury (RRI). Using the acute:chronic workload ratio (ACWR), we simulated the dynamic relationship between changes in weekly running distance and RRI through the manipulation of various ‘athlete management tools’. Results The findings confirmed that building weekly running distances over time, even within the reported ACWR ‘sweet spot’, will eventually result in RRI as athletes reach and surpass their individual physical workload limits. Introducing training-related error into the simulation and the modelling of a ‘hard ceiling’ dynamic resulted in a higher RRI incidence proportion across the population at higher absolute workloads. Conclusions The presented simulation offers a practical starting point to further apply more sophisticated computational models that can account for the complex nature of sports injury aetiology. Alongside traditional forms of scientific inquiry, the use of ABM and other simulation-based techniques could be considered as a complementary and alternative methodological approach in sports injury research.
AP-2β inhibits hepatocellular carcinoma invasion and metastasis through Slug and Snail to suppress epithelial-mesenchymal transition
Authors: Liu Yang, Junlu Qiu, Yuzhong Xiao, Xiang Hu, Qing Liu, Li Chen, Wenhuan Huang, Xinxin Li, Limin Li, Jian Zhang, Xiaofeng Ding, Shuanglin Xiang
Journal: Theranostics (2018)

Transcription factor AP-2β plays an important role in human cancer, but its clinical significance in hepatocellular carcinogenesis is largely unknown. Methods: AP-2β expression was detected in human hepatocellular cancer (HCC) tissues and cell lines. The effects of AP-2β on HCC proliferation, migration, invasion, tumor formation and metastasis were evaluated by MTT, colony formation and transwell assays in vitro and mouse experiments in vivo. The association between AP-2β and miR-27a/EMT markers in HCC cell lines and tissues was analyzed. Results: AP-2β expression was decreased in HCC tissues and cell lines. Reduced expression of AP-2β was significantly associated with more advanced tumor stages and larger tumor sizes. The overexpression of AP-2β reduced HCC proliferation, migration, invasion, tumor formation and metastasis in vitro and in vivo. Additionally, AP-2β overexpression increased the sensitivity of HCC cells to cisplatin. Moreover, AP-2β modulates the levels of EMT markers through Slug and Snail in HCC cell lines and tissues. Furthermore, oncogenic miR-27a inhibits AP-2β expression by binding to the AP-2β 3' untranslated region (UTR) and reverses the tumor suppressive role of AP-2β. Conclusion: These results suggested that AP-2β is lowly expressed in HCC by inhibiting EMT signaling to regulate HCC cell growth and migration. Therefore, AP-2β in the novel miR-27a/AP-2β/Slug/EMT regulatory axis enhances the chemotherapeutic drug sensitivity of HCC and might represent a potential target for evaluating the treatment and prognosis of human HCC.
LGG-15. REQUIREMENT OF ADJUVANT TREATMENT IN CHILDHOOD LOW GRADE GLIOMAS (LGG) OF THE SPINAL CORD: EXPERIENCES FROM THE GERMAN LGG STUDY GROUP
Authors: Thomas Perwein, Martin Benesch, Daniela Kandels, Torsten Pietsch, Beate Timmermann, Brigitte Bison, Monika Warmuth-Metz, Astrid Katharina Gnekow
Journal: Neuro-Oncology (2018)

To evaluate the risk of progression and the proportion of patients with childhood spinal cord LGG requiring multiple treatments. Clinical data-sets of 117 pediatric patients (male, n=74; median age 8 [range, 0.7-16.2] years) registered in the prospective multicenter trials HIT-LGG-1996 (n=36), SIOP-LGG-2004 (n=56) and the subsequent LGG-Interim registry (n=25) were analyzed (median follow-up 6.6 years). 107 patients were observed following complete (n=22) or partial resection (n=73), biopsy (n=20), or radiologic diagnosis only (n=2). 10 patients received initial chemotherapy (n=8) or irradiation (n=2). 60 of 107 initially observed patients (56%) developed radiological/clinical progressive disease. Median time to progression was 7 months (range, 0.1-11 years) after diagnosis. 10-year event-free survival (EFS) of the entire cohort was 33.5 ± 5.5%. Overall, 43 patients underwent 2-4 surgical interventions and 42 patients (36%) required adjuvant treatment (chemotherapy, n=21; radiotherapy, n=11; multimodal treatment, n=10). 10-year PFS after chemo- and radiotherapy was 37.7 ± 9.7% and 59.5 ± 16.2%, respectively. Disease control (median, 5.1 years) was achieved in 70 patients (67%) after one (n=52) or repeated (n=18) resections, in 12/21 after chemotherapy, 11/11 after irradiation and 5/10 patients with multimodal treatment. 10-year overall survival (OS) was 92.7 ± 2.8%. Patients with dissemination (n=16) had inferior OS and EFS, while age ≥11 years and complete resection were favorable factors for EFS. The majority of children with spinal LGG experience progressive disease, even after years, and more than a third require repeated resections and/or adjuvant treatment. Despite frequent progression following adjuvant chemo-/radiotherapy, long-term disease control is achieved even in cases with multiple progressions.
Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes
Authors: Špela Konjar, Ulrika C. Frising, Cristina Ferreira, Reinhard Hinterleitner, Toufic Mayassi, Qifeng Zhang, Birte Blankenhaus, Nejc Haberman, Yunhua Loo, Joana Guedes, Marta Baptista, Silvia Innocentin, Joerg Stange, Douglas Strathdee, Bana Jabri, Marc Veldhoen
Journal: Science Immunology (2018)

The semi-activation state of IELs is maintained by an altered cardiolipin makeup of their mitochondrial membranes.
Diagnosis and selection of method of combined treatment of local-distributed cancer of the rectum with invasion into organs of the genitals
Authors: S. Lukmonov, O. Usmanov, K. Madatov, U. Allazarov, U. Kurbankulov, M. Ismailov
Journal: Annals of Oncology (2018)

Introduction: Diagnosis optimization and treatment choice of the locally advanced rectal cancer with invasion in the organs of the genitals. Methods: We analyzed the results of combined operations for rectal cancer with invasion in the genital organs, for 2013-2017 on the basis of the Department of Oncology and Radiology of the Tashkent Medical Academy. Under our supervision, there were 118 women aged 21 to 68 years. Methods of examination of patients included the following: colonoscopy with biopsy, irrigoscopy, transrectal ultrasonography (TRUS), CT, hysteroscopy. 12 patients underwent hormonal status examination. The tumor in the rectosigmoid section of the rectum was in 12 patients, in the upper ampullar department in 17 patients, in the middle-ampullar department in 32 patients, in the lower ampullar department in 45 patients, in the anal canal in 12 patients. The nature of operations on the rectum with combined surgical interventions was as follows: abdominal perineal extirpation of the rectum with sigmostomy was performed in 57 patients (48.3%), abdominal-anal rectal resection in 22 patients (18.6%), anterior resection of the rectum in 12 patients (10.2%), Hartmann's operation was performed in 27 patients (22.9%). Results: Vaginal resections were performed most often in 58 patients, nasal amputation of the uterus without appendages in 21, extirpation of the uterus with appendages in 22 patients, removal of the uterine appendages in 31 patients. It should be noted that more than one organ was resected or removed in 14 patients from these patients. It is important to note that the metastatic lesion of regional lymph nodes was established in 28.0% of patients (in 33 of 118), whereas for all radically operated patients this indicator was 29.1%. Postoperative complications of a purulent-inflammatory nature occurred in 21 patients (17.7%). The overall lethality was 3.4%, 4 patients from 118 patients died after combined operations. The incidence of relapse after combined operations for colorectal cancer was 28%. The average duration without a relapse period was 14 months. 5-year survival after combined operations with locally advanced rectal cancer in our observations was 47.1%. Conclusion: Thus, the data presented indicate that such important indicators as the rate of recurrence (28%), 5-year survival (47.1%), with combined interventions and standard volume operations for colon cancer are approximately the same. Given that the true invasion of a tumor into neighboring structures can often be established only after histological examination of a distant macro preparation and that combined surgical interventions currently do not actually worsen the immediate results of treatment (according to the number of postoperative complications and lethality from them), then the expediency of their implementation in our opinion there is no doubt.