tbuckley/cabot-search huggingface dataset:
IMMU-15. HEPARIN INHIBITS THE EXTRACELLULAR VESICLE-MEDIATED INDUCTION OF IMMUNOSUPPRESSIVE MONOCYTES IN GLIOBLASTOMA
Authors: Benjamin Himes, Cori Fain, Zachariah Tritz, Helen Li, Philipp Geiger, Timothy Peterson, Ian Parney
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common and fatal primary brain tumor in adults. The development of novel therapies is critical, as little has changed regarding the standard of care in nearly two decades. Immunotherapy holds much promise, as treatments including chimeric antigen receptor (CAR) T cells and immune checkpoint blockade inhibitors have transformed the treatment of a number of cancers in recent years. However, GBM patients exhibit profound immunosuppression, limiting the efficacy of these therapies. Understanding the mechanisms of GBM-mediated immunosuppression is critical to overcoming this barrier. GBM-derived extracellular vesicles (EVs) have been shown to mediate the induction of immunosuppressive monocytes, which may point to a mechanism of immunosuppression. EVs make initial contact with target cells through interactions between heparan sulfate proteoglycans, and soluble heparin has been shown to inhibit these interactions in some models. We demonstrate that soluble heparin inhibits the binding of GBM-derived EVs to monocytes in a dose-dependent manner, and that heparin treatment reduces the induction of immunosuppressive monocytes upon in vitro conditioning of monocytes with GBM-derived EVs (p&amp;lt; 0.01). Further, we demonstrate that heparin treated EV-conditioned monocytes are functionally less immunosuppressive than untreated EV-conditioned monocytes as measured by T cell proliferation in co-culture studies (p&amp;lt; 0.05). Taken together, these findings underscore the import of tumor-derived EVs in immunosuppression in GBM, and demonstrate the feasibility of targeting EV-monocyte interactions in treating GBM-mediated immunosuppression.
Sexual health among adolescent and young adult cancer survivors: A scoping review from the Children's Oncology Group Adolescent and Young Adult Oncology Discipline Committee
Authors: Brooke Cherven, Amani Sampson, Sharon L. Bober, Kristin Bingen, Natasha Frederick, David R. Freyer, Gwendolyn P. Quinn
Journal: CA A Cancer Journal for Clinicians (2020)

Abstract Sexual function is a vital aspect of quality of life among adolescent and young adult (AYA) (ages 15‐39 years) cancer survivors. Sexual function encompasses physical, psychosocial, and developmental factors that contribute to sexual health, all of which may be negatively impacted by cancer and treatment. However, limited information is available to inform the care of AYA cancer survivors in this regard. This scoping review, conducted by the Children's Oncology Group AYA Oncology Discipline Committee, summarizes available literature regarding sexual function among AYA cancer survivors, including relevant psychosexual aspects of romantic relationships and body image. Results suggest that, overall, AYA cancer survivors experience a substantial burden of sexual dysfunction. Both physical and psychosocial sequelae influence survivors' sexual health. Interventions to support sexual health and psychosexual adjustment after cancer treatment are needed. Collaborations between the Children's Oncology Group and adult‐focused cooperative groups within the National Cancer Institute's National Clinical Trials Network are warranted to advance prospective assessment of sexual dysfunction and test interventions to improve sexual health among AYA cancer survivors.
Targeted Therapy of <i>TERT</i>-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy
Authors: Jingwei Chen, Christopher Nelson, Matthew Wong, Andrew E. Tee, Pei Y. Liu, Ting La, Jamie I. Fletcher, Alvin Kamili, Chelsea Mayoh, Christoph Bartenhagen, Toby N. Trahair, Ning Xu, Nisitha Jayatilleke, Marie Wong, Hui Peng, Bernard Atmadibrata, Belamy B. Cheung, Qing Lan, Tracy M. Bryan, Pieter Mestdagh, Jo Vandesompele, Valerie Combaret, Valentina Boeva, Jenny Y. Wang, Isabelle Janoueix-Lerosey, Mark J. Cowley, Karen L. MacKenzie, Alla Dolnikov, Jinyan Li, Patsie Polly, Glenn M. Marshall, Roger R. Reddel, Murray D. Norris, Michelle Haber, Matthias Fischer, Xu D. Zhang, Hilda A. Pickett, Tao Liu
Journal: Clinical Cancer Research (2020)

TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma.Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice.The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression.OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: Is it Time to Slacken the Reins?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Bernhard Witzenbichler
Journal: Journal of the American College of Cardiology (2012)
TAMI-48. ENGRAFTMENT PHENOTYPES IN PRECLINICAL MODEL SYSTEMS REVEAL A FUNCTIONAL SUBGROUP OF PATIENT TUMORS DEPENDENT ON THE BRAIN TUMOR MICROENVIRONMENT FOR GROWTH
Authors: Nicholas Bayley, Christopher Tse, Henan Zhu, Weihong Yan, Laura Gosa, Lynn Baufeld, Lisa Ta, Robert Prins, William Yong, Timothy Cloughesy, Linda Liau, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2020)

Abstract The derivation of model systems from patient tumors is a requisite for reproducible and high throughput translational cancer research. However, not all tumors can form a model and those that do often fail to capture the molecular diversity specific to their cancer. The potential tumor-intrinsic underpinnings remain largely unknown. In gliomas, the brain tumor microenvironment (TME) is increasingly acknowledged as a regulator of tumor proliferation, invasion, and therapy response. The dissimilar environment of in vitro and heterotopic xenograft models could potentially play a role in the limited fidelity of these model systems. Here we established a culture-free workflow and biobank of 144 glioma direct-from-patient orthotopic xenografts (DPDOX) and 51 parallel gliomasphere cultures (GS). Our direct-from-patient workflow enabled the exclusive in vivo establishment of several gliomas – hereafter termed TME-dependent tumors – including low and high grade mtIDH gliomas and histone H3.3 G34 glioblastomas notoriously difficult to culture in vitro. Through molecular profiling of over 75 patient tumors and their matched derivative models, we find that DPDOX tumors preserve a gene expression signature of neural and glial interactions not found in GS and enriched in brain TME-dependent patient tumors. While these patient tumors span a diversity of clinical diagnoses, network-based inferred transcription factor activity suggests that they converge on shared master regulators of self-renewal driving proneural and OPC/NPC-like cellular state enrichment. Integrating multi-omic profiling from TCGA and other publicly available datasets reveals that this expression signature corresponds to a shared DNA methylation signature across disparate epigenetic subgroups. These findings suggest a brain TME dependence in patient tumors across multiple molecular and clinical classifications of glioma which leads to a lack of representation in model systems failing to recapitulate tumor-promoting components of the TME. Further this work provides a resource to guide translational investigations accounting for influences of the model environment.
Cost effective quality-of-life and tolerability analysis of first line chemotherapy versus hormone therapy in post menopausal women with limited visceral metastasis from breast cancer
Authors: Suresh Attili, Bapsy Pp, Govind Babu K, Anupama G, Lakshmaiah Kc, RAmachandra C
Journal: Cancer Research (2007)

4288  Aim: Cost effective quality-of-life and tolerability analysis of first line chemotherapy versus hormone therapy in post menopausal women with limited visceral metastasis from breast cancer  Patients and methods: 89 consecutive patients with newly diagnosed metastatic breast cancer were stratified to receive either Letrozole2.5mg daily, if receptor positive or FAC given 3 weekly for maximum of 6 cycles if receptor negative. Patients with extensive visceral metastasis &estimated survival of  Results: Both the groups were evenly matched for age, number of patients, baseline performance status & sites of metastases. Mean TTP was (mean ± SD) 52.6 ± 16.5 weeks in the Letrozole group&56.9±18.3 weeks in chemotherapy group (P = 0.2).Overall response rates were38%in Letrozole group& 45% in chemotherapy group (p=0.7). For all patients, QOL decreased approximately 2 units from thefirst to second assessment. Significant improvement observedat 6 months (P =0.02) was sustained at 12 months (p=0.03), with a better improvement in the hormone therapy arm compared to chemotherapy arm. Grade 3/4 toxicities are more in chemotherapy arm (8.6 ± 2.6) compared to hormone therapy (2.8 ±1.6) p=0.001.The cost of treatment in the Letrozole arm was approximately 16 times less as compared to chemotherapy arm  Conclusion: Although chemotherapy appears to have better TTP and RR as compared to Letrozole It did not reach the statistical significance. The better QOL, low toxicity profile and cost of treatment might favor the later as treatment of choice even in limited visceral metastasis of patients with hormone positive metastatic breast cancer in third world countries like India.
SMYD3–PARP16 axis accelerates unfolded protein response and mediates neointima formation
Authors: Fen Long, Di Yang, Jinghua Wang, Qing Wang, Ting Ni, Gang Wei, Yizhun Zhu, Xinhua Liu
Journal: Acta Pharmaceutica Sinica B (2020)

Neointimal hyperplasia after vascular injury is a representative complication of restenosis. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is involved in the pathogenesis of vascular intimal hyperplasia. PARP16, a member of the poly(ADP-ribose) polymerases family, is correlated with the nuclear envelope and the ER. Here, we found that PERK and IRE1α are ADP-ribosylated by PARP16, and this might promote proliferation and migration of smooth muscle cells (SMCs) during the platelet-derived growth factor (PDGF)-BB stimulating. Using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) analysis, PARP16 was identified as a novel target gene for histone H3 lysine 4 (H3K4) methyltransferase SMYD3, and SMYD3 could bind to the promoter of Parp16 and increased H3K4me3 level to activate its host gene's transcription, which causes UPR activation and SMC proliferation. Moreover, knockdown either of PARP16 or SMYD3 impeded the ER stress and SMC proliferation. On the contrary, overexpression of PARP16 induced ER stress and SMC proliferation and migration. In vivo depletion of PARP16 attenuated injury-induced neointimal hyperplasia by mediating UPR activation and neointimal SMC proliferation. This study identified SMYD3–PARP16 is a novel signal axis in regulating UPR and neointimal hyperplasia, and targeting this axis has implications in preventing neointimal hyperplasia related diseases.
Carbohydrate Requirements for Prolonged, Fasted Exercise With and Without Basal Rate Reductions in Adults With Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion
Authors: Sarah M. McGaugh, Dessi P. Zaharieva, Rubin Pooni, Ninoschka C. D’Souza, Todd Vienneau, Trang T. Ly, Michael C. Riddell
Journal: Diabetes Care (2020)

OBJECTIVE Exercising while fasted with type 1 diabetes facilitates weight loss; however, the best strategy to maintain glucose stability remains unclear. RESEARCH DESIGN AND METHODS Fifteen adults on continuous subcutaneous insulin infusion completed three sessions of fasted walking (120 min at 45% VO2max) in a randomized crossover design: 50% basal rate reduction, set 90 min pre-exercise (−90min50%BRR); usual basal rate with carbohydrate intake of 0.3 g/kg/h (CHO-only); and combined 50% basal rate reduction set at exercise onset with carbohydrate intake of 0.3 g/kg/h (Combo). RESULTS Combo had a smaller change in glucose (5 ± 47 mg/dL) versus CHO-only (−49 ± 61 mg/dL, P = 0.03) or −90min50%BRR (−34 ± 45 mg/dL). The −90min50%BRR strategy produced higher β-hydroxybutyrate levels (0.4 ± 0.3 vs. 0.1 ± 0.1 mmol/L) and greater fat oxidation (0.51 ± 0.2 vs. 0.39 ± 0.1 g/min) than CHO-only (both P &amp;lt; 0.05). CONCLUSIONS All strategies examined produced stable glycemia for fasted exercise, but a 50% basal rate reduction, set 90 min pre-exercise, eliminates carbohydrate needs and enhances fat oxidation better than carbohydrate feeding with or without a basal rate reduction set at exercise onset.
Abstract 14785: The Reactive Lipid Mediators Isolevuglandins Promote Atrial Fibrillation Mediated by Inflammation
Authors: Matthew B Murphy, Tuerdi Subati, Joseph C Van Amburg, Charles D Smart, Ashley L Pitzer, Prince J Kannankeril, Zhenjiang Yang, Joshua M Stark, Isis L Christopher, Annet Kirabo, Meena S Madhur, Joey V Barnett, Dan M Roden, Katherine T MURRAY
Journal: Circulation (2020)

Introduction: Inflammation and oxidative stress are linked to multiple risk factors for atrial fibrillation (AF), and to AF itself in the setting of sterile injury (e.g. after catheter ablation or cardiac surgery). However, anti-inflammatory therapies and conventional antioxidants cause adverse effects or are ineffective to prevent AF. Highly reactive mediators of lipid peroxidation such as isolevuglandins (IsoLGs) have been identified as a major component of oxidative stress-related injury. We hypothesized that during AF promoted by cardiac inflammation, a scavenger of IsoLG will decrease AF susceptibility. Methods: We studied mice with a systemic inflammatory phenotype due to deficiency in the lymphocyte adaptor protein ( Lnk -/- ), a negative regulator of cytokine signaling. At weaning, Lnk -/- mice and their wild-type (WT) littermates received either vehicle or a potent IsoLG scavenger, 2-hydroxybenzylamine (2-HOBA), by oral administration. At age 14 weeks, animals underwent transesophageal burst pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation and IsoLG-adducts. Results: Cardiac histology and echocardiography revealed no major histologic or structural abnormalities in Lnk -/- mice. Nevertheless, Lnk -/- mice demonstrated a significant increase in AF burden compared to WT controls (124.8±43.3 vs 6.8±3 sec, respectively [mean±SEM, n=28, 12; P&lt;0.05]), as well as increased sustained AF (&gt; 30 sec; 48.1% vs 0%; P&lt;0.01]). Leukocyte infiltration was present in the atria of Lnk -/- mice, with a significant increase in CD3, CD19, NK1.1, and CD11b/MHCII positive cells, compared to atria from WT control mice. Furthermore, there was a 2 to 4-fold increase in IsoLG-adducts for Lnk -/- atrial immune cells positive for CD3, CD19, NK1.1 and CD11b/MHCII, compared to cells from WT atria. Lnk -/- mice treated with 2-HOBA had significantly reduced AF burden (4.7±4.5 sec, n=7; P&lt;0.05) with a trend towards reduction in sustained AF (0%, n=7; P=0.057). Conclusions: IsoLGs play a critical role in the pathogenesis of inflammation-mediated AF, and 2-HOBA, a scavenger of IsoLGs, represents a potentially novel therapeutic strategy for AF in this clinical setting.
EPEN-09. IMPACT OF MOLECULAR SUBGROUP ON OUTCOME FOR INFANTS &amp;lt;12 MONTHS WITH INTRACRANIAL EPENDYMOMA - GERMAN EXPERIENCE FROM HIT2000, INTERIM-2000-REGISTRY AND I-HIT-MED REGISTRY
Authors: Denise Obrecht, Martin Mynarek, Katja von Hoff, Hendrik Witt, Kristian W Pajtler, B Ole Juhnke, Monika Warmuth-Metz, Brigitte Bison, Rolf-Dieter Kortmann, Beate Timmermann, Stefan M Pfister, Felix Sahm, Dominik Sturm, Andreas von Deimling, Ulrich Schüller, Torsten Pietsch, Martin Benesch, Nicolas U Gerber, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND For infant ependymoma (EP), decision for radiotherapy during first-line therapy is a dilemma. We analyzed therapy outcomes of EP patients younger than 12 months at diagnosis according to molecular subgroup. PATIENTS AND METHODS Between 2001 and 2017, 30 patients with histological diagnosis of intracranial EP &amp;lt;12 months at diagnosis with DNA-methylation profiling available were registered in HIT-MED-studies/-registries. RESULTS In 3/30, DNA methylation-based CNS tumor classification suggested a diagnosis other than EP or could not be assigned to a reference class. Of the remaining 27 tumors, 16 were classified as PF-A, 8 as RELA-fusion positive and 3 as YAP-fusion positive. Median age at diagnosis was 0.73 (0.30–0.99) years. After a median follow-up time of 5.36 (0.20–12.90) years, 59.3% experienced progressive disease (PD). 5y-PFS and -OS for the whole cohort were 38.2% and 73.1%. RELA- and YAP-fusion positive EP had significantly better OS than PF-A (5y-OS for PF-A: 55.9%; RELA 100%; YAP 100%; p=0.023). PFS was not significantly different. All but one patient with relapsed PF-A died despite multimodal salvage strategies. In contrast, patients with relapsing RELA- and YAP-fusion positive EP (n=5), survived with a combination of re-surgery and first or second local radiotherapy. CONCLUSION In this cohort of infants &amp;lt;12 months, patients with PF-A had a significantly inferior OS compared to patients with RELA- and YAP-fusion positive EP. Salvage therapy was ineffective for patients with PF-A, whereas patients with can RELA- and YAP-fusion positive EP can be long-term survivors after PD. Therefore, subgroups-specific therapy should be discussed.
DDRE-22. NOVEL LonP1 INHIBITORS FOR TARGETING GLIOMA STEM CELLS
Authors: Christopher Douglas, Kaijun Di, Naomi Lomeli, Daniela Bota
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) has an exceptional high rate of reoccurrence that largely explains its &amp;lt; 15 months median survival. LonP1 is a serine protease that degrades misfolded proteins and regulates mitochondrial DNA replication. It drives tumor progression towards a malignant cancer phenotype in colorectal cancer, melanoma, oral cancer and cervical cancer. Dr. Daniela Bota has previously shown that LonP1 is overexpressed in human malignant gliomas and is associated with higher tumor grade and poor survival prognosis. In collaboration with Professor Bhaskar Das, we have used structure activity Relationship (SAR) analysis to generate compounds with on-target inhibition of LonP1 protease activity. Preliminary work on these novel compounds shows that these proprietary inhibitors can drastically decrease cell viability in the established D54 and U251 GBM lines. The lead compound BT317, shows on-target LonP1 and exceptional chymotrypsin-like proteasome inhibition. This has led to further testing, which has shown that BT317 has enhanced activity against glioma stem cell lines (GSC) and can cause global downregulation of hypoxia inducible factor 1 alpha (Hif1α) in a heterogenous GSC-derived organoid model. Finally, we have demonstrated that BT317 has less activity against differentiated GSC lines (e.g. through successive passages) and appears to have enhanced activity against TNFa-induced, differentiated GSC. This preliminary data highlights combinatorial, pharmacological LonP1 and proteasome inhibition as a novel strategy for targeting GSC in GBM.
Optimizing the management of intermediate-stage hepatocellular carcinoma: Current trends and prospects
Authors: Takuji Torimura, Hideki Iwamoto
Journal: Clinical and Molecular Hepatology (2020)

Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.
Addressing Medical Misinformation in the Patient-Clinician Relationship
Authors: Vineet M. Arora, Sonia Madison, Lisa Simpson
Journal: JAMA (2020)

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