tbuckley/cabot-search huggingface dataset:
Diagnostic and Therapeutic Uptake of Intrathyroid Metastasis of Midgut Neuroendocrine Tumor on 68Ga-DOTANOC PET/CT and 177Lu-DOTATATE Imaging
Authors: Lavinia Vija Racaru, Mathieu Sinigaglia, Sebastien Fontaine, Dominique D'Aure, Frederic Courbon, Lawrence Dierickx
Journal: Clinical Nuclear Medicine (2019)

Abstract A 58-year-old woman with 5-year history of grade 1 progressive metastatic intestinal neuroendocrine tumor with metachronous liver metastases initially treated by surgery and liver embolization underwent 68 Ga-DOTANOC PET/CT before 177 Lu-DOTATATE therapy. 68 Ga-DOTANOC PET/CT revealed increased uptake in several liver metastases and right iliac lymph nodes, consistent with radiopeptide therapy, including a hypodense isthmic thyroid nodule. Fine needle ultrasound-guided biopsy of the thyroid nodule was realized. Immunohistochemistry was positive for CD56, chromogranin, and synaptophysin and negative for calcitonin, confirming neuroendocrine tumor intrathyroid metastasis. 177 Lu-DOTATATE SPECT/CT showed therapeutic uptake on the thyroid metastasis.
PI3K/Akt signaling pathway regulates c-Myc via NFkB and GSK3b in mouse iMyc-Em B lymphoma cells
Authors: Ki-Hwan Kim, R. Eric Davis, Seung-Tae Chung, Siegfried Janz
Journal: Cancer Research (2006)

3879  MYC-activating chromosomal t(8;14)(q24;q32) translocations are widely believed to be the initiating oncogenic events in the pathogenesis of the human post-germinal center non-Hodgkin lymphoma, Burkitt lymphoma. To mimic these translocations in transgenic mice, we recently generated three different “iMyc” gene-insertion strains, including iMycEμ, that contain mouse Myc in three different sites of the immunoglobulin heavy-chain gene cluster. Using the B cell lymphoma-derived cell line iMycEμ-1 as a model system, we demonstrated here that inhibition of phosphatidylinositol 3-kinase (PI3K) by the small drug LY294002, or by a dominant negative form of p85, resulted in apoptosis of the lymphoma cells. LY294002 abolished I kappa B alpha (IkBα) kinase activation following hypophosphorylation of the NF-kappaB component, p65. This change coincided with a drop of Myc, which is degraded in the proteasome in a PI3K/Akt-dependent manner via phosphorylation of glycogen synthase kinase (GSK)-3β. Our results suggest that the PI3K/Akt pathway plays an important role in Myc regulation, either through Rel/NFkB-dependent transcription of the inserted iMycEμ gene or the post-transcriptional regulation of Myc protein levels. The iMycEμ mice may provide a good tool for the design and testing of new approaches to treat and prevent MYC-dependent B cell and plasma cell neoplasms in human beings.
Abstract 16543: Concomitant Left Atrial Appendage Closure During Cardiac Surgery: A Meta-analysis
Authors: Saurabh Aggarwal, Abhilash Akinapelli, Amjad Kabach, Mohamed Ayan, Alok Saurav, Ojas Bansal, Aiman Smer, Jitendra Pandya, Manu Kaushik, Venkata Alla
Journal: Circulation (2015)

Introduction: Surgical left atrial appendage (LAA) closure is an option in patients undergoing cardiac surgery who have a history of atrial fibrillation. Despite multiple studies, it is not clear whether LAA closure during cardiac surgery results in improved outcomes. Hypothesis: We hypothesized that LAA closure is associated with significant decrease in risk of stroke and mortality. Methods: We conducted Pubmed, EMBASE and CENTRAL searches for studies comparing cardiac surgery alone or with concomitant LAA closure. Efficacy outcome was future risk of stroke. Safety outcomes were total mortality and postoperative bleeding. Results: A total of six studies with 3267 patients fulfilled the inclusion criteria. Primary surgeries were mitral valve surgeries in four studies and coronary artery bypass grafting in 2 studies. Successful LAA closure confirmed by trans-esophageal echocardiography was achieved in 97.8% of patients. Concomitant left atrial appendage closure was not associated with any significant difference in risk of future stroke (Odds ratio (OR) 0.61, 95% Confidence Interval (CI) 0.30 to 1.24, p=0.12) or recurrence of atrial fibrillation (OR 0.92, 95% CI 0.66 to 1.29, p=0.63). However, the combined procedure was associated with lower long-term mortality (OR 0.41, 95% CI 0.22 to 0.77, p=0.005) when compared to cardiac surgery alone. Conclusions: Concomitant left atrial appendage closure is a safe procedure but is not associated with a significant decrease in future risk of stroke. Patients with LAA closure had significantly lower mortality but this may be related to lower long term use of anticoagulants and bleeding events in this group. These findings need to be investigated further in large prospective studies.
Biomarkers detected in dried blood spots from atopic dermatitis patients strongly correlate with disease severity
Authors: Judith L. Thijs, Renée Fiechter, Barbara Giovannone, Marjolein S. de Bruin‐Weller, Edward F. Knol, Carla A. F. M. Bruijnzeel‐Koomen, Julia Drylewicz, Stefan Nierkens, DirkJan Hijnen
Journal: Allergy (2019)

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GENE-10. DEVELOPMENTAL ORIGINS OF SEX DIFFERENCES IN RESPONSE TO TUMOR SUPPRESSOR LOSS
Authors: Lauren Broestl, Jasmin Sponagel, Nicole M Warrington, Joshua B Rubin
Journal: Neuro-Oncology (2019)

Malignant brain tumors are more common in males regardless of life stage. Sex differences in brain tumor incidence suggest cells may exhibit sex-specific responses to oncogenic stress. Male predominance in brain tumor incidence across the life span suggests this is not a consequence of circulating sex hormones. In the absence of circulating hormones, sex differences can arise from one of two mechanisms: sex chromosome complement or organizational effects of gonadal hormones. We utilized the four core genotypes (FCG) mouse model to investigate these two potential mechanisms. In the FCG model, the testis-determining gene, Sry, is removed from the Y-chromosome and inserted on to an autosome. This results in four genotypes, XY/Sry+ (XY; testes), XY/Sry- (XY; ovaries), XX/Sry+ (XX; testes), and XX/Sry-(XX; ovaries), and allows for the separation of gonadal and chromosomal sex effects. Using astrocytes harvested from FCG pups, we introduced loss of function of the tumor suppressor p53, one of the most commonly mutated genes in pediatric brain cancer, and then assessed cell proliferation, stem cell phenotype, and response to DNA damage. We identified roles for both organizational effects and sex chromosome effects in mechanisms that could underlie increased cancer resistance in females. Following loss of p53 function, astrocytes from mice with ovaries had lower rates of cell proliferation than those from mice with testes, regardless of chromosomal sex. In contrast, XX cells had greater upregulation of pro-apoptotic and senescence-associated genes than XY cells in response to DNA damage, regardless of gonadal sex. Finally, both organizational effects and sex chromosome effects appeared to influence stem cell frequency. These results suggest that multiple developmental mechanisms may contribute to the sex differences observed in pediatric brain cancer. Understanding these mechanisms could lead to the identification of new targets or help guide personalized treatment for pediatric brain tumor patients of both sexes.
Abstract 23: Exosome Inhibition Improved Blood Perfusion in Ischemic Hindlimb of db/db Diabetic Mice
Authors: Zhongjian Cheng, Venkata Naga Srikanth Garikipati, Maria Cimini, Chunlin Wang, May Trungcao, Yan Tang, Yujia Ye, Cindy Benedict, David Goukassian, Suresh K Verma, Raj Kishore
Journal: Circulation Research (2017)

Background: Critical limb ischemia (CLI), a life-threatening condition characterized by pain at rest and tissue loss with ulcer and gangrene, imposes a major public healthy burden, resulting in high mortality and disability. The occurrence of CLI in patients with diabetes mellitus is very frequent. However, the effective therapy for CLI in diabetic patients is absent. Recent studies demonstrated that exosome from diabetic animals/cells has detrimental effects on the post-injury cardiovascular repair. Here, we tested the hypotheses that exosome inhibition in vivo improves blood flow recovery and protects skeletal muscle in ischemic hindlimbs of diabetic db/db mice following surgical ischemia. Methods and Results: Exosomes were isolated from bone-marrow derived progenitor cells or plasma in non-diabetic db/+ and diabetic db/db mice by ultracentrifugation. Diabetic exosome (5 ug/ml) inhibited tube formation of human cardiac microvascular endothelial cells. Unilateral hindlimb ischemia surgery was conducted by ligation of left femoral artery in 12-week old, male db/+ and db/db mice. Exosome inhibitor GW4869 (2 μg/g body weight) was given by intraperitoneal injection every other day for 4 weeks starting from one week before the HLI surgery. HLI mice injected with vehicle served as controls. Mice were divided into four groups: 1) db/+ + vehicle; 2) db/db+ vehicle; 3) db/+ GW4869; 4) db/db + GW4869. GW4869 decreased necrosis and loss of toe/toenail, improved blood flow, enhanced capillary/arterial density, skeletal muscle architecture and cell survival in ischemic hindlimb of diabetic db/db mice 21 days post-ligation. Conclusions: Although preliminary, our experiments suggest that therapeutic targeting of dysfunctional exosome secretion could represent a new avenue for the prevention and treatment of ischemic injury in diabetic patients.
Priorities to reduce the burden of stroke in Latin American countries
Authors: Sheila C Ouriques Martins, Claudio Sacks, Werner Hacke, Michael Brainin, Francisco de Assis Figueiredo, Octávio Marques Pontes-Neto, Pablo M Lavados Germain, Maria F Marinho, Arnold Hoppe Wiegering, Diana Vaca McGhie, Salvador Cruz-Flores, Sebastian F Ameriso, Walter M Camargo Villareal, Juan Carlos Durán, José E Fogolin Passos, Raul Gomes Nogueira, João J Freitas de Carvalho, Gisele Sampaio Silva, Carla H Cabral Moro, Jamary Oliveira-Filho, Rubens Gagliardi, Eduardo D Gomes de Sousa, Felipe Fagundes Soares, Katia de Pinho Campos, Paulo F Piza Teixeira, Ivete Pillo Gonçalves, Irving R Santos Carquin, Mário Muñoz Collazos, Germán E Pérez Romero, Javier I Maldonado Figueredo, Miguel A Barboza, Miguel Á Celis López, Fernando Góngora-Rivera, Carlos Cantú-Brito, Nelson Novarro-Escudero, Miguel Á Velázquez Blanco, Carlos A Arbo Oze de Morvil, Aurora B Olmedo Bareiro, Gloria Meza Rojas, Alan Flores, Jorge Arturo Hancco-Saavedra, Vivian Pérez Jimenez, Carlos Abanto Argomedo, Liliana Rodriguez Kadota, Roberto Crosa, Daissy L Mora Cuervo, Ana C de Souza, Leonardo A Carbonera, Tony F Álvarez Guzmán, Nelson Maldonado, Norberto L Cabral, Craig Anderson, Patrice Lindsay, Anselm Hennis, Valery L Feigin
Journal: The Lancet Neurology (2019)
TMOD-01. CREDENTIALING NOVEL PEDIATRIC GLIOBLASTOMA AND EPENDYMOMA MODELS WITH SINGLE-CELL RNA SEQUENCING
Authors: David Rincon Fernandez Pacheco, Gi Bum Kim, David Saxon, Amy Yang, Sara Sabet, Hannah Park, Shea Chandra, Kristyna Sendivakova, Paul Linesch, Chintda Santiskulvong, Yizhou Wang, Jie Tang, Mariella Filbin, Mario Suva, Moise Danielpour, Joshua Breunig
Journal: Neuro-Oncology (2019)

We have developed a simple and generalizable in vivo method for brain tumor modeling, mosaic analysis by dual recombinase-mediated cassette exchange (MADR). MADR allows for stable labeling of mutant cells expressing transgenic elements from a precisely-defined chromosomal locus. We have demonstrated the power and versatility of MADR by creating novel glioma models with mixed, reporter-defined zygosity, or with “personalized” H3. 3-containing driver mutation signatures from pediatric glioma--each manipulation altering the spatiotemporal profile of resulting tumors. Further we have generated ependymoma models by employing patient-derived fusion driver mutations. Notably, each model displays divergent spatiotemporal tumor expansion profiles and cellular phenotypes. Now, we use single-cell RNA-seq to compare these models to their cells of mutation and to human datasets to elucidate the fundamental transcriptional programs and markers within and across these tumor types. This investigation will assess and credential these models against their clinical counterparts by scrutinizing the resulting datasets and validating their clinical relevance as pre-clinical models for therapeutic discovery and testing.
Dexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia
Authors: Anfang Cui, Heng Fan, Yinliang Zhang, Yujie Zhang, Dong Niu, Shuainan Liu, Quan Liu, Wei Ma, Zhufang Shen, Lian Shen, Yanling Liu, Huabing Zhang, Yuan Xue, Ying Cui, Qinghua Wang, Xinhua Xiao, Fude Fang, Jichun Yang, Qinghua Cui, Yongsheng Chang
Journal: Journal of Clinical Investigation (2019)

Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Krüppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirus-mediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy-induced diabetes.
Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells
Authors: Marion Wobser, Alexandra Weber, Amelie Glunz, Saskia Tauch, Kristina Seitz, Tobias Butelmann, Sonja Hesbacher, Matthias Goebeler, René Bartz, Hella Kohlhof, David Schrama, Roland Houben
Journal: Journal of Hematology & Oncology (2019)

Targeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1). We performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied. While FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation. We demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent.
ATRT-05. PRC1 IS AN ESSENTIAL DEPENDENCY AND THERAPEUTIC TARGET IN SMARCB1 DEFICIENT ATYPICAL TERATOID RHABDOID TUMORS
Authors: Irina Alimova, Ettiene Danis, Marla Weetall, Angelela M Pierce, Ilango Balakrishnan, Dong Wang, Nicholas K Foreman, John Baird, Lindsey Hoffman, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2019)

Atypical Teratoid Rhabdoid Tumors (ATRT) occur in young children with poor survival. ATRT are characterized by the absence of the chromatin remodeling protein SMARCB1 resulting in epigenetic dysregulation. To identify specific epigenetic factors essential for ATRT tumorigenesis, we performed a shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived ATRT cell lines. This unbiased screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as essential for ATRT cell viability. We hypothesized that BMI1 promotes ATRT tumorigenesis by co-operating with SMARCB1 loss to suppress scheduled transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. We found that BMI1 expression is elevated in ATRT patient samples and cell lines compared to the normal pediatric cerebellum. Genetic depletion of BMI-1 suppressed ATRT cell clonogenicity and decreased in vitro stem cell maintenance. Using RNA-seq-based gene set enrichment analysis we show that BMI1 depletion decreases c-MYC driven transcriptomic programs and induces p53 driven apoptotic programs. This suggests that BMI-1 drives ATRT tumorigenesis by promotingc-Myc driven tumor stem cell self-renewal and driving resistance to therapy by inactivating p53 mediated apoptotic pathways. Finally, we sought to evaluate whether BMI1 is a therapeutic vulnerability in ATRT. We found that PTC596, the clinical lead compound inhibitor of BMI-1, significantly inhibited clonogenic potential, decreased S-phase length and induced apoptosis in ATRT cells in vitro. Furthermore, using ChIP-seq we show that PTC596 alters chromatin occupancy of BMI1 away from differentiation associated gene promoters in ATRT cells. In vivo PTC 596 significantly decreased growth of intracranial orthotopic ATRT tumors compared to control animals as evaluated by MRI imaging. Moreover, treated mice survived significantly longer than control animals. These studies are the first pre-clinical validation of PRC1/BMI1 inhibition as a novel therapeutic approach in ATRT.
MEDU-28. ELIMINATING THE ROOT OF MEDULLOBLASTOMA BY TARGETING A VOLTAGE-GATED POTASSIUM CHANNEL
Authors: Jerry Fan, Ronwell Pusong, Sorana Morrissy, Hamza Farooq, Michael Taylor, Xi Huang
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB) is the most common pediatric brain tumor. Current treatment modalities are aggressive and highly toxic to the developing brain, and survivors are left with long term cognitive defects and reduced quality of life. Furthermore, intratumoral heterogeneity and the presence of MB-propagating cells (MPCs) presents a major obstacle in the effective treatment of MB. Rare, self-renewing MPCs sustain long-term tumor maintenance, resist chemotherapy, and are a likely source of disease relapse. Together, these therapeutic challenges underscore the need for novel molecular targets which can eradicate MPCs while sparing the normal developing brain. We identified that the voltage-gated potassium channel KCNB2 is overexpressed in MB. Strikingly, while Kcnb2 is dispensable for normal murine development, loss of Kcnb2 markedly improves survival in genetic MB mouse models. Interestingly, Kcnb2 is enriched in MPCs. Loss of Kcnb2 significantly depletes the MPC population in part through increased differentiation. Prior to our studies, the role of ion channels in tumor-propagating cells was unknown. Our results suggest that the potassium channel KCNB2 plays a crucial role in the self-renewal and maintenance of MPCs, and that anti-KCNB2 therapies may be leveraged to eliminate MPCs and abrogate MB growth. The current study aims to elucidate the cellular and molecular mechanisms through which KCNB2 regulates MB growth.
Lower Risk of Hepatocellular Carcinoma With Tenofovir vs Entecavir in Patients With Chronic Hepatitis B
Authors: Zhihong Liu, Jian Sun, Jinlin Hou
Journal: JAMA Oncology (2019)

To the Editor Dr Choi and colleagues1 reported striking findings in 2 large-scale retrospective cohorts, which indicated that the risk of hepatocellular carcinoma (HCC) was lower in patients with chronic hepatitis B treated with tenofovir than entecavir. We have some concerns about this article.
Jejunal perforation and central retinal vein occlusion in a 55-year-old European man
Authors: Amanda Louise Thomas, Luke Summers, James R Goodhand, Sarah Saunders
Journal: Gut (2019)

A 53-year-old white European male builder presented emergently with haematemesis and melaena. Four months previously, he underwent an exploratory laparotomy, small bowel resection and anastomosis for a spontaneous jejunal perforation. His immediate postoperative course was uneventful. One month prior to this admission he lost the sight in his right eye because of a central retinal vein occlusion (CRVO): blood cultures, vasculitis and thrombophilia screens were negative and an echocardiogram and carotid Dopplers unremarkable. There was no significant family history. For the treatment of his CRVO, he was taking 15 mg of prednisolone daily and 150 mg of aspirin. He consumed 14 units of alcohol per week …