tbuckley/cabot-search huggingface dataset:
ENDOSCOPIC ISCHEMIC THERAPY FOR SMALL INTESTINAL POLYPS IN PATIENTS WITH PEUTZ-JEGHERS SYNDROME
Authors: Y Sagara, T Yano, H Sakamoto, Y Kobayashi, M Nagayama, M Sekiya, K Sunada, A Lefor, H Yamamoto
Journal: Endoscopy (2019)

Most polyps in patients with Peutz-Jeghers syndrome (PJS) are pedunculated which is suited to snare polypectomy. To decrease the risk of bleeding or perforation, we perform selective ligation, so-called “ischemic therapy”, using a detachable snare or clip placed endoscopically. Some polyps do not auto-amputate with a single treatment and the efficacy of this technique is unknown. The aim of this study is to determine the efficacy and safety of ischemic therapy.
Risk of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-1RA Therapy
Authors: Chintan V. Dave, Seoyoung C. Kim, Allison B. Goldfine, Robert J. Glynn, Angela Tong, Elisabetta Patorno
Journal: Circulation (2020)

Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits.
BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State
Authors: Lei Wang, Megan Rice, Sandra Swist, Thomas Kubin, Fan Wu, Shengpeng Wang, Simone Kraut, Norbert Weissmann, Thomas Böttger, Matthew Wheeler, Andre Schneider, Thomas Braun
Journal: Circulation (2020)

Vascular smooth muscle cells (VSMCs) show a remarkable phenotypic plasticity, allowing acquisition of contractile or synthetic states, but critical information is missing about the physiologic signals, promoting formation, and maintenance of contractile VSMCs in vivo. BMP9 and BMP10 (bone morphogenetic protein) are known to regulate endothelial quiescence after secretion from the liver and right atrium, whereas a direct role in the regulation of VSMCs was not investigated. We studied the role of BMP9 and BMP10 for controlling formation of contractile VSMCs.We generated several cell type-specific loss- and gain-of-function transgenic mouse models to investigate the physiologic role of BMP9, BMP10, ALK1 (activin receptor-like kinase 1), and SMAD7 in vivo. Morphometric assessments, expression analysis, blood pressure measurements, and single molecule fluorescence in situ hybridization were performed together with analysis of isolated pulmonary VSMCs to unravel phenotypic and transcriptomic changes in response to absence or presence of BMP9 and BMP10.Concomitant genetic inactivation of Bmp9 in the germ line and Bmp10 in the right atrium led to dramatic changes in vascular tone and diminution of the VSMC layer with attenuated contractility and decreased systemic as well as right ventricular systolic pressure. On the contrary, overexpression of Bmp10 in endothelial cells of adult mice dramatically enhanced formation of contractile VSMCs and increased systemic blood pressure as well as right ventricular systolic pressure. Likewise, BMP9/10 treatment induced an ALK1-dependent phenotypic switch from synthetic to contractile in pulmonary VSMCs. Smooth muscle cell-specific overexpression of Smad7 completely suppressed differentiation and proliferation of VSMCs and reiterated defects observed in adult Bmp9/10 double mutants. Deletion of Alk1 in VSMCs recapitulated the Bmp9/10 phenotype in pulmonary but not in aortic and coronary arteries. Bulk expression analysis and single molecule RNA-fluorescence in situ hybridization uncovered vessel bed-specific, heterogeneous expression of BMP type 1 receptors, explaining phenotypic differences in different Alk1 mutant vessel beds.Our study demonstrates that BMP9 and BMP10 act directly on VSMCs for induction and maintenance of their contractile state. The effects of BMP9/10 in VSMCs are mediated by different combinations of BMP type 1 receptors in a vessel bed-specific manner, offering new opportunities to manipulate blood pressure in the pulmonary circulation.
DDEL-06. DRUG INTERACTION BETWEEN EVEROLIMUS AND CANNABIDIOL IN PEDIATRIC PATIENTS WITH SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Ashley Sabus, Shelby Winzent, Molly Hemenway, Jean Mulcahy Levy, Nicholas Foreman
Journal: Neuro-Oncology (2020)

Abstract Tuberous sclerosis complex (TSC) is an autosomal recessive genetic disorder associated with clinical manifestations including subependymal giant cell astrocytomas (SEGA) and seizures. The combination of everolimus and Epidiolex, a purified form of cannabidiol, has become an increasingly common treatment regimen in this population. Everolimus is primarily metabolized via CYP3A4, which may be inhibited by cannabidiol. We seek to describe our institution’s experience with this drug interaction. METHODS: Investigators conducted a retrospective review of neuro-oncology patients with TSC and SEGA who were treated concurrently with everolimus and cannabidiol. Data collected included demographics, body surface area, everolimus dose, everolimus troughs, date of cannabidiol initiation, documented symptoms, liver and renal function tests, and reason for discontinuing therapy. RESULTS: Three patients (ages 11–17 years) met inclusion criteria. All patients were stable on everolimus doses ranging from 6.5 to 9.5 mg/m2/day and achieving trough goals of 5–10 ng/mL. Two to four weeks after initiating cannabidiol, everolimus trough concentrations rose 200–860% above goal. One patient reported new-onset involuntary movements, but no other toxicities were noted. Cannabidiol was discontinued in all cases due to caregiver concerns regarding drug interactions. All patients were able to achieve goal trough concentrations on previously stable doses of everolimus after discontinuing cannabidiol. CONCLUSIONS: Cannabidiol appears to modulate everolimus metabolism leading to significantly elevated serum concentrations. Additional research is required to determine the need for empiric dose adjustments upon cannabidiol initiation. Patient counseling, frequent trough monitoring, and surveillance for adverse effects are crucial for optimizing outcomes in patients prescribed this regimen.
IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA
Authors: Lan Hoang-Minh, Angelie Rivera-Rodriguez, Fernanda Pohl-Guimarães, Seth Currlin, Christina Von Roemeling, Paul Castillo-Caro, Kevin Otto, Carlos Rinaldi, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.
Extensive expansion of the chemical diversity of fusidane-type antibiotics using a stochastic combinational strategy
Authors: Xiaojun Song, Jianming Lv, Zhiqin Cao, Huiyun Huang, Guodong Chen, Takayoshi Awakawa, Dan Hu, Hao Gao, Ikuro Abe, Xinsheng Yao
Journal: Acta Pharmaceutica Sinica B (2020)

Fusidane-type antibiotics, represented by helvolic acid, fusidic acid and cephalosporin P1, are fungi-derived antimicrobials with little cross-resistance to commonly used antibiotics. Generation of new fusidane-type derivatives is therefore of great value, but this is hindered by available approaches. Here, we developed a stochastic combinational strategy by random assembly of all the post-tailoring genes derived from helvolic acid, fusidic acid, and cephalosporin P1 biosynthetic pathways in a strain that produces their common intermediate. Among a total of 27 gene combinations, 24 combinations produce expected products and afford 58 fusidane-type analogues, of which 54 are new compounds. Moreover, random gene combination can induce unexpected activity of some post-tailoring enzymes, leading to a further increase in chemical diversity. These newly generated derivatives provide new insights into the structure‒activity relationship of fusidane-type antibiotics. The stochastic combinational strategy established in this study proves to be a powerful approach for expanding structural diversity of natural products.
Rapid antigen and molecular tests had varied sensitivity and ≥97% specificity for detecting SARS-CoV-2 infection
Authors: Christopher R. Carpenter
Journal: Annals of Internal Medicine (2020)

Source CitationDinnes J, Deeks JJ, Adriano A, et al. Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev. 2020;8:CD013705. https://pubmed.ncbi.nlm.nih.gov/32845525/AbstractClinical Impact RatingsGIM/FP/GP: Emergency Med: Hospitalists: Infectious Disease: Pulmonology: Public Health:
ATRT-32. GENOME-WIDE CRISPR AND SMALL-MOLECULE SCREENS UNCOVER TARGETABLE DEPENDENCIES IN AT/RTs
Authors: Daniel Merk, Sophie Hirsch, Bianca Walter, Lara Häusser, Nicole Persky, David Root, Ulrich Schüller, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2020)

Abstract Brain tumors are the leading cause of cancer-related deaths in children and adolescents. Embryonal brain tumors are a group of high-grade neoplasms which primarily affect young patients, and atypical teratoid rhabdoid tumors (AT/RTs) are the second most common type of tumor within this group. In spite of intensive research efforts and the knowledge of molecular mechanisms driving subgroup-specific heterogeneity within ATRTs, survival estimates stay relatively low as compared to other tumor entities with a median survival of around 17 months. More efficacious and durable therapies are urgently needed to improve the situation of patients. We here used a combination of genome-wide CRISPR dependency screens and small-molecule drug assays to identify genetic vulnerabilities and novel therapeutic targets for this tumor entity. Here, we successfully generated a chemical library that shows preferential activity in AT/RT cell lines, thereby validating our CRISPR approach to identify tumor-specific vulnerabilities. Of note, none of the identified dependencies seemed to be subgroup-specific, suggesting that targets identified here can be used as pan-AT/RT therapeutic avenues. Among others, these include inhibition of EGF signaling and CDK4/6. Our data provide a comprehensive map of dependencies for AT/RTs which will serve as a starting point in the development of targeted therapies for this tumor entity.
TAMI-33. AURKA INHIBITION REPROGRAMS METABOLISM AND IS SYNTHETICALLY LETHAL WITH FATTY ACID OXIDATION INHIBITION IN GLIOBLASTOMA
Authors: Trang Nguyen, Enyuan Shang, Chang Shu, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Catarina Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey Bruce, Peter Canoll, Markus Siegelin
Journal: Neuro-Oncology (2020)

Abstract Aurora kinase A (AURKA) has emerged as a viable drug target for glioblastoma (GBM), the most common malignant primary brain tumor in adults with a life expectancy of 12-15 months. However, resistance to therapy remains a critical issue, which partially may be driven by reprogramming of metabolism. By integration of transcriptome, chromatin immunoprecipitation with sequencing (CHIP-seq.), assay for transposase-accessible chromatin with sequencing (ATAC-seq.), proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming mediated in part by inhibition of MYC targets and concomitant activation of PPARA (e.g. PGC1A) signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate (OCR) fueled by fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1A, a master regulator of oxidative metabolism, upon AURKA inhibition. Silencing of PGC1A reversed the increase in OCR and sensitized GBM cells to AURKA inhibition mediated reduction in cellular viability. CHIP experiments confirmed binding of c-Myc to the promoter region of PGC1A, which is abrogated by AURKA inhibition and in turn unleashed PGC1A expression. ATAC-seq. confirmed higher accessibility of the MYC binding region within the PGC1A promoter. Forced expression of c-Myc blocked AURKA inhibition mediated increase of PGC1A, suggesting that c-Myc acted as a repressor. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with blockers of FAO (etomoxir), which elicited substantial synergistic growth inhibition and extension of overall survival in orthotopic patient derived xenografts of GBM in mice without induction of toxicity in normal tissue. Taken together, these data support that simultaneous targeting of oxidative metabolism and AURKA inhibition might be a potential novel therapy against GBM.
GCT-43. GAIN OF SHORT ARM OF CHROMOSOME 12 IS A MOLECULAR MARKER TO PREDICT PROGNOSIS AND REPRESENTS AN EARLY EVENT IN TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMORS
Authors: Kaishi Satomi, Hirokazu Takami, Shintaro Fukushima, Yoichi Nakazato, Shota Tanaka, Nobuhito Saito, Masayuki Kanamori, Toshihiro Kumabe, Keiichi Kobayashi, Motoo Nagane, Toshihiko Iuchi, Koji Yoshimoto, Masahiro Mizoguchi, Kaoru Tamura, Taketoshi Maehara, Keiichi Sakai, Kazuhiko Sugiyama, Kiyotaka Yokogami, Hideo Takeshima, Masahiro Nonaka, Akio Asai, Ryo Nishikawa, Masao Matsutani, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract Gain of short arm of chromosome 12 (12p) is commonly observed in testicular germ cell tumors (tGCTs) and also seen in intracranial GCTs (iGCTs). However, little is known about the clinical significance of 12p gain in iGCTs. We have collected over 200 fresh frozen tissue samples of iGCTs through the Intracranial Germ Cell Tumor Genome Analysis Consortium in Japan. Firstly, we analyzed DNA methylation profile in 83 iGCTs, 3 tGCTs (seminomas) and 6 normal control samples using Infinium Human Methylation 450K BeadChip array (Illumina, CA, USA) in order to determine 12p gain status. Then, fluorescence in situ hybridization (FISH) study was carried out on 3 mixed iGCT cases using 12p/CEP12 probe (Abbott Molecular, Abbott park, IL, USA). Lastly, 58 iGCTs with clinicopathological information were analyzed for progression-free survival (PFS) and overall survival (OS). Gain of 12p was observed in 100% (3/3) of seminoma, 14% (3/22) of germinoma, 17% (1/6) of mature teratoma, 25% (1/4) of immature teratoma, 55% (11/20) of mixed germ cell tumor, 100% (4/4) of yolk sac tumor, 100% (1/1) of embryonal carcinoma, and 100% (1/1) of choriocarcinoma. In total, 45% (37/83) of iGCT showed 12p gain. Different histological components in each mixed GCT shared the same 12p copy number status within each mixed GCT case. Both PFS and OS were significantly worse in iGCTs with 12p gain (PFS: P=0.027, OS: P=0.0012). Gain of 12p can be a molecular marker to predict prognosis and represents an early event in tumorigenesis prior to histological differentiation in iGCTs.
Corrigendum to: Molecular subgrouping of atypical teratoid/rhabdoid tumors—a reinvestigation and current consensus
Authors: Ben Ho, Pascal D Johann, Yura Grabovska, Mamy Jean De Dieu Andrianteranagna, Fu Pan Yao, Michael Frühwald, Martin Hasselblatt, Franck Bourdeaut, Daniel Williamson, Annie Huang, Marcel Kool
Journal: Neuro-Oncology (2020)

Additional criteria apply.Please refer to protocol 14379-201 for full inclusion and exclusion criteria.† Patients can participate if they had some skin cancers, superficial bladder cancer (cancer that was only on the surface of the lining of the bladder), or carcinoma in situ (cancer that had not spread) of the cervix or breast that had been cured.HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; IGF-1R, insulin-like growth factor 1 receptor; KPS, Karnofsky Performance Scale; RT, radiotherapy; SOC, standard of care; TMZ, temozolomide.
SURG-08. SUPRASELLAR DERMOID CYST IN A PEDIATRIC PATIENT
Authors: Carlos Almeida, Bruna Minniti Mançano, Gisele Caravina Almeida, Gilda D’Agostino Eugui, Carlos Bezerra Cavalcante
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Intracranial dermoid cysts (DC) are rare congenital non-neoplastic lesions that account for 0.04 – 0.6% of all intracranial tumors. They are formed by a fibrous capsule composed of epidermal and dermal derivatives (hair follicles, sebaceous and sweat glands), enclosing a viscous fluid. Intradural DC often arise in the midline and are more common in infratentorial locations. CASE REPORT: A 14-year-old male patient presented with headache, partial motor seizures and behavioral changes. Neurological examination and endocrine workup revealed no abnormalities. Brain magnetic resonance imaging showed a lesion that was 4.4cm x 2.2cm x 4.4cm in size, located at supraselar region, and extended superiorly to the left lateral ventricle and anterolaterally to the left orbitofrontal lobe, associated with hyperintense fat droplets in the right lateral ventricle. We performed a left transventricular microsurgical approach. The tumor capsule was coagulated and opened and a subtotal resection with peacemeal removal of the the lesion was obtained: it had gelatinous consistency, composed of droplets of fat and hair and keratinized scamous epihelium content. A total removal of the DC capsule was not possible due to its firm adherence to optic chiasm and to hypothalamus. Histological examination revealed dermoid cyst. CONCLUSION Surgery is the only effective treatment, and its goal should be the radical resection of the lesion to avoid recurrence. Whenever radical resection is not possible, because of the adhesions of the cyst capsule to surrounding tissues, a subtotal resection with piecemeal removal may be a satisfactory option in such cases to avoid high morbidity.
Characterization of ntES cell derived from clone embryo of cancer cell
Authors: Hiroko Fukasawa, Shuji Hirata, Teruhiko Wakayama, Kazuhiko Hoshi
Journal: Cancer Research (2006)

326  A clone animal, generated by transferring a somatic cell nucleus into an enucleated oocyte, was produced by the reprogramming and re-differentiation of terminally differentiated cells. The “reprogramming factor” and “re-differentiation factor” in ooplasm act on the transferred nucleus in this process, but the molecular identities and mechanisms of action of these factors have not yet been clarified. Furthermore, the clone embryo generated by transfer of the cancer cell nucleus has been reported to be able to arrive at various developmental stages. In the present study, we established the nuclear transfer (nt)-derived embryonic stem (ES) cell lines from the clone embryo of the cancer cell and characterized the ntES cells. The oocytes at the metaphase stage of the second mitosis, retrieved from B6D2F1 female mice, were enucleated in the medium containing cytochalasin B. Nuclei from murine testicular teratocarcinoma cells (PCC) were transferred into the enucleated oocytes using a glass micropipette with a piezo-driven micromanipulator system. The reconstructed oocytes were activated for 6 hr in the medium containing strontium chloride. The development of the clone embryos were observed in vitro. The pronuclei were formed in the nuclear transferred oocytes during activation. 72 h after activation, 30% of the embryos had progressed to the morulae stage. 15% had developed into the blastocyst stage after 96 h of activation. Ten ntES cell lines were established from the blastocysts. The ntES cells uniformly showed a spindle-like shape in contrast to the original PCC cells that exhibited cellular pleomorphism. Moreover, the proliferation rate of the ntES cells was reduced from that of the PCC cells. These results imply that characteristics of cancer in the PCC cells diminishs in the ntES cells. The present study demonstrats that the reprogramming and re-differentiation factors in the ooplasm act not only on the nucleus of the normal somatic cells but also on the nucleus of the cancer cells, and that the ooplasmic factors might be applied to future cancer therapy.
ATRT-20. CDK7 INHIBITION IN AT/RT
Authors: Andrew Morin, Bethany Veo, Susan Fosmire, Michele Crespo, Shadi Zahedi, Rajeev Vibhakar, Jean M Mulcahy Levy
Journal: Neuro-Oncology (2020)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are characterized by loss-of-function mutations in the SMARCB1 component (and less commonly SMARCA4) of the SWI/SNF chromatin-remodeling complex. AT/RT demonstrate an overall silent genomic landscape with epigenetic dysregulation of the genome. CDK7 is a key transcriptional regulator that preferentially phosphorylates the Ser5 and Ser7 positions on RNA Polymerase C terminal domain and is involved early in transcription. In tumor cells, CDK7 is enriched at super enhancers which preferentially regulate genes involved in cell transformation, and expressed at significantly higher levels in transformed tissues than the surrounding normal brain. Our preliminary data shows that CDK7 is expressed in a number of AT/RT tumor cell lines and patient-derived tumor cultures, and that loss of CDK7 function though exposure to the novel CDK7 inhibitor THZ2 results in lack of proliferation at lower doses, and caspase-mediated apoptosis at higher concentrations. shRNA-based inhibition confirms that this effect is due specifically to loss of CDK7. RNA sequencing of cells treated with lower doses of THZ2 show significant alterations in transcript expression consistent with altered balance between antagonistic SWI/SNF and PRC2 chromatin-modeling complex activities, as well as alterations in DNA damage response pathways, cell cycle checkpoints, miRNA transcription, and numerous proliferative factors. THZ2 penetrates the blood brain barrier (BBB), is well tolerated, and results in prolonged survival in murine xenograft models of AT/RT. CDK7 inhibition also synergizes with a number of currently-approved oncology drugs, as well as with ionizing radiation, in order to inhibit AT/RT growth and viability.