tbuckley/cabot-search huggingface dataset:
MBCL-07. NON-METASTATIC MEDULLOBLASTOMA OF EARLY CHILDHOOD: RESULTS FROM THE PROSPECTIVE CLINICAL TRIAL HIT-2000 AND AN EXTENDED VALIDATION COHORT
Authors: Martin Mynarek, Katja von Hoff, Torsten Pietsch, Holger Ottensmeier, Monika Warmuth-Metz, Brigitte Bison, Stefan Pfister, Andrey Korshunov, Tanvi Sharma, Natalie Jaeger, Marina Ryzhova, Olga Zheludkova, Andrey Golanov, Elisabeth Jane Rushing, Martin Hasselblatt, Arend Koch, Ulrich Schüller, Andreas von Deimling, Felix Sahm, Martin Sill, Markus J Riemenschneider, Hildegard Dohmen, Camelia-Maria Monoranu, Clemens Sommer, Ori Staszewski, Christian Mawrin, Jens Schittenhelm, Wolfgang Brück, Katharina Filipski, Christian Hartmann, Matthias Meinhardt, Klaus Pietschmann, Christine Haberler, Irene Slavc, Nicolas U Gerber, Michael Grotzer, Martin Benesch, Paul-Gerhardt Schlegel, Frank Deinlein, André O von Bueren, Carsten Friedrich, Denise Obrecht, Gudrun Fleischhack, Robert Kwiecien, Andreas Faldum, Rolf-Dieter Kortmann, Marcel Kool, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To avoid craniospinal irradiation (CSI) in children younger than four years with non-metastatic medulloblastoma by chemotherapy, intraventricular methotrexate and risk-adapted local radiotherapy. PATIENTS AND METHODS Eighty-seven patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for non-response or progression. After 2006, local radiotherapy was introduced for non-responders or classic (CMB), anaplastic or large-cell medulloblastoma (LCA). Infantile SHH-activated medulloblastomas (SHH_INF) were subdivided by DNA-methylation profiling. Survival in SHH_INF subtypes were also assessed in a validation cohort (n=71). RESULTS Patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) (n=42) had 93% 5-year PFS, 100% 5-year OS and 93% 5-year CSI-free survival. Patients with CMB/LCA (n=45) had 37% 5y-PFS, 62% 5y-OS and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in CMB/LCA patients. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH_INF subgroup. Group 3 patients (5y-PFS 36% [n=14]) relapsed more frequently than SHH_INF (5y-PFS 93% [n=28]) or Group 4 patients (5y-PFS 83% [n=6], p&amp;lt;0.001). SHH_INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I 73% vs. iSHH-II 83%, p=0.25, n=99). Mean IQ was 90 (radiotherapy-free survivors) vs. 74 (patients that received CSI) [p=0.012]. CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH-subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in non-WNT/non-SHH CMB/LCA patients was not improved by local radiotherapy. Survival was more favorable in patients with Group 4 than in patients with Group 3 medulloblastoma.
P16.08 Inhibition of melanoma brain metastasis by targeting miR-146a
Authors: J Wang, E K Rigg, T R Lunavat, W Zhou, Z Feng, T Hoang, R Bjerkvig, F Thorsen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Melanoma has the highest propensity of any cancer to metastasize to the brain, with late-stage patients developing brain metastasis (MBM) in 40% of cases. Survival of patients with MBM is around 8 months with current therapies, illustrating the need for new treatments. MBM development is likely caused by molecular interactions between tumor cells and the brain, constituting the brain metastatic niche. miRNAs delivered by exosomes released from the primary tumor cells may play a role in niche establishment, yet the mechanisms are poorly understood. Here, the aim was to identify miRNAs released by exosomes from melanomas, which may be important in niche establishment and MBM progression. MATERIAL AND METHODS miRNAs in exosomes collected from human astrocytes, melanocytes, and MBM cell lines were profiled to determine differential expression. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR knockdown in MBM cell lines. An in silico docking study was performed to determine drugs that potentially inhibit transcription of miR-146a to impede MBM development. RESULTS miR-146a was the most upregulated miRNA in exosomes from MBM cells and was highly expressed in human and animal MBM samples. miR-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. In animal studies, knockdown of miR-146 in MBM cells injected intracardially into mice reduced BM burden and increased animal survival. Based on the docking studies, deserpidine was found to be an effective inhibitor of MBM growth in vitro and in vivo. CONCLUSION miR-146a may play an important role in MBM development, and deserpidine is a promising candidate for clinical use.
Covid-19: Failure to control pandemic and inequalities made England worst affected in Europe, says report
Authors: Shaun Griffin
Journal: BMJ (2020)

A failure to control the coronavirus pandemic, coupled with widening inequality over the past decade, has led to England having the highest rate of excess deaths from covid-19 in Europe, a new report concluded. 1Rather than focusing on narrow economic goals, health and wellbeing should be at the heart of government strategy, it says. 1 Institute of Health Equity.Build back fairer: the covid-19 Marmot review.Dec 2020.
IMMU-20. SINGLE-CELL RNASEQ OF TUMOR INFILTRATING IMMUNE CELLS FROM NEOADJUVANT ANTI-PD1 TREATED GBM PATIENTS REVEALS GLOBAL TRANSCRIPTIONAL CHANGES AND IMMUNOSUPPRESSIVE ADAPTIVE RESPONSES BY MYELOID CELLS
Authors: Alexander Lee, Aaron Mochizuki, Frances Chow, Jeremy Reynoso, Joey Orpilla, Lu Sun, Carolina Chavez, Mildred Galvez, Jenny Kienzler, William Yong, Richard Everson, David Nathanson, Steven Bensinger, Linda Liau, Timothy Cloughesy, Willy Hugo, Robert Prins
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Neoadjuvant anti-PD1 therapy (neo-aPD1) was previously shown to significantly increase the survival of recurrent glioblastoma patients in a small randomized clinical trial. However, neo-aPD1 alone was not curative so defining the limitations of neo-aPD1 and discovering where other immunotherapies can be used alongside neo-aPD1 is needed. METHODS To understand how immune cells in the tumor microenvironment change with neo-aPD1, we used single-cell RNAsequencing to analyze cells from 27 glioma patients (n = 105,143 cells) of which 9 patients had received neo-aPD1 (n = 33,325 cells). Using unsupervised clustering and pseudotime trajectory analysis, we characterized the transcriptional changes within immune cells and how these populations changed with therapy. RESULTS We defined the immune landscape of the glioblastoma tumor microenvironment. Compared to no immunotherapy treatment, neo-aPD1 significantly increased the ratio of T cells to myelo-monocytic cells and led to significant increases in the effector and memory T cell populations but no significant changes in myeloid cell composition. Our differential gene expression analysis of the myeloid compartment showed significant increases in interferon-γ-responsive genes and down-regulation of genes associated with M2 macrophages and MDSCs, suggestive that neo-aPD1 influences the transcriptional profile of myeloid cells in the tumor microenvironment. Interestingly, our psuedotime trajectory analysis showed that neo-aPD1 was associated with cells expressing both lymphoid and myeloid-related genes, which we theorized to actually be lymphoid-myeloid cell doublets caused by increased interactions between myeloid and lymphoid cells. These doublets were highly enriched in MHC I and II, macrophage, T cell, and T cell activation and exhaustion genes indicating that neo-aPD1 may result in some adaptive immunosuppressive mechanism by increasing these interactions. This could explain why neo-aPD1 alone is not curative for glioblastoma patients. CONCLUSIONS In total, neoadjuvant anti-PD1 therapy enhances effector T cell activity, but may concomitantly induce adaptive resistance mediated by myeloid cells in glioblastoma.
GCT-19. MODELING GERM CELL TUMORS WITH KIT MUTANT hiPSCs
Authors: Sakura Kuzuoka, Yoji Kojima, Koichi Ichimura, Mitinori Saitou
Journal: Neuro-Oncology (2020)

Abstract Central Nervous System Germ Cell Tumor (CNS GCT) is the second most common pediatric brain tumor in Japan, and within CNS GCT, germinoma is the most common subtype, accounting for 62.3%. Recent reports of transcriptome and methylome analysis suggested that germinoma highly resemble the state of gonocytes, the germ cells at around 5th to 7th week of human embryo development. It is also identified that 60% of germinoma harbored somatic mutations in KIT/RAS pathway. As the protocol to derive gonocytes from human iPSCs have been reported, we aimed to recapitulate tumorigenesis by generating human iPSCs bearing common genetic mutations and derive gonocytes from them. We first introduced the most common mutation KITD816V to human iPSCs using CRISPR/Cas9, and confirmed in iPSCs that mutated KIT was phosphorylated in the absence of ligand stimulation, and also found that KIT activation contribute to the phosphorylation of AKT but not of ERK. Upon differentiation towards primordial germ cell -like cells (PGCLCs), KIT mutant lines were efficiently induced into PGCLCs, however, by comparing conditions with or without KIT ligand (SCF), mutant lines exhibited less dependency to SCF compared to wildtype cells. Mutant cells were further differentiated to gonocytes following published protocol and the cells were collected for transcriptome analysis. By comparing with the transcriptome of germinoma, we confirmed that germinoma samples express germ cell genes similar to gonocytes. We are attempting to identify the molecular mechanism of tumorigenesis in relation to KIT activation using this system.
Stratification of athletes’ gut microbiota: the multifaceted hubs associated with dietary factors, physical characteristics and performance
Authors: Maozhen Han, Kun Yang, Pengshuo Yang, Chaofang Zhong, Chaoyun Chen, Song Wang, Qunwei Lu, Kang Ning
Journal: Gut Microbes (2020)

Gut microbial communities of athletes differ from that of sedentary persons in both diversity and the presence of certain taxa. However, it is unclear to what degree elite athletes and non-elite athletes harbor different gut microbial community patterns and if we can effectively monitor the potential of athletes based on microbiota. A team of professional female rowing athletes in China was recruited and 306 fecal samples were collected from 19 individuals, which were separated into three cohorts: adult elite athlete's (AE), youth elite athlete's (YE), and youth non-elite athlete's (YN). The differences in gut microbiome among different cohorts were compared, and their associations with dietary factors, physical characteristics, and athletic performance were investigated. The microbial diversities of elite athletes were higher than those of youth non-elite athletes. The taxonomical, functional, and phenotypic compositions of AE, YE and YN were significantly different. Additionally, three enterotypes with clear separation were identified in athlete's fecal samples, with majority of elite athletes stratified into enterotype 3. And this enterotype-dependent gut microbiome is strongly associated with athlete performances. These differences in athlete gut microbiota lead to establishment of a random forest classifier based on taxonomical and functional biomarkers, capable of differentiating elite athletes and non-elite athletes with high accuracy. Finally, these versatilities of athlete microbial communities of athletes were found to be associated with dietary factors and physical characteristics, which can in concert explain 41% of the variability in gut microbiome.
Концепция супердонора и другие возможные факторы эффективности трансплантации фекальной микробиоты
Authors: S.M. Tkach, A.E. Dorofeev, Yu.G. Kuzenko
Journal: GASTROENTEROLOGY (2020)

Трансплантация фекальной микробиоты (ТФМ) является высокоэффективной терапевтической процедурой для лечения рецидивирующей инфекции Clostridium difficile. Между тем эффективность ТФМ для лечения других хронических заболеваний, связанных с кишечным дисбиозом, до недавнего времени оставалась весьма скромной и очень вариабельной. Ряд исследований, проведенных в последние годы, позволил предположить, что успех ТФМ во многом зависит от микробного разнообразия и состава донорского стула, что привело к концепции существования супердоноров ТФМ, в качестве которых рассматриваются лица, ТФМ от которых сопровождается высокой эффективностью. В обзоре представлены некоторые результаты проведения ТФМ с привлечением супердоноров, рассмотрены возможные механизмы и факторы, влияющие на успех ТФМ. Сделан вывод о том, что высокое разнообразие кишечной микробиоты, особенно у донора, по-видимому, лучше всего предсказывает реакцию пациента на проведение ТФМ. Предполагается, что выявление и последующая подробная характеристика супердонорских кишечных микробиомов неизбежно улучшат наше представление о микробном компоненте хронических заболеваний и позволят в будущем применять ТФМ более целенаправленно.
Phosphodiesterase-4 Activity: A Critical Modulator of Atrial Contractility and Arrhythmogenesis⁎⁎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: David R. Van Wagoner, Bruce D. Lindsay
Journal: Journal of the American College of Cardiology (2012)
LGG-42. BEVACIZUMAB-ASSOCIATED SECONDARY AMENORRHEA AND PREMATURE OVARIAN FAILURE IN ADOLESCENT FEMALE PATIENTS WITH LOW-GRADE CNS DISEASE
Authors: Nataliya Zhukova, Kiri Chan, Kathryne Walshe, Peter A Downie, Paul Wood
Journal: Neuro-Oncology (2020)

Abstract Compelling body of evidence exists to use bevacizumab, a humanized monoclonal anti-VEGF antibody, in selected paediatric patients with low-grade CNS tumours. Common toxicities of bevacizumab, hypertension, proteinuria, epistaxis, mucosal perforation, decreased wound healing are well reported. However, the effect of bevacizumab on female ovarian function and long-term fertility is still being documented. Current evidence for bevacizumab-associated decline in ovarian function is largely from breast and colon cancer cohorts where exposure to multimodal chemotherapy confounds causative relationships. Fertility counseling and oocyte cryopreservation is currently offered as standard of care to post-pubertal females at high risk of infertility due to high-dose radiation and chemotherapy. Adolescent females with low-grade CNS tumours on bevacizumab represent a unique population which could potentially be at high risk for infertility. We report 2 cases of adolescent girls treated with bevacizumab as a single agent and in combination with vinblastine for NF2-associated vestibular schwannomas and brainstem glioma respectively. Both patients were post-pubertal with established menstrual cycles and normal baseline FSH/LH/oestradiol/AMH values prior to commencement of therapy. They became amenorrhoeic shortly after starting of therapy with levels of FSH/LH/oestradiol suggestive of premature ovarian failure. One patient has remained asymptomatic, whereas the other has developed profound post-menopausal symptoms interfering with quality of life which necessitated commencement of hormone-replacement therapy. Appropriate pretreatment fertility investigation and consultation should be offered to all post-pubertal females starting on bevacizumab. Further research into the long-term effects of gonadal toxicity in both females and males with drugs inhibiting angiogenesis is needed.
BIOM-52. A PROGNOSTIC GENE EXPRESSION RISK SCORE FOR MENINGIOMA
Authors: William Chen, Harish N Vasudevan, Abrar Choudhury, Calixto-Hope G Lucas, Stephen Magill, Matthew S Susko, Steve Braunstein, Lauren Boreta, Jean Nakamura, Penny K Sneed, Nancy Ann Oberheim Bush, Javier Villanueva-Meyer, Arie Perry, David Solomon, Michael McDermott, Philip Theodosopoulos, David Raleigh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Clinical biomarkers for identifying patients at risk for recurrence after resection of meningioma are lacking and are needed for guiding adjuvant therapy. The aim of this study was to identify a prognostic gene expression signature for meningioma. METHODS Targeted gene expression analysis was performed on a discovery dataset of 96 meningiomas with suitable tissue identified from a retrospective institutional biorepository. Recurrence was dichotomized based on the median time to local recurrence (TTR). With median follow-up of 6.4 years, the discovery dataset was enriched for clinical endpoints of local recurrence (58%), mortality (42%), and disease-specific mortality (49% of deaths). A 266 gene expression panel was used to interrogate the discovery dataset, and a prognostic gene signature and risk score was generated using prediction analysis for microarrays (PAM) and elastic net regression. The risk score was validated using gene expression data (GSE58037) from 56 meningiomas resected at an independent institution (20% local recurrence, 18% mortality, median follow-up 5.4 years). RESULTS A 36-gene signature was identified achieving an AUC of 0.86 for TTR faster than the median in the discovery cohort. A risk score between 0 and 1 based on this signature was strongly associated with shorter TTR (F-test, P&amp;lt; 0.0001), and on multivariate Cox regression (MVA), was independently associated with recurrence (RR 1.56 per 0.1 increase, 95% CI 1.30–1.90, P&amp;lt; 0.0001) and mortality (RR 1.32 per 0.1 increase, 1.07–1.64, P=0.01) after adjusting for WHO grade, age, extent of resection, and sex. Similarly, in the validation dataset, the gene risk score was correlated with shorter TTR (P=0.002) and associated with mortality on MVA (RR 1.86 per 0.1 increase, 1.19–2.88, P=0.005) after adjustment for WHO grade. CONCLUSIONS The prognostic meningioma gene expression risk score presented here could be useful in identifying patients at higher risk of progression after resection.
ATRT-24. CELL SURFACE PROTEOME ANALYSIS OF ATRT IDENTIFIES TARGETS FOR IMMUNOTHERAPY
Authors: Allison Cole, Eric Hoffmeyer, Marco Zanini, Rajeev Vibhakar, Anandani Nellan, Olivier Ayrault, Siddhartha Mitra
Journal: Neuro-Oncology (2020)

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a rare and fast-growing childhood tumor of the brain and spinal cord. While the recent advances in DNA and RNA sequencing have given deep insights into the biology of cancer, about 90% of ATRTs harbor a single deletion which leads to uncontrolled tumor growth. The lack of targetable genetic abnormalities in ATRT makes it a tough target for therapy and hence radical new approaches are required to develop a treatment. In many cases, the gene expression profile alone DOES NOT represent the presence of the gene product on the surface and cannot detect post-translational modifications such as the addition of sugars which are essential for the interaction of surface proteins with the tumor microenvironment. The ability to escape from surveillance by the immune system is regarded as one of the essential hallmarks of cancer cells. Here we carried out a comprehensive unbiased large-scale surface receptor profiling using high throughput multicolor flow cytometry on surgically resected ATRT patient samples, primary ATRT cell lines, and patient-derived xenograft models. By multiplexing primary samples with antibodies for CD31, CD45, CD11b, CCR2, Cx3cr1, and CD4, and CD8 we eliminated endothelial and immune cells from analysis while also identifying immune populations within the tumor. We identified increased surface expression of CD44, CD146, CD59, CD151, and CD276. These were validated in our screening of primary tumor samples. A combination of CAR-T cell and function-blocking monoclonal antibody approaches have been tested to verify the proof of principle of this approach.
Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells
Authors: Xinxin Yuan, Niansong Qian, Shukuan Ling, Yuheng Li, Weijia Sun, Jianwei Li, Ruikai Du, Guohui Zhong, Caizhi Liu, Guotao Yu, Dengchao Cao, Zizhong Liu, Yinbo Wang, Zhihong Qi, Yingpeng Yao, Fang Wang, Jingjing Liu, Shanshan Hao, Xiaoyan Jin, Yinlong Zhao, Jianqi Xue, Dingsheng Zhao, Xingcheng Gao, Shuai Liang, Youyou Li, Jinping Song, Shuyang Yu, Yingxian Li
Journal: Theranostics (2020)

Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.