tbuckley/cabot-search huggingface dataset:
GCT-76. 24Gy WHOLE VENTRICULAR RADIOTHERAPY ALONE IS SUFFICIENT FOR DISEASE CONTROL IN LOCALISED GERMINOMA IN CR AFTER INITIAL CHEMOTHERAPY – EARLY RESULTS OF THE SIOP CNS GCT II STUDY
Authors: Gabriele Calaminus, Brigitte Bison, Cecile Faure-Conter, Didier Frappaz, Andreas Peyrl, Nicolas Gerber, Jans-Enno Müller, Ajithkumar Thankamma, Dipayan Mitra, Justin Cross, Torsten Pietsch, Colin Smith, Kristin Solem, Irene Devenney, Maria Luisa Garre, Herve Brisse, Martin Zimmermann, Rolf-Dieter Kortmann, Claire Alapetite, James Nicholson
Journal: Neuro-Oncology (2020)

Abstract SIOP CNS GCT II aimed to establish if 24Gy Whole Ventricular Radiotherapy (WVRT) in localised germinoma is sufficient for tumour control. After central review of radiological response after ‘CarboPEI’ chemotherapy, patients in complete remission (CR) were consolidated with 24Gy WVRT. Between 2/2012 and 7/2018, 182 patients from 8 European countries with histologically-confirmed fully-staged localised germinoma were registered. 70 patients were in CR after chemotherapy, 98 in partial remission (PR), seven had stable disease, two progressive disease, and in five no response data were documented. Of the 70 patients in CR, 58 received 24Gy WVRT alone; two of these relapsed, one local and one disseminated, two and six years after diagnosis. Of the 98 patients in PR after chemotherapy, 86 received 24Gy WVRT and 16Gy boost, of which five relapsed (three local, two distant) 12–24 months from diagnosis. Twelve patients in each of the CR/PR groups received non-protocol or undocumented radiotherapy fields/doses. Median follow-up was 3.7 years. Event-free survival (EFS) for patients in CR and with WVRT only (n=58) was 98% at 4 years. 4-years EFS of patients with PR and WVRT 24Gy and 16Gy tumor boost (n=86) was 95%. Localised germinoma in CR after chemotherapy had an excellent outcome with 24Gy WVRT alone; 24GY WVRT can therefore be considered standard consolidation treatment in this group. International consensus on radiological response criteria is of utmost importance to avoid over- and undertreatment of such patients and to pave the way for further treatment reduction in this group of patients.
A Klebsiella pneumoniae ST307 outbreak clone from Germany demonstrates features of extensive drug resistance, hypermucoviscosity, and enhanced iron acquisition
Authors: Stefan E. Heiden, Nils-Olaf Hübner, Jürgen A. Bohnert, Claus-Dieter Heidecke, Axel Kramer, Veronika Balau, Wolfgang Gierer, Stephan Schaefer, Tim Eckmanns, Sören Gatermann, Elias Eger, Sebastian Guenther, Karsten Becker, Katharina Schaufler
Journal: Genome Medicine (2020)

Abstract Background Antibiotic-resistant Klebsiella pneumoniae are a major cause of hospital- and community-acquired infections, including sepsis, liver abscess, and pneumonia, driven mainly by the emergence of successful high-risk clonal lineages. The K. pneumoniae sequence type (ST) 307 lineage has appeared in several different parts of the world after first being described in Europe in 2008. From June to October 2019, we recorded an outbreak of an extensively drug-resistant ST307 lineage in four medical facilities in north-eastern Germany. Methods Here, we investigated these isolates and those from subsequent cases in the same facilities. We performed whole-genome sequencing to study phylogenetics, microevolution, and plasmid transmission, as well as phenotypic experiments including growth curves, hypermucoviscosity, siderophore secretion, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance for an in-depth characterization of this outbreak clone. Results Phylogenetics suggest a homogenous phylogram with several sub-clades containing either isolates from only one patient or isolates originating from different patients, suggesting inter-patient transmission. We identified three large resistance plasmids, carrying either NDM-1, CTX-M-15, or OXA-48, which K. pneumoniae ST307 likely donated to other K. pneumoniae isolates of different STs and even other bacterial species (e.g., Enterobacter cloacae ) within the clinical settings. Several chromosomally and plasmid-encoded, hypervirulence-associated virulence factors (e.g., yersiniabactin, metabolite transporter, aerobactin, and heavy metal resistance genes) were identified in addition. While growth, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance were comparable to several control strains, results from siderophore secretion and hypermucoviscosity experiments revealed superiority of the ST307 clone, similar to an archetypical, hypervirulent K. pneumoniae strain (hvKP1). Conclusions The combination of extensive drug resistance and virulence, partly conferred through a “mosaic” plasmid carrying both antibiotic resistance and hypervirulence-associated features, demonstrates serious public health implications.
IMMU-14. ONCOLYTIC ADENOVIRUS DELTA-24-RGD ENGINEERED TO EXPRESS 4-1BBL AS A THERAPEUTIC APPROACH FOR DIPG
Authors: Virginia Laspidea, Montserrat Puigdelloses, Naiara Martinez-Velez, Marc Garcia-Moure, Sara Labiano, Iker Ausejo, Ana Patiño-García, Oren J Becher, Hong Jiang, Sumit Gupta, Juan Fueyo, Candelaria Gomez-Manzano, Marta M Alonso
Journal: Neuro-Oncology (2020)

Abstract Despite the advances in our understanding of pediatric diffuse midline gliomas (DMG) they remain the leading cause of pediatric death caused by cancer. Our group has demonstrated that the administration of Delta-24-RGD in DIPG models is safe and therapeutically efficacious. An on-going clinical trial with this virus has proven to be safe for these patients. To further improve the anti-tumoral response of the virus, we armed Delta-24-RGD with 4-1BBL (Delta-24-ACT). 41BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. Here, we showed that in vitro Delta-24-ACT can infect and express 4-1BBL in murine and human DIPG cell lines. Importantly, 4-1BBL expression in DIPG cell lines was able to activate lymphocytes and increase their IFN-gamma production. In addition, Delta-24-ACT triggered immunogenic cell death in DIPG cell lines, as shown by the release of DAMPs such as ATP, HMGB1, Hsp90a and calreticulin translocation. Delta-24-ACT administration in orthotopic DIPG models was well tolerated and safe. We confirmed the expression of the ligand within the tumor. Moreover, using flow cytometry and multispectral immunohistochemistry we observed profound changes in the tumor microenvironment with an increase in the T-cell populations and a remodeling of the myeloid component before and after treatment. Functional studies showed no differences in lymphocytes isolated from mice treated splenocytes but uncovered TILS that showed a significantly increased in the production of IFN-gamma. Delta-24-ACT treatment of mice bearing orthotopic DIPG murine tumors resulted in a significant increase in the median survival and led to free of disease long-term survivors. In summary, Delta-24-ACT is a virus that builds in our clinical experience with Delta-24-RGD in DIPG patients going a step further to boost the antitumor effect of viral therapy while maintaining a safe profile.
Thrombosis and Risk of Mortality in Newly Diagnosed High-Risk Polycythemia Vera: An Analysis of the Medicare Claims Database in the United States
Authors: Naveen Pemmaraju, Aaron T. Gerds, Shreekant Parasuraman, Jingbo Yu, Anne Shah, Ann Xi, Shambhavi Kumar, Robyn M. Scherber, Srdan Verstovsek
Journal: Blood (2020)
New guaiane-type sesquiterpenoid dimers from Artemisia atrovirens and their antihepatoma activity
Authors: Lihua Su, Xintian Zhang, Yunbao Ma, Changan Geng, Xiaoyan Huang, Jing Hu, Tianze Li, Shuang Tang, Cheng Shen, Zhen Gao, Xuemei Zhang, Ji-Jun Chen
Journal: Acta Pharmaceutica Sinica B (2020)

Leading by cytotoxicity against HepG2 cells, bioactivity-guided fractionation of the EtOAc fraction from Artemisia atrovirens led to the isolation of 18 new guaianolide dimers, artematrolides A–R and lavandiolides A, B, C, H, and J. Eight compounds (1, 4, 10, 12, 13, and 19–21) were unambiguously confirmed by the single-crystal X-ray diffraction analyses, and the others were elucidated based on IR, UV, HRESIMS, 1D and 2D NMR experiments, and comparison of the experimental and calculated ECD data. Structurally, all of them were [4 + 2] Diels–Alder adducts of two monomeric guaianolides. The isolates were evaluated for their cytotoxicity against three human hepatoma cell lines, and 19 compounds demonstrated cytotoxicity against HepG2, SMMC-7721, and Huh7 cell lines. Especially, compounds 1, 12, 14, and 15 exhibited cytotoxicity with IC50 values of 4.4, 3.8, 7.6, and 6.7 μmol/L (HepG2), 9.6, 4.6, 6.6, and 6.0 μmol/L (SMMC-7721), and 7.6, 4.5, 6.9, and 5.6 μmol/L (Huh7), respectively. Notably, compound 12 showed the most promising activity against three human hepatoma cell lines and dose-dependently inhibited cell migration and invasion, induced G2/M cell cycle arrest and cell apoptosis in HepG2 cells, down-regulated the expression of BCL-2 and PARP-1, and activated PARP-1 to up-regulate the expression of cleaved-PARP-1.
Simultaneous incorporation of PTH(1–34) and nano-hydroxyapatite into Chitosan/Alginate Hydrogels for efficient bone regeneration
Authors: Zhiyuan Zou, Le Wang, Zhifei Zhou, Qing Sun, Delong Liu, Yan Chen, Hao Hu, Yu Cai, Sixiong Lin, Zhengran Yu, Bizhi Tan, Wei Guo, Zemin Ling, Xuenong Zou
Journal: Bioactive Materials (2020)

Tissue regeneration based on the utilization of artificial soft materials is considered a promising treatment for bone-related diseases. Here, we report cranial bone regeneration promoted by hydrogels that contain parathyroid hormone (PTH) peptide PTH(1–34) and nano-hydroxyapatite (nHAP). A combination of the positively charged natural polymer chitosan (CS) and negatively charged sodium alginate led to the formation of hydrogels with porous structures, as shown by scanning electron microscopy. Rheological characterizations revealed that the mechanical properties of the hydrogels were almost maintained upon the addition of nHAP and PTH(1–34). In vitro experiments showed that the hydrogel containing nHAP and PTH(1–34) exhibited strong biocompatibility and facilitated osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) via the Notch signaling pathway, as shown by the upregulated expression of osteogenic-related proteins. We found that increasing the content of PTH(1–34) in the hydrogels resulted in enhanced osteogenic differentiation of BMSCs. Implantation of the complex hydrogel into a rat cranial defect model led to efficient bone regeneration compared to the rats treated with the hydrogel alone or with nHAP, indicating the simultaneous therapeutic effect of nHAP and PTH during the treatment process. Both the in vitro and in vivo results demonstrated that simultaneously incorporating nHAP and PTH into hydrogels shows promise for bone regeneration, suggesting a new strategy for tissue engineering and regeneration in the future.
Expression of CCR6 and CXCR3 by activated CD8+ T lymphocytes following immunotherapeutic vaccination correlates with enhanced survival
Authors: Irene M. Mullins, Craig L. Slingluff, Sara G. Anderson, Jae K. Lee, Melanie E. Mayer, William A. Knaus, David W. Mullins
Journal: Cancer Research (2004)

1409  Immunotherapy based on the induction of antigen-specific CD8+ T cell responses has generated inconsistent results in multiple clinical trials. An understanding of the phenotypic characteristics of effector and memory T cells induced by vaccination may provide insights into the mechanisms of success or failure of immunotherapies. Because multiple studies have demonstrated the role of chemokine receptors in determining T cell migration characteristics and functionality, we evaluated the expression of select CCR molecules on activated CD8+ T-cells derived from tumor-involved lymph node or peripheral blood of forty melanoma patients with stage III or stage IV disease. CCR gene expression was evaluated by multiplex RT-PCR using gene-specific primers, and surface protein expression was assessed by flow cytometry using specific monoclonal antibodies. Regardless of disease stage or prior therapy, the molecules CCR1, CCR3, CCR7, and CXCR4 were consistently expressed by CD8+CD45RO+ cells. In twenty patients with stage III and IV disease who received no immuntherapy, variable expression of CCR2, CCR4, CCR5, CCR6, and CXCR3 was observed; however, there was no correlation between receptor expression pattern and survival post-diagnosis. In all melanoma patients with stage III disease who were vaccinated with melanoma-associated peptides in combination with GM-CSF, two distinct clusters of CCR expression emerged. CCR6 and CXCR3 message constructs and surface protein were absent in CD8+CD45RO+ T cells from five patients, with mean survival post-vaccination of 14.4±3.1 months. In contrast, five patients with CD8+CD45RO+ T cells that maintained expression of CCR6 and CXCR3 exhibited enhanced post-vaccination survival (22.6±3.3 months, P   0.1). Therefore, vaccination strategies that induce antigen-specific effector CCR6+CXCR3+CD8+ T cells may offer an advantage in the control of early or moderate-stage disease.
RBIO-03. HETEROGENEITY OF HUMAN PATIENT-DERIVED XENOGRAFTS GROWTH RATES RESPONSES TO THE RADIATED MICROENVIRONMENT
Authors: Jibo zhang, Ian E Olson, Lucas P Carlstrom, Masum Rahman, Karishma Rajani, Kshama Gupta, Libo Liu, Zhi Tang, Eliot F Sananikone, Anqin Dong Dong, Arthur E Warrington, Moses Rodriguez, Jincao Chen, Mark A Schroeder, Samar Ikram, Jann Sarkaria, Sandeep Burma, Terry C Burns
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Radiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumors are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. METHODS Female athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected patient-derived xenograft (PDX) GBM cell lines (GBM 6, 10, 12, 39, 46, 76, 123, 164, 196; total n=8-15, per group, per line). Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. RESULT Of nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196). However, two lines yielded prolonged survival in the pre-radiated brain (GBM 10, 12); GBM 39, 123 whose rate of growth was not impacted by the radiated brain. CONCLUSION These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.
Maternal health, in-utero, and perinatal exposures and risk of thyroid cancer in offspring: a Nordic population-based nested case-control study
Authors: Cari M Kitahara, Dagrun Slettebø Daltveit, Anders Ekbom, Anders Engeland, Mika Gissler, Ingrid Glimelius, Tom Grotmol, Ylva Trolle Lagerros, Laura Madanat-Harjuoja, Tuija Männistö, Henrik Toft Sørensen, Rebecca Troisi, Tone Bjørge
Journal: The Lancet Diabetes & Endocrinology (2020)
RARE-31. RECURRENT CHOROID PLEXUS CARCINOMA IN THE SETTING OF LI-FRAUMENI SYNDROME: REPORT OF TWO CHILDREN MANAGED WITH INTENSIVE RE-INDUCTION AND MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITHOUT IRRADIATION FOLLOWED BY MOLECULARLY-TARGETED BIOLOGICAL THERAPY
Authors: Margaret Shatara, Iwona Filipek, Maciej Ciołkowski, Paweł Kowalczyk, Diana S Osorio, Mohamed S AbdelBaki, Elizabeth A Varga, Rolla Abu-Arja, Claire Heinerich, Daniel R Boué, Christopher R Pierson, Jeremy Jones, Catherine E Cottrell, Elaine R Mardis, Richard K Wilson, Jeffrey R Leonard, Jonathan L Finlay
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The optimal management for children with recurrent choroid plexus carcinoma (CPC), is not established. We report two children with germline TP53 mutations, whose CPC relapses were managed with marrow-ablative chemotherapy and oral biologically-targeted therapies. PATIENTS: Patient A: A 17 months old male presented with non-metastatic bilateral CPC. A de novo mosaic germline TP53 mutation was identified. After near-total resections, 16 months of standard chemotherapy were administered; 18 months later, localized tumor growth developed, again near-totally resected. Two cycles of re-induction chemotherapy were administered followed by three cycles of thiotepa/carboplatin with autologous hematopoietic cell rescue (AuHCR) and subsequently 21 months of sirolimus and thalidomide, continuing without residual or recurrent disease. Patient B: A 30 months old male presented with left lateral ventricular non-metastatic CPC. A de novo TP53 germline mutation was identified. Following sub-total resection, craniospinal irradiation with boost was administered followed by eight cycles of standard chemotherapy; 18 months later, localized recurrence developed; gross total resection was followed by 15 months of standard dose chemotherapies; four months thereafter, a second local recurrence developed, again gross totally resected. He then received one cycle of high-dose cyclophosphamide followed by three cycles of thiotepa/carboplatin with AuHCR. Subsequently he received sirolimus and thalidomide for 12 months, complicated by progressive pancytopenia. A small localized CPC recurrence was noted, gross totally resected, concomitant with myelodysplastic syndrome; he underwent an allogeneic matched unrelated donor marrow transplantation. CONCLUSIONS Marrow-ablative chemotherapy with post-transplant targeted biological therapy may afford durable survival for select children with recurrent CPC.
Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies
Authors: Reuben Benjamin, Charlotte Graham, Deborah Yallop, Agnieszka Jozwik, Oana C Mirci-Danicar, Giovanna Lucchini, Danielle Pinner, Nitin Jain, Hagop Kantarjian, Nicolas Boissel, Marcela V Maus, Matthew J Frigault, André Baruchel, Mohamad Mohty, Athos Gianella-Borradori, Florence Binlich, Svetlana Balandraud, Fabien Vitry, Elisabeth Thomas, Anne Philippe, Sylvain Fouliard, Sandra Dupouy, Ibtissam Marchiq, Maria Almena-Carrasco, Nicolas Ferry, Sylvain Arnould, Cyril Konto, Paul Veys, Waseem Qasim, Reuben Benjamin, Charlotte Graham, Deborah Yallop, Agnieszka Jozwik, Antonio Pagliuca, Ghulam Mufti, Piers Patten, Shireen Kassam, Stephen Devereux, Majid Kazmi, Kirsty Cuthill, Victoria Potter, Andrea Kuhnl, Victoria Metaxa, Laarni Bonganay, Orla Stewart, Rose Ellard, Lorraine Catt, Jen Lewis, Farzin Farzaneh, Jackie Chappell, Alice Mason, Vicky Chu, Alan Dunlop, Adeel Saleem, Gary Cheung, Helena Munro, Elka Giemza, Waseem Qasim, Paul Veys, Oana Ciocarlie, Giovanna Lucchini, Danielle Pinner, Jan Chu, Persis Amrolia, Kanchan Rao, Robert Chiesa, Juliana Silva, Annette Hill, Maria Finch, Lindsey Young, Harvinder Hara, Sujith Samarasinghe, Anupama Rao, Ajay Vora, Kimberley Gilmour, Christine Rivat, Clare Murphy, Gulrukh Ahsan, Rasha Said Shamsah, Jesmina James, Sarah Inglott, Gary Wright, Stuart Adams, Natalia Izotova, Nitin Jain, Marina Konopleva, William Wierda, Elias Jabbour, Hagop Kantarjian, Partow Kebrieai, Emily Jones, Kara McGee, Marcela Maus, Matthew Frigault, Jami Brown, Vesselina Toncheva, Keagan Casey, Hanno Hock, Meaghan A McKeown, Richard Mathews, Thomas Spitzer, Nicolas Boissel, Emmanuel Raffoux, Etienne Lengliné, Raphael Itzykson, Florence Rabian, Jérôme Larghero, Isabelle Madelaine, Elie Azoulay, Emmanuelle Clappier, Sophie Caillat-Zucman, Martine Meunier, Karine Celli-Lebras, Marie-Thérèse Tremorin, André Baruchel, Karima Yakouben, Françoise Mechinaud-Heloury, Audrey Grain, Aurélia Alimi, Julie Roupret, Delphine Chaillou, Jérôme Larghero, Isabelle Madelaine, Hélène Cavé, Aurelie Caye-Eude, Odile Fenneteau, Elodie Lainey, Jerome Naudin, Mohamad Mohty, Eolia Brissot, Remy Dulery, Florent Malard, Clémence Mediavilla, Agnès Bonnin, Anne Vekhoff, Tounes Ledraa, Jérôme Larghero, Anne Daguenel-Nguyen
Journal: The Lancet (2020)
Targeting neuroplasticity in patients with neurodegenerative diseases using brain stimulation techniques
Authors: Ti-Fei Yuan, Wei-Guang Li, Chencheng Zhang, Hongjiang Wei, Suya Sun, Nan-Jie Xu, Jun Liu, Tian-Le Xu
Journal: Translational Neurodegeneration (2020)

Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD). Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity, which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers. In this review, we discuss several brain stimulation techniques, with a special emphasis on transcranial magnetic stimulation and deep brain stimulation (DBS), and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD. The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases. However, current brain stimulation techniques, with a notable exception of DBS for PD treatment, cannot serve as adequate clinical tools to assist in the diagnosis, treatment, or prognosis of individual patients with AD or PD. Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD.
Venoarterial Extracorporeal Membrane Oxygenation to Heart Transplant—An Inflamed Bridge?
Authors: Muddassir Mehmood
Journal: JAMA Cardiology (2020)

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