tbuckley/cabot-search huggingface dataset:
Classification criteria for autoinflammatory recurrent fevers
Authors: Marco Gattorno, Michael Hofer, Silvia Federici, Federica Vanoni, Francesca Bovis, Ivona Aksentijevich, Jordi Anton, Juan Ignacio Arostegui, Karyl Barron, Eldad Ben-Cherit, Paul A Brogan, Luca Cantarini, Isabella Ceccherini, Fabrizio De Benedetti, Fatma Dedeoglu, Erkan Demirkaya, Joost Frenkel, Raphaela Goldbach-Mansky, Ahmet Gul, Veronique Hentgen, Hal Hoffman, Tilmann Kallinich, Isabelle Kone-Paut, Jasmin Kuemmerle-Deschner, Helen J Lachmann, Ronald M Laxer, Avi Livneh, Laura Obici, Seza Ozen, Dorota Rowczenio, Ricardo Russo, Yael Shinar, Anna Simon, Nataša Toplak, Isabelle Touitou, Yosef Uziel, Marielle van Gijn, Dirk Foell, Claudia Garassino, Dan Kastner, Alberto Martini, Maria Pia Sormani, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. <h3>Methods</h3> Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. <h3>Results</h3> The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). <h3>Conclusion</h3> Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Abstract 18056: Activation of Nox4 Promotes Cardiomyocyte Autophagy and Survival During Nutrient Starvation
Authors: Sebastiano Sciarretta, Peiyong Zhai, Massimo Volpe, Junichi Sadoshima
Journal: Circulation (2012)

Autophagy is an adaptive mechanism for cardiomyocytes (CMs) during energy deprivation (ED), such as myocardial ischemia. The signaling mechanism activating autophagy during ED is not fully understo...
Sixty seconds on . . . moral injury
Authors: Abi Rimmer
Journal: BMJ (2019)

It could be. The term was originally used to describe soldiers’ responses to their actions in war. It’s now used in the US to describe what we would call burnout in the UK.

While the term was first used in a medical context by US based psychiatrist Wendy Dean and reconstructive plastic surgeon Simon Talbot,1 Andrew Goddard, president of the Royal College of Physicians (RCP), has suggested that it could also …
ICA-1: A novel antiproliferative and anticancer drug for neuroblastoma
Authors: Prajit Pillai, Shraddha Desai, David Ostrov, Hla Win, Mildred Acevedo-Duncan
Journal: Cancer Research (2008)

2387  Neuroblastomas are highly lethal tumors and 85% of cerebral neuroblastoma occurs in children and 15% in adults. Neuroblastoma is the fourth most common type of cancer in children. According to the American Cancer Society, there are approximately 650 new cases of neuroblastoma each year in the United States. Despite significant educational efforts, improved diagnostic techniques, and rigorous therapies, neuroblastoma control remains static. To address this health issue, the objectives of this research was to investigate the use protein kinase C-iota (PKC-ι) inhibitors on the proliferation of neuroblastoma cells. Previous work has shown that inhibition of PKC-ι is a promising means by which to prevent and treat certain cancers. Here, we report the identification of a PKC-ι inhibitor (1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy) methyl]cyclopentyl]-,[1R-(1α, 2β, 3β, 4α)] (ICA-1) that targets a unique sequence (amino acid residues 469-475) in the catalytic domain of PKC-ι, inhibits PKC-ι activity and is effective in blocking the proliferation of BE(2)C neuroblastoma cells. Our data support significant proof of concept that ICA-1 inhibits the proliferation of neuroblastoma cells and may be a novel chemotherapeutic for the treatment of patients with neuroblastoma.
Risk factors and complications contributing to mortality in elderly patients with fall-induced femoral fracture: A cross-sectional analysis based on trauma registry data of 2,407 patients
Authors: Sheng-En Chou, Cheng-Shyuan Rau, Yu-Chin Tsai, Shiun-Yuan Hsu, Hsiao-Yun Hsieh, Ching-Hua Hsieh
Journal: International Journal of Surgery (2019)
A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity
Authors: Jodi L. Karnell, Marius Albulescu, Stacey Drabic, Liangwei Wang, Rachel Moate, Manuel Baca, Vaheh Oganesyan, Michele Gunsior, Thomas Thisted, Li Yan, Jing Li, Ximing Xiong, Steven C. Eck, Melissa de los Reyes, Isharat Yusuf, Katie Streicher, Ulf Müller-Ladner, David Howe, Rachel Ettinger, Ronald Herbst, Jörn Drappa
Journal: Science Translational Medicine (2019)

VIB4920, a nonantibody scaffold protein, blocks CD40L and reduces autoantibodies and disease activity in patients with rheumatoid arthritis.
Doctors should have protected time to conduct research in trusts, says college
Authors: Elisabeth Mahase
Journal: BMJ (2019)

More research should be conducted in NHS trusts, with clinicians being given protected time to carry it out, according to the Royal College of Physicians (RCP).1

In the report, launched at the Medicine 2019 annual conference in Manchester on 26 April, the college argued that research active trusts have improved outcomes for patients, as well as improved staff …
HGG-15. SUCCESSFUL TREATMENT OF AN NTRK-FUSION POSITIVE INFANTILE GLIOBLASTOMA WITH LAROTRECTINIB, A TARGETED TRK INHIBITOR
Authors: Robin Buerki, Anuradha Banerjee, Alexandra Zamorski, Michael Cox, Shannon Raber, David Solomon, Sabine Mueller
Journal: Neuro-Oncology (2019)

PURPOSE: Targeted inhibition of NTRK-fusion proteins has shown promise in treatment of infantile fibrosarcoma in a phase 1 open-label study. Herein we report successful treatment of an NTRK-driven infantile glioblastoma with larotrectinib, a small molecule TRK inhibitor. RESULTS: A 2-month-old term female presented with hydrocephalus due to 10-cm right frontal lobe mass plus leptomeningeal (LM) dissemination to the posterior fossa and spinal cord. She underwent a sub-total resection of the supratentorial tumor, which harbored an in-frame TPM3-NTRK1 activating fusion as the solitary pathogenic alteration, absent alterations involving IDH1, IDH2, H3F3A, HIST1H3B, ATRX, TERT, TP53, SETD2, PPM1D, ACVR1, MET, EGFR, PTEN, NF1, BCOR, BCORL1, BRAF, RAF1, FGFR1, CIC, or INI1. She received 1 cycle of oral etoposide without response and then started larotrectinib (LOXO-101) 100 mg/m2 BID (NCT03025360). Due to neutropenia, dose reductions were required to 25 mg/m2BID. Tumor responses noted were an initial decrease in the intensity of LM Gadolinium enhancement followed by measurable decrease in the frontal lobe tumor bulk after 6 cycles. At age 17 months, larotrectinib was held for a procedure (shunt revision) unrelated to the therapy during which time there was evidence of tumor growth. Upon restarting larotrectinib, decrease in the size of intracranial enhancing lesions and stabilization of LM disease was noted again. She is currently 22 months old with resolved neutropenia and is tolerating full dose (100mg/m2BID) larotrectinib. CONCLUSION: Our experience with targeted treatment for NTRK-driven infantile glioblastoma demonstrates favorable early results even in the setting of disseminated disease. However, long-term outcomes for TRK inhibitor therapy have not been established. Treatment with small molecule inhibitors targeting the kinase gene fusions that are frequent in infantile glioblastomas may allow for delaying radiation therapy during this critical developmental period. Genomic testing should be considered an essential screening study for this tumor population.
Abstract 15981: DNA Single-strand Break-induced DNA Damage Response Causes Heart Failure
Authors: Tomoaki Higo, Atsuhiko Naito, Masato Shibamoto, Jong-Kook Lee, Shungo Hikoso, Yasushi Sakata, Issei Komuro
Journal: Circulation (2015)

Introduction: The DNA damage response (DDR) pathway is activated upon DNA damage. In mitotic cells, the DDR plays essential role in maintaining genomic stability and preventing cancer formation. DNA damage and activation of the DDR are also observed in the post-mitotic cardiomyocytes of patients with end-stage heart failure, however, their roles in the pathogenesis of heart failure remains elusive. Methods and Results: We performed transverse aortic constriction (TAC) operation to produce mice model of pressure-overload induced heart failure. Alkaline- and neutral- comet assay revealed that unrepaired DNA single-strand break (SSB), not double-strand break, is accumulated in cardiomyocytes of the failing heart. Mice with cardiomyocyte-specific deletion of XRCC1, a scaffold protein essential for SSB repair, exhibited more severe heart failure and higher mortality after TAC operation. Knockdown of Xrcc1 using siRNA produced SSB accumulation in cardiomyocytes and SSB accumulation induced persistent DDR through activation of ataxia telangiectasia mutated (ATM) kinase. Activated ATM also induced nuclear translocation of NF-κB and increased the expression of inflammatory cytokines. Activation of DDR, nuclear translocation of NF-κB, and increased expression of inflammatory cytokines were also observed in the failing heart and were enhanced in the heart of cardiomyocyte-specific XRCC1 knockout mice. Conclusions: Unrepaired DNA SSB accumulates in post-mitotic cardiomyocytes and plays a pathogenic role in pressure overload-induced heart failure. Approaches that promote efficient SSB repair or suppress aberrant activation of DDR pathway may become a novel therapeutic strategy against heart failure.
TMOD-18. AN INTEGRATED SET OF PEDIATRIC HIGH GRADE GLIOMA RESOURCES FOR TRANSLATIONAL STUDIES
Authors: Heba Ijaz, Valerie Baubet, Mateusz Koptyra, Pichai Raman, Lamiya Tauhid, Krutika Gaonkar, Yuankun Zhu, Bo Zhang, Namrata Choudhari, Jamie Galanaugh, Elizabeth Appert, Jennifer Mason, Linnea Cripe, Taylor Lis, Maria Rita Santi, Jay Storm, Angela Waanders, Adam Resnick, Kristina Cole
Journal: Neuro-Oncology (2019)

PURPOSE: Pediatric high grade glioma (pHGG) remains a fatal disease. Increasing the number of patient derived tumor models and reagents will encourage research in pHGG and support the translation of basic science research discoveries. This work describes a recent multi-institution initiative to provide such a resource. METHODS: pHGG tumors with associated clinical data were prospectively collected and sequenced through the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA) with data deposited into PedcBioPortal for easy access and visualization. Primary tumor was dissociated and cultured to create both adherent and glioma stem cell lines analyzed by targeted and WGS/RNA sequencing. A tissue microarray (TMA) of primary pHGG tumors was created and examined by immunohistochemistry. RESULTS: The pHGG set included 81 collection events (70 patients, 54% at diagnosis, median age of 11 yrs, 52% female, 43% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). There were rare germline variants in mismatch repair genes with resultant tumor hyper-mutation. At least one established adherent and/or suspension glioma stem cell line was generated from 22 (31%) patients and validated by targeted sequencing for driver pHGG mutations. A subset of lines had WGS and RNAseq profiling which computationally clustered with their parental primary tumors. The lines’ cell biology makeup and in vivo tumor formation was also evaluated. A pHGG TMA (n=77), including 37 (53%) of the sequenced pHGG tumors, showed concordance with mutation status when stained for ATRX, H3.3 K27M and TP53. CONCLUSION: The CBTTC and PBTA have created a freely available integrated resource of characterized pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.
‘The Dormouse’: my story as a lightweight rower with overtraining syndrome
Authors: Lindsay Woodford
Journal: British Journal of Sports Medicine (2019)

To be a successful high-performance lightweight rower, I required exceptional physical attributes such as fitness and strength, together with high levels of dedication and resilience. However, when faced with frustrating setbacks such as injury and illness, like many athletes, the qualities that made me a champion became my own worst enemy.

Vigorous specifically targeted training followed by sufficient recovery is essential to improve athletic performance. It is difficult to balance training and recovery and when you layer on the added constraint of a weight-limited sport like lightweight rowing, training becomes more complex. In my sport, lightweight rowing, women compete under 57 kg and men under 70 kg. Making weight was a real challenge for me at 5′7″, so I maximised every opportunity to burn calories. That often meant choosing an active recovery session over a rest day, in my already challenging training schedule.

The extreme weight loss strategies I employed in the days leading up to the National Championships in 2000 seem ridiculous and incomprehensible now. I was not at race weight the night before the finals, so I severely restricted my food and drink intake, to the point of dehydration. I remember the blissful sensation of sucking the moisture out of my toothbrush, I savoured that moment when the cool, minty water slid down my throat. Despite turning the heating up and sleeping under …
ATRT-15. TARGETING LIN28 REGULATED PATHWAYS IN NOVEL THERAPEUTICS DEVELOPMENT FOR CNS ATYPICAL TERATOID/RHABDOID TUMOR (CNS ATRT)
Authors: Sunand Kannappan, Mehul Gupta, Chunfen Zhang, Bradley Hofmann, Susan Chi, Derek Hanson, Aru Narendran
Journal: Neuro-Oncology (2019)

INTRODUCTION: Elevated levels of LIN28A expression in AT/RT samples provide the rationale to search for agents that may interfere with cellular pathways regulated by this molecule. Ornithine decarboxylase (ODC) modulates eIF-5A through polyamines production and has been shown to directly influence the LIN28/Let-7 axis. The anti-protozoan drug α-difluoromethylornithine (DFMO) irreversibly inhibits ODC and its activity is potentiated by GC7 and Aurothioglucose (AuTG). METHODS: Bioinformatics: ATRT Pediatric Patient Dataset from Children’s Brain Tumour Tissue Consortium was evaluated (n=32). In-vitro studies: Expression levels of LIN28 and ODC in three CNS ATRT cell lines, BT12, BT16 and KCCF1, were examined by western blotting. Cells were treated with increasing concentrations of DFMO, GC7 and AuTG and viability was measured by alamar blue assay. RESULTS: mRNA expression profile of patients suggest strong evidence of co-expression between three proteins: LIN28A – ODC1: 0.37 Pearson Coefficient (p = 0.037), ODC1 – EIF5A: 0.35 Pearson Coefficient (p = 0.049) and LIN28A – EIF5A: 0.54 Pearson Coefficient (p = 0.001). Drug sensitivity studies indicated DFMO, GC7 and AuTG were cytotoxic in-vitro. IC50 values of DFMO for BT12, BT16 and KCCF1 were 80uM, 50uM and 80uM respectively. GC-7 was cytotoxic at IC50 of 115uM, 25uM and 25uM and AuTG displayed IC50 of 15uM, 42 uM and 50uM. Markers of apoptosis, including PARP cleavage, were present at 48 hours although kinetics varied between cell lines. Drug combination studies showed significant synergy between DMFO and GC7. DISCUSSION: Data from this study identified alterations in expression and activity of components in LIN28 mediated pathways in ATRT. Interference in the LIN28 pathway by the tested drugs leads to apoptosis at physiologically attainable concentrations. Therapeutic efficacy can be further enhanced by mechanistically validated drug combinations. We discuss in detail the implications of these findings with respect to the biology and novel therapeutics development for ATRT.
Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Zefei Jiang, Wei Li, Xichun Hu, Qingyuan Zhang, Tao Sun, Shude Cui, Shusen Wang, Quchang Ouyang, Yongmei Yin, Cuizhi Geng, Zhongsheng Tong, Ying Cheng, Yueyin Pan, Yuping Sun, Hong Wang, Tao Ouyang, Kangsheng Gu, Jifeng Feng, Xiaojia Wang, Shubin Wang, Tianshu Liu, Jinghua Gao, Massimo Cristofanilli, Zhiqiang Ning, Xianping Lu
Journal: The Lancet Oncology (2019)
Emodin alleviates cardiac fibrosis by suppressing activation of cardiac fibroblasts via upregulating metastasis associated protein 3
Authors: Dan Xiao, Yue Zhang, Rui Wang, Yujie Fu, Tong Zhou, Hongtao Diao, Zhixia Wang, Yuan Lin, Zhange Li, Lin Wen, Xujuan Kang, Philipp Kopylov, Dmitri Shchekochikhin, Yong Zhang, Baofeng Yang
Journal: Acta Pharmaceutica Sinica B (2019)

Excess activation of cardiac fibroblasts inevitably induces cardiac fibrosis. Emodin has been used as a natural medicine against several chronic diseases. The objective of this study is to determine the effects of emodin on cardiac fibrosis and the underlying molecular mechanisms. Intragastric administration of emodin markedly decreased left ventricular wall thickness in a mouse model of pathological cardiac hypertrophy with excess fibrosis induced by transaortic constriction (TAC) and suppressed activation of cardiac fibroblasts induced by angiotensin II (AngII). Emodin upregulated expression of metastasis associated protein 3 (MTA3) and restored the MTA3 expression in the setting of cardiac fibrosis. Moreover, overexpression of MTA3 promoted cardiac fibrosis; in contrast, silence of MTA3 abrogated the inhibitory effect of emodin on fibroblast activation. Our findings unraveled the potential of emodin to alleviate cardiac fibrosis via upregulating MTA3 and highlight the regulatory role of MTA3 in the development of cardiac fibrosis.
DIPG-23. EFFICACY OF THE SOLUBLE PANOBINOSTAT (MTX110) IN PRECLINICAL DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MODELS
Authors: Nathalene Truffaux, Xiaodong Yang, Piotr Hadaczek, Krystof Bankiewicz, Stephen J P Damment, Sabine Mueller
Journal: Neuro-Oncology (2019)

INTRODUCTION: Large drug screening and preclinical studies identified the pan-histone deacetylate inhibitor panobinostat as a promising treatment for DIPG. However, blood brain barrier functional integrity in DIPG limits drug penetration and remains a key cause of resistance to therapies. Therefore, we explored the therapeutic potential of water-soluble formulation of panobinostat MTX110 in our preclinical models and tested the efficacy in DIPG in vivo models using convection-enhanced delivery (CED). METHODS: CellTiter-Glo assay was used assess antiproliferative effects in DIPG derived cell lines (SF8628, NEM157, SF10423, SF10693). Effect on cell cycle was assessed using FACS analysis. To test safety, concentrations from 30 uM to 3000 uM were administered via CED into the striatum of the rat brain. In vivo activity of MTX110 via CED was assessed using a DIPG patient derived model (SF8628). RESULTS: MTX100 showed a strong antiproliferative and cytostatic effect on halting progression through G0/G1 in all tested DIPG cell lines with similar efficacy than the original formulation at submicromolar concentrations. Immunohistochemistry analysis showed no significant changes in doses up to 1000uM. CED of 100uM MTX110 significantly prolonged survival (control: median survival 52 days; MTX CED: median survival 64 days; p=0.0372). CONCLUSION: Our study confirmed that CED administration of MTX110 provides a potent antitumor effect. An ongoing trial is testing the safety and efficacy of CED of MTX110 in newly diagnosed patients.
A niche-dependent myeloid transcriptome signature defines dormant myeloma cells
Authors: Weng Hua Khoo, Guy Ledergor, Assaf Weiner, Daniel L. Roden, Rachael L. Terry, Michelle M. McDonald, Ryan C. Chai, Kim De Veirman, Katie L. Owen, Khatora S. Opperman, Kate Vandyke, Justine R. Clark, Anja Seckinger, Natasa Kovacic, Akira Nguyen, Sindhu T. Mohanty, Jessica A. Pettitt, Ya Xiao, Alexander P. Corr, Christine Seeliger, Mark Novotny, Roger S. Lasken, Tuan V. Nguyen, Babatunde O. Oyajobi, Dana Aftab, Alexander Swarbrick, Belinda Parker, Duncan R. Hewett, Dirk Hose, Karin Vanderkerken, Andrew C. W. Zannettino, Ido Amit, Tri Giang Phan, Peter I. Croucher
Journal: Blood (2019)
MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
Authors: Zhong Zheng, Rui Sun, Hui-Jin Zhao, Di Fu, Hui-Juan Zhong, Xiang-Qin Weng, Bin Qu, Yan Zhao, Li Wang, Wei-Li Zhao
Journal: Molecular Cancer (2019)

MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated.MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model.Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function.As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies.