tbuckley/cabot-search huggingface dataset:
Attenuated TRAF3 Fosters Activation of Alternative NF-κB and Reduced Expression of Antiviral Interferon, TP53, and RB to Promote HPV-Positive Head and Neck Cancers
Authors: Jialing Zhang, Tony Chen, Xinping Yang, Hui Cheng, Stephan S. Späth, Paul E. Clavijo, Jianhong Chen, Christopher Silvin, Natalia Issaeva, Xiulan Su, Wendell G. Yarbrough, Christina M. Annunziata, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2018)

Abstract Human papilloma viruses (HPV) are linked to an epidemic increase in oropharyngeal head and neck squamous cell carcinomas (HNSCC), which display viral inactivation of tumor suppressors TP53 and RB1 and rapid regional spread. However, the role of genomic alterations in enabling the modulation of pathways that promote the aggressive phenotype of these cancers is unclear. Recently, a subset of HPV+ HNSCC has been shown to harbor novel genetic defects or decreased expression of TNF receptor–associated factor 3 (TRAF3). TRAF3 has been implicated as a negative regulator of alternative NF-κB pathway activation and activator of antiviral type I IFN response to other DNA viruses. How TRAF3 alterations affect pathogenesis of HPV+ HNSCC has not been extensively investigated. Here, we report that TRAF3-deficient HPV+ tumors and cell lines exhibit increased expression of alternative NF-κB pathway components and transcription factors NF-κB2/RELB. Overexpression of TRAF3 in HPV+ cell lines with decreased endogenous TRAF3 inhibited NF-κB2/RELB expression, nuclear localization, and NF-κB reporter activity, while increasing the expression of IFNA1 mRNA and protein and sensitizing cells to its growth inhibition. Overexpression of TRAF3 also enhanced TP53 and RB tumor suppressor proteins and decreased HPV E6 oncoprotein in HPV+ cells. Correspondingly, TRAF3 inhibited cell growth, colony formation, migration, and resistance to TNFα and cisplatin-induced cell death. Conversely, TRAF3 knockout enhanced colony formation and proliferation of an HPV+ HNSCC line expressing higher TRAF3 levels. Together, these findings support a functional role of TRAF3 as a tumor suppressor modulating established cancer hallmarks in HPV+ HNSCC. Significance: These findings report the functional role of TRAF3 as a tumor suppressor that modulates the malignant phenotype of HPV+ head and neck cancers. Cancer Res; 78(16); 4613–26. ©2018 AACR.
Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status
Authors: Md Yuzaiful Md Yusof, Antonios Psarras, Yasser M El-Sherbiny, Elizabeth M A Hensor, Katherine Dutton, Sabih Ul-Hassan, Ahmed S Zayat, Mohammad Shalbaf, Adewonuola Alase, Miriam Wittmann, Paul Emery, Edward M Vital
Journal: Annals of the Rheumatic Diseases (2018)

Objective To evaluate clinical, interferon and imaging predictors of progression from ‘At Risk’ to autoimmune connective tissue diseases (AI-CTDs). Methods A prospective observational study was conducted in At-Risk of AI-CTD (defined as antinuclear antibody (ANA) positive; ≤1 clinical systemic lupus erythematosus (SLE) criterion; symptom duration &lt;12 months and treatment-naïve). Bloods and skin biopsy (non-lesional) were analysed for two interferon-stimulated gene expression scores previously described (IFN-Score-A and IFN-Score-B). Forty-nine healthy controls (HCs) and 114 SLE were used as negative and positive controls. Musculoskeletal ultrasound was performed. Progression was defined by meeting classification criteria for AI-CTDs at 12 months. Results 118 individuals with 12-month follow-up were included. Of these, 19/118 (16%) progressed to AI-CTD (SLE=14, primary Sjogren’s=5). At baseline, both IFN scores differed among At-Risk, HCs and SLE groups (p&lt;0.001) and both were elevated in At-Risk who progressed to AI-CTD at 12 months versus non-progressors, to a greater extent for IFN-Score-B (fold difference (95% CI) 3.22 (1.74 to 5.95), p&lt;0.001) than IFN-Score-A (2.94 (1.14 to 7.54); p=0.018). Progressors did not have significantly greater baseline clinical characteristics or ultrasound findings. Fold difference between At-Risk and HCs for IFN-Score-A was markedly greater in skin than blood. In multivariable logistic regression, only family history of autoimmune rheumatic disease, OR 8.2 (95% CI 1.58 to 42.53) and IFN-Score-B, 3.79 (1.50–9.58) increased the odds of progression. Conclusion A two-factor interferon score and family history predict progression from ANA positivity to AI-CTD. These interferon scores may allow stratification of individuals At-Risk of AI-CTD permitting early intervention for disease prevention and avoid irreversible organ damage.
NURS-02. CAR-T CELL THERAPY IN PEDIATRIC BRAIN TUMORS- EARLY SUPPORTIVE CARE LESSONS
Authors: Corrine Hoeppner, Susan Holtzclaw
Journal: Neuro-Oncology (2018)

CAR-T Cell therapy is an exciting and innovative therapy that has just recently been FDA approved for pediatric brain tumor patients at Seattle Children’s Hospital. It is a phase one study of CD-4 and CD-8 T cells, infused through indwelling catheters into the resection cavity or ventricular system of patients with recurrent or refractory brain tumors. In order to best support these patients, much of the supportive care data will need to be extrapolated through the experiences of CAR-T cell therapy in leukemia and other solid tumors. Cytokine-release Syndrome is of particular concern in all patients receiving CAR-T cells, and many clinical care strategies have been learned through prior clinical trials. The focus of this presentation will be to provide algorithms that structure care for cytokine-release syndrome post CAR-T cell infusion, and unique issues that are faced by pediatric brain tumor patients. Case studies will be provided and discussed to illustrate the clinical course of this complex therapy.
Impact of improved cookstoves on women’s and child health in low and middle income countries: a systematic review and meta-analysis
Authors: Megha Thakur, Paulien A W Nuyts, Esther A Boudewijns, Javier Flores Kim, Timor Faber, Giridhara R Babu, Onno C P van Schayck, Jasper V Been
Journal: Thorax (2018)

Improved biomass cookstoves may help reduce the substantial global burden of morbidity and mortality due to household air pollution (HAP) that disproportionately affects women and children in low and middle income countries (LMICs).Systematic review and meta-analysis of (quasi-)experimental studies identified from 13 electronic databases (last update: 6 April 2018), reference and citation searches and via expert consultation.LMICs PARTICIPANTS: Women and children INTERVENTIONS: Improved biomass cookstoves MAIN OUTCOME MEASURES: Low birth weight (LBW), preterm birth, perinatal mortality, paediatric acute respiratory infections (ARIs) and COPD among women.We identified 53 eligible studies, including 24 that met prespecified design criteria. Improved cookstoves had no demonstrable impact on paediatric lower ARIs (three studies; 11 560 children; incidence rate ratio (IRR)=1.02 (95% CI 0.84 to 1.24)), severe pneumonia (two studies; 11 061 children; IRR=0.88 (95% CI 0.39 to 2.01)), LBW (one study; 174 babies; OR=0.74 (95% CI 0.33 to 1.66)) or miscarriages, stillbirths and infant mortality (one study; 1176 babies; risk ratio (RR) change=15% (95% CI -13 to 43)). No (quasi-)experimental studies assessed preterm birth or COPD. In observational studies, improved cookstoves were associated with a significant reduction in COPD among women: two studies, 9757 participants; RR=0.74 (95% CI 0.61 to 0.90). Reductions in cough (four studies, 1779 participants; RR=0.72 (95% CI 0.60 to 0.87)), phlegm (four studies, 1779 participants; RR=0.65 (95% CI 0.52 to 0.80)), wheezing/breathing difficulty (four studies; 1779 participants; RR=0.41 (95% CI 0.29 to 0.59)) and conjunctivitis (three studies, 892 participants; RR=0.58 (95% CI 0.43 to 0.78)) were observed among women.Improved cookstoves provide respiratory and ocular symptom reduction and may reduce COPD risk among women, but had no demonstrable child health impact.PROSPERO: CRD42016033075.
Connective tissue growth factor contributes to joint homeostasis and osteoarthritis severity by controlling the matrix sequestration and activation of latent TGFβ
Authors: Xiaodi Tang, Hayat Muhammad, Celia McLean, Jadwiga Miotla-Zarebska, Jacob Fleming, Athanasios Didangelos, Patrik Önnerfjord, Andrew Leask, Jeremy Saklatvala, Tonia L Vincent
Journal: Annals of the Rheumatic Diseases (2018)

Objectives One mechanism by which cartilage responds to mechanical load is by releasing heparin-bound growth factors from the pericellular matrix (PCM). By proteomic analysis of the PCM, we identified connective tissue growth factor (CTGF) and here investigate its function and mechanism of action. Methods Recombinant CTGF (rCTGF) was used to stimulate human chondrocytes for microarray analysis. Endogenous CTGF was investigated by in vitro binding assays and confocal microscopy. Its release from cut cartilage (injury CM) was analysed by Western blot under reducing and non-reducing conditions. A postnatal, conditional Ctgf cKO mouse was generated for cartilage injury experiments and to explore the course of osteoarthritis (OA) by destabilisation of the medial meniscus. siRNA knockdown was performed on isolated human chondrocytes. Results The biological responses of rCTGF were TGFβ dependent. CTGF displaced latent TGFβ from cartilage and both were released on cartilage injury. CTGF and latent TGFβ migrated as a single high molecular weight band under non-reducing conditions, suggesting that they were in a covalent (disulfide) complex. This was confirmed by immunoprecipitation. Using Ctgf cKO mice, CTGF was required for sequestration of latent TGFβ in the matrix and activation of the latent complex at the cell surface through TGFβR3. In vivo deletion of CTGF increased the thickness of the articular cartilage and protected mice from OA. Conclusions CTGF is a latent TGFβ binding protein that controls the matrix sequestration and activation of TGFβ in cartilage. Deletion of CTGF in vivo caused a paradoxical increase in Smad2 phosphorylation resulting in thicker cartilage that was protected from OA.
EMBR-16. SURVIVAL OF INFANTS AND YOUNG CHILDREN WITH MALIGNANT BRAIN TUMORS TREATED WITH INTENSIVE INDUCTION AND MYELOABLATIVE CHEMOTHERAPY AND AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (AUHCR) WITH OR WITHOUT IRRADIATION (XRT) POST-AUHCR
Authors: Eesha Chakravartty, Jemily Malvar, Nathan Robison, Hung Ngoc Tran, Ashley Margol, Laura Vasquez, Kenneth Wong, Girish Dhall
Journal: Neuro-Oncology (2018)
68Ga-PSMA PET/CT in Patients With Biochemical Recurrence of Prostate Cancer
Authors: Helle D. Zacho, Julie B. Nielsen, Katja Dettmann, Uwe Haberkorn, Niels C. Langkilde, Jørgen B. Jensen, Lars J. Petersen
Journal: Clinical Nuclear Medicine (2018)

The aim of this study was to prospectively investigate the detection rate of Ga-PSMA PET/CT in biochemical recurrence (BCR) of prostate cancer and its impact on patient management.Patients with BCR after curatively intended treatment of prostate cancer were included. Each patient underwent a Ga-PSMA PET/CT. Changes in patient management based on the results of Ga-PSMA PET/CT were assessed.Seventy patients were included. Sixty-four patients (91%) had radical prostatectomy, of whom 17 patients (24%) received salvage radiation therapy due to first biochemical relapse. Six patients (9%) underwent radiation therapy as the primary treatment. Ga-PSMA PET/CT detected recurrent disease in 37 patients (53%). The detection rate was 22% for prostate-specific antigen (PSA) levels up to 0.5 ng/mL compared with 83% for PSA levels greater than 0.5 ng/mL. Pathological uptake of Ga-PSMA was observed in 4 (16%) of 21, 4 (44%) of 9, 0 of 1, 7 (70%) of 10, and 22 (88%) of 25 patients with PSA levels from 0.2 to 0.3 ng/mL, 0.31 to 0.4 ng/mL, 0.41 to 0.5 ng/mL, 0.51 to 1 ng/mL, and greater than 1 ng/mL, respectively. Prostate-specific antigen was significantly higher in PSMA-positive patients than in PSMA-negative patients. In 15 (22%) of 69 patients, the results caused a definite change in patient management, and in another 15 (22%) of 69 patients, Ga-PSMA PET/CT guided the choice of treatment.Ga-PSMA PET/CT detects lesions in a large proportion of patients with BCR. Detection rates at low PSA levels (<0.5 ng/mL) were notably below the values reported in previous retrospective studies; however, detection rates improved with increasing PSA levels.
Estrone and prolactin can be markers of risk of metastasis and pre-metastatic niche in patients with stomach cancer
Authors: O. Kit, E. Frantsiyants, V. Bandovkina, Y. Pogorelova, Y. Gevorkyan, N. Soldatkina, N. Samoylenko
Journal: Annals of Oncology (2018)

Introduction: The tumor ability to metastasize can be determined by the characteristics of the tumor itself and of surrounding tissues. Together with the formation of the pre-metastatic niche, the tumor niche formation takes place in the primary tumor, and changes in hormonal profile are important. The peritoneum, including the greater omentum, is the most common site of stomach cancer (SC) metastasis, while it is not a metastatic niche for colorectal cancer (CRC). Our purpose was to study changes in the hormonal profile of pre-metastatic niches – the peritoneum and omentum, and to determine parameters for predicting the stomach cancer progression and metastasis. Methods: The study included 4 groups of patients: 1 - SC without metastases (mts) to the peritoneum and omentum (T2-4N0-3M0, n=20); 2 – SC with mts to the peritoneum and omentum (T2-4N0-3M1, n=25); 3 – CRC without distant mts (T2-4N0-3M0, n=18); 4 – controls without cancer operated on for cholecystitis and hernia (n=15). Estrone (E1) levels in tissues of the peritoneum and omentum, and estrone (E1) and prolactin (PRL) levels in tumor and peritumoral tissues were determined by ELISA. All patients gave their written informed consent. Statistical processing of the results was performed using Microsoft Office Excel 2010. Results: Tumor tissues in patients of group 1 showed higher estrone levels and lower prolactin levels compared to group 2, while peritumoral tissues showed the opposite results (lower E1 and higher PRL levels in non-metastatic cancer). The ratio of E1 levels in tumor/peritumoral tissues in metastatic SC was 0.65, non-metastatic – 1.43. The ratio of PRL levels in tumor/peritumoral tissues in metastatic SC was 3.34, non-metastatic – 0.7. The E1 levels in the omentum of patients in groups 1 (T2-4N0-3M0), 3 (T2-4N0-3M0) and 4 were similar. The E1 levels in metastatic SC (T2-4N0-3M1) were 14.6 times higher than in non-metastatic SC (T2-4N0-3M0) and more than 9 times higher than in CRC and in controls. The exception was 35% of patients with SC without detected mts with a high content of E1 in omentum and peritoneal tissues and with increased ratio of PRL levels in tumor/peritumoral tissues. Distant metastases from SC were detected in one of the patients within 3 months. Conclusion: The peritoneum and omentum affected by metastasis are characterized by high estrone levels. The ratios of E1 and PRL in tumor/peritumoral tissues change in metastasis development. Determination of E1 and PRL in tumor and peritumoral tissues and in the omentum can be an additional prognostic criterion for the cancer progression and the development of metastasis.
Molecular signatures of liver dysfunction are distinct in fungal and bacterial infections in mice
Authors: Barbara Schaarschmidt, Sebastian Vlaic, Anna Medyukhina, Sophie Neugebauer, Sandor Nietzsche, Falk A. Gonnert, Jürgen Rödel, Mervyn Singer, Michael Kiehntopf, Marc Thilo Figge, Ilse D. Jacobsen, Michael Bauer, Adrian T. Press
Journal: Theranostics (2018)

Rationale: The liver is a central organ not only for metabolism but also immune function. Life-threatening infections of both bacterial and fungal origin can affect liver function but it is yet unknown whether molecular changes differ depending on the pathogen. We aimed to determine whether the hepatic host response to bacterial and fungal infections differs in terms of hepatic metabolism and liver function. Methods: We compared murine models of infection, including bacterial peritoneal contamination and infection (PCI), intraperitoneal and systemic C. albicans infection, at 6 and 24 h post-infection, to sham controls. The molecular hepatic host response was investigated by the detection of regulatory modules based on large-scale protein-protein interaction networks and expression data. Topological analysis of these regulatory modules was used to reveal infection-specific biological processes and molecular mechanisms. Intravital microscopy and immunofluorescence microscopy were used to further analyze specific aspects of pathophysiology such as cholestasis. Results: Down-regulation of lipid catabolism and bile acid synthesis was observed after 6 h in all infection groups. Alterations in lipid catabolism were characterized by accumulation of long chain acylcarnitines and defective beta-oxidation, which affected metabolism by 6 h. While PCI led to an accumulation of unconjugated bile acids (BA), C. albicans infection caused accumulation of conjugated BA independent of the route of infection. Hepatic dye clearance and transporter expression revealed reduced hepatic uptake in fungal infections vs. defects in secretion following polybacterial infection. Conclusion: Molecular phenotypes of lipid accumulation and cholestasis allow differentiation between pathogens as well as routes of infection at early stages in mice. Targeted metabolomics could be a useful tool for the profiling of infected/septic patients and the type of pathogen, with subsequent customization and targeting of therapy.
EPEN-29. INDIVIDUALIZED THERAPY OF AN ANAPLASTIC EPENDYMOMA PEDIATRIC PATIENT WITH A NOTCH1 GERMLINE MUTATION
Authors: Alexandra Russo, Claudia Paret, Nadine Lehmann, Hannah Bender, Arthur Wingerter, Marie Astrid Neu, Francesca Alt, Nora Backes, Lea Roth, Larissa Seidmann, Jörg Faber
Journal: Neuro-Oncology (2018)

The treatment of relapsed pediatric cancers represents a challenge, also due to possible underlying rare germline mutations. The introduction of next sequencing technologies allows a deeper understanding of molecular mechanisms involved in cancer progression helping in the identification of personalized therapies for these patients. However, most tumors harbor several pathway alterations and it is necessary to prioritize the treatment options. Here we applied the concept of personalized therapy to a pediatric patient with an anaplastic ependymoma and who relapsed three times under standard chemio and radiotherapy. By RNA sequencing we identified in the tumor a Notch1 mutation which was confirmed by Sanger Sequencing and which was also present in the blood DNA. Pathway analysis revealed an activation of the sonic hedgehog (SHH), the WNT, the IGF and the Notch pathway. In an attempt to prioritize possible targeted therapies, we treated the patient-specific tumor cells with relevant inhibitors in vitro. The cells were particularly sensitive to Arsenic Trioxide, an inhibitor of the SHH pathway, and to ceritinib, an off-target inhibitor of IGF-1R. Combination of Arsenic Trioxide with chemotherapy reduced the growth rate of the tumor. However, because we were not able to reach the needed Arsenic concentration in CSF, we switched to ceritinib. The patient is currently receiving the first cycle of ceritinib and chemotherapy. In the era of personalized medicine, the molecular analysis of the tumor and the use of patient-specific tumor cells may represent a powerful tool to identify new therapeutic treatments for patients with underlying rare mutations.
MBCL-42. SECOND GENERATION MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA: TOWARDS A WORKING CONSENSUS OF GROUP 3/4 SUBTYPES
Authors: Tanvi Sharma, Edward C Schwalbe, Daniel Williamson, Volker Hovestadt, Lukas Chavez, Marcel Kool, Paul A Northcott, Stefan M Pfister, Steven C Clifford
Journal: Neuro-Oncology (2018)

An international consensus study reported in 2012 that medulloblastoma comprises four molecular subgroups (WNT, SHH, Grp3, Grp4), each associated with distinct genomic features and clinical behaviours. Independently, recent work by three groups, using either DNA-methylation microarrays or combined DNA-methylation and expression-microarrays has defined varying intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes within subgroups. However, due to differences in patient cohorts and analytical methods, estimates of subtype number and their precise definition differed, especially within Grp3/Grp4. This study aims to establish consensus on the number and definition of Grp3/Grp4 medulloblastoma subtypes. By combining published cohorts with novel cases, we assembled a cohort of 1,506 Grp3/4 samples with methylation data, including 852 with matched DNA-methylation and transcriptome data. We analysed these cohorts using the techniques previously employed in the recent subgrouping studies (i.e. NMF, t-SNE/DBSCAN, SNF), additionally adding objective subgroup definition and robustness measures by multiple resampling of the datasets. Regardless of technique, increasing cohort size did not increase the number of identified Grp3/Grp4 subtypes beyond a maximum of eight. Through mapping of subtype calls across different analytical methods, we identified many areas of agreement between the published studies (e.g. ‘subtype VIII’ is equivalent to ‘Grp4_HighRisk’, etc.), and are working to understand remaining inconsistencies before presenting a final consensus which current data indicates is broadly consistent with the previously published subtypes I-VIII. After establishing a consensus on Grp3/4 medulloblastoma subtypes, we will identify their molecular determinants, describe their clinico-pathological correlates, and explore their translational potential and clinical relevance.
Early Proteinuria Lowering by Angiotensin-Converting Enzyme Inhibition Predicts Renal Survival in Children with CKD
Authors: Sophie M. van den Belt, Hiddo J.L. Heerspink, Valentina Gracchi, Dick de Zeeuw, Elke Wühl, Franz Schaefer
Journal: Journal of the American Society of Nephrology (2018)

Background Although pharmacotherapeutic proteinuria lowering was found to be nephroprotective in adults, the predictive value of early drug-induced proteinuria reduction for long-term renal survival in pediatric CKD is unknown. We analyzed data from the ESCAPE Trial for a potential association between initial antiproteinuric effect of standardized angiotensin-converting enzyme (ACE) inhibition and renal disease progression in children with CKD. Methods In total, 280 eligible children with CKD stages 2–4 (mean age 11.7 years old, median eGFR 46 ml/min per 1.73 m 2 , 71% congenital renal malformations) received a fixed dose of ramipril (6 mg/m 2 per day) and were subsequently randomized to conventional or intensified BP control. We assessed initial proteinuria reduction from baseline to first measurement on ramipril (at 2.5±1.3 months). We used multivariable Cox modeling to estimate the association between initial proteinuria reduction and the risk of reaching a renal end point (50% eGFR decline or ESRD), which occurred in 80 patients during 5 years of observation. Results Ramipril therapy lowered proteinuria by a mean of 43.5% (95% confidence interval, 36.3% to 49.9%). Relative to proteinuria reduction &lt;30%, 30%–60% and &gt;60% reduction resulted in hazard ratios (95% confidence intervals) of 0.70 (0.40 to 1.22) and 0.42 (0.22 to 0.79), respectively. This association was independent of age, sex, CKD diagnosis, baseline eGFR, baseline proteinuria, initial BP, and concomitant BP reduction. Conclusions The early antiproteinuric effect of ACE inhibition is associated with long-term preservation of renal function in children with CKD. Proteinuria lowering should be considered an important target in the management of pediatric CKD.
Mechanically cartilage-mimicking poly(PCL-PTHF urethane)/collagen nanofibers induce chondrogenesis by blocking NF–kappa B signaling pathway
Authors: Tongmeng Jiang, Dan Kai, Sijia Liu, Xianyuan Huang, Shujun Heng, Jinmin Zhao, Benjamin Qi Yu Chan, Xian Jun Loh, Ye Zhu, Chuanbin Mao, Li Zheng
Journal: Biomaterials (2018)