tbuckley/cabot-search huggingface dataset:
The prognostic value of glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) positive myeloid derived suppressor cells (MDSCs) in peripheral blood of metastatic renal cell carcinoma (mRCC) patients.
Authors: Tomoyuki Kato, Yuji Takeda, Yuta Kurota, Sei Naito, Hiromi Ito, Akemi Araki, Hironobu Asao, Norihiko Tsuchiya
Journal: Journal of Clinical Oncology (2019)

601 Background: Myeloid derived suppressor cells (MDSCs) are found to play essential roles in various tumors and to associate with the prognosis of patients. However, the prognostic values of MDSCs in metastatic renal cell cancer (mRCC) are still undefined. Glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) is known as a regulator of Mac-1 (CD11b/CD18) and closely related with differentiation of myeloid cells. The object of our study was to interrogate the association of MDSCs in peripheral blood with clinical outcomes of mRCC patients by using GPI-80. Methods: Peripheral blood samples, collected from 23 mRCC patients before treatment and 16 healthy volunteers, were stained with several myeloid cell antigens such as CD16, CD15, CD33, and GPI-80 to mark neutrophils and monocytes. We measured the expression levels (mean of florescence intensity, MFI) and deviation (coefficient variation, CV) of myeloid antigens by flow cytometry. To investigate the immunosuppressive function of GPI-80 positive cells, reactive oxygen species (ROS) and LAP-1 (precursor of TGF-β1) were measured. The impact of the cell surface antigens on overall survival (OS) was evaluated using the univariate and multivariate Cox regression analysis. Results: The MFI or CV of GPI-80 on neutrophilic or monocytic cells were significantly difference in between patients and healthy volunteers. LAP-1 expression and ROS production in monocytic cells were increased in patients than in healthy volunteers, and correlated with expression of GPI-80 MFI (p = 0.0107 and p = 0.0381, respectively). Regarding the prognostic values, both GPI-80 CV of neutrophilic cells and GPI-80 MFI of monocytic cells were associated with poor OS of mRCC patients (p &lt; 0.01). Multivariate analysis showed that GPI-80 MFI of monocytic cells were independent unfavorable prognosis marker (HR 2.427, p = 0.044). Conclusions: These results showed that change of GPI-80 expression on myeloid cells in peripheral blood representing appearance of MDSCs was likely to be negative predictors in patients with mRCC.
Syntenin regulates hepatitis C virus sensitivity to neutralizing antibody by promoting E2 secretion through exosomes
Authors: Libin Deng, Wang Jiang, Xiaoning Wang, Andreas Merz, Marie-Sophie Hiet, Yujie Chen, Xiaoyu Pan, Yaming Jiu, Yu Yang, Bowen Yu, Yongning He, Zhengkun Tu, Junqi Niu, Ralf Bartenschlager, Gang Long
Journal: Journal of Hepatology (2019)
Comparison of two large, genetically and clinically annotated head and neck cancer (HNC) cohorts (TCGA, CHGC) and differential treatment effects on TP53 mutated, as well as oral cavity cancers.
Authors: Johannes Bragelmann, Zhixiang Zuo, Arun Khattri, Michaela K. Keck, Victoria Meucci Villaflor, Jonas DeSouza, Daniel J. Haraf, Mark W. Lingen, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2015)

6080 Background: Whileeffects of specific genetic aberrations on outcome in HNC have been described (Poeta 2007, Gross 2014), the impact of therapies in genetic subgroups remains unknown. We therefore examined in an exploratory, hypothesis-forming analysis two large, genetically annotated cohorts, which preferentially employed different treatment regimens, with respect to impact on outcome in certain genetic backgrounds. Methods: Data of 238 patients (pts) from the Cancer Genome Atlas (TCGA), and 131 pts of the Chicago HNC Genomic Cohort (CHGC) receiving curative intent treatment for locoregionally-advanced HNC were included. Subgroups of patients were analyzed evaluating anatomic site, HPV status, TP53 mutation status, and survival in an exploratory, hypothesis-forming study. Results: Pts in both cohorts were largely treated at high-volume North American referral centers. Pts in CHGC received more frequently induction chemotherapy and primarily taxane/FHX, non-platinum containing regimens and less frequently surgery. The genetic profiles were very similar when controlling for HPV status. In both cohorts HPV-positive and HPV-negative tumors 5-year survival rates were similar (NS), however with improved outcomes in the HPV-positive pts in CHGC compared to HPV-positive pts in TCGA (p = 0.02). In HPV-negative tumors in TCGA TP53 mutations conferred a negative prognosis, while in CHGC pts with TP53 mutations showed an increased survival. Furthermore in CHGC outcome in oral cavity cancers was improved (5-year survival CHGC 59%, TCGA 41%, p = 0.046). Conclusions: While bias due to differences in cohort composition and lack of standardization of treatment cannot be controlled for, this analysis provides for the first time hypotheses regarding the interaction of treatment choices with genetic background in the curative intent setting. In particular the possible impact of taxane-containing induction chemotherapy or non-platinum based taxane/FHX regimens on worse prognosis TP53 mutant tumors, as well as non-surgical approaches for oral cavity/laryngeal Stage IV tumors deserves additional study.
Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas
Authors: Julia Rühl, Carmen Citterio, Christine Engelmann, Tracey Haigh, Andrzej Dzionek, Johannes Dreyer, Rajiv Khanna, Graham S. Taylor, Joanna B. Wilson, Carol S. Leung, Christian Münz
Journal: Journal of Clinical Investigation (2019)

The Epstein-Barr virus (EBV) is one of the predominant tumor viruses in humans, but so far no therapeutic or prophylactic vaccination against this transforming pathogen is available. We demonstrated that heterologous prime-boost vaccination with the nuclear antigen 1 of EBV (EBNA1), either targeted to the DEC205 receptor on DCs or expressed from a recombinant modified vaccinia virus Ankara (MVA) vector, improved priming of antigen-specific CD4+ T cell help. This help supported the expansion and maintenance of EBNA1-specific CD8+ T cells that are most efficiently primed by recombinant adenoviruses that encode EBNA1. These combined CD4+ and CD8+ T cell responses protected against EBNA1-expressing T and B cell lymphomas, including lymphoproliferations that emerged spontaneously after EBNA1 expression. In particular, the heterologous EBNA1-expressing adenovirus, boosted by EBNA1-encoding MVA vaccination, demonstrated protection as a prophylactic and therapeutic treatment for the respective lymphoma challenges. Our study shows that such heterologous prime-boost vaccinations against EBV-associated malignancies as well as symptomatic primary EBV infection should be further explored for clinical development.
Association of Protein Phosphatase 2A (PP2A) overexpression with improved survival in patients with locally-advanced cervical cancer.
Authors: Sareena Singh, Analisa DiFeo, Raymond Redline, Hadi Shojaei, Kimberly Erin Resnick
Journal: Journal of Clinical Oncology (2015)

e16594 Background: PP2A is a widely conserved phosphatase that functions as a major tumor suppressor. Inhibition of PP2A is a necessary prerequisite for the transformation of cancer cells. Dephosphorylation of the transcription factor c-Myc is required for tumor suppressor activity of PP2A. There exists an endogenous oncoprotein, CIP2A (Cancerous Inhibitor of PP2A), that inhibits PP2A dephosphorylation of c-Myc. This leads to stabilization of c-Myc and subsequent cellular transformation. While the role of PP2A itself has not yet been directly elucidated in cervical cancer (CC), previous investigations demonstrate CIP2A overexpression in several other human squamous cell cancers. The objective of this study was to directly correlate PP2A expression with survival in CC using a Tissue Microarray (TMA). Methods: Immunohistochemical staining of a CC TMA was performed on specimens from patients with locally-advanced disease who underwent definitive radiation (±chemotherapy) to determine expression patterns of PP2A. Stained slides were reviewed by 2 independent investigators to determine cytoplasmic H-Scores (HS). Median HS for all specimens was 8. Samples were then divided into 2 groups: HS < 8 [Low PP2A Expression (PP2A-L)] and HS ≥ 8 [High PP2A Expression (PP2A-H)]. The association between HS and survival was evaluated. Results: 65 patient samples were stained and analyzed. 25 samples had PP2A-L and 40 had PP2A-H. Groups did not differ between age, histology, grade, or stage. Median follow-up time was 33 (1 – 82) months (mos). Progression-free survival (PFS) was significantly longer for PP2A-H (52.2 mos, 95% CI 42.0 – 62.4) than PP2A-L (23.6 mos, 95% CI 15.7 – 31.7) (p = 0.045). Overall survival (OS) was significantly longer for the PP2A-H (63.4 mos, 95% CI 54.7 – 72.0) than for PP2A-L (32.3 mos, 95% CI 24.2 – 40.4) (p = 0.047). Conclusions: PP2A overexpression is correlated with improved PFS and OS in CC. This preliminary data provides that rationale for therapeutically targeting the interactions between PP2A and CIP2A with investigational agents for the treatment of CC.
Poor Concordance between Sequential Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy in the Diagnosis of Diffuse Interstitial Lung Diseases
Authors: Micaela Romagnoli, Thomas V. Colby, Jean-Philippe Berthet, Anne Sophie Gamez, Jean-Pierre Mallet, Isabelle Serre, Alessandra Cancellieri, Alberto Cavazza, Laurence Solovei, Andrea Dell’Amore, Giampiero Dolci, Aldo Guerrieri, Paul Reynaud, Sébastien Bommart, Maurizio Zompatori, Giorgia Dalpiaz, Stefano Nava, Rocco Trisolini, Carey M. Suehs, Isabelle Vachier, Nicolas Molinari, Arnaud Bourdin
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)-versus surgical lung biopsy (SLB) as the current gold standard-in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5-8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01-0.44), percentage agreement = 38% (95% CI, 18-62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06-0.56), percentage agreement = 48% (95% CI, 26-70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27-0.75), percentage agreement = 62% (95% CI, 38-82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.
Progress in adolescent health and wellbeing: tracking 12 headline indicators for 195 countries and territories, 1990–2016
Authors: Peter S Azzopardi, Stephen J C Hearps, Kate L Francis, Elissa C Kennedy, Ali H Mokdad, Nicholas J Kassebaum, Stephen Lim, Caleb M S Irvine, Theo Vos, Alex D Brown, Surabhi Dogra, Stuart A Kinner, Natasha S Kaoma, Mariam Naguib, Nicola J Reavley, Jennifer Requejo, John S Santelli, Susan M Sawyer, Vegard Skirbekk, Marleen Temmerman, Jordan Tewhaiti-Smith, Joseph L Ward, Russell M Viner, George C Patton
Journal: The Lancet (2019)

BackgroundRapid demographic, epidemiological, and nutritional transitons have brought a pressing need to track progress in adolescent health. Here, we present country-level estimates of 12 headline indicators from the Lancet Commission on adolescent health and wellbeing, from 1990 to 2016.MethodsIndicators included those of health outcomes (disability-adjusted life-years [DALYs] due to communicable, maternal, and nutritional diseases; injuries; and non-communicable diseases); health risks (tobacco smoking, binge drinking, overweight, and anaemia); and social determinants of health (adolescent fertility; completion of secondary education; not in education, employment, or training [NEET]; child marriage; and demand for contraception satisfied with modern methods). We drew data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016, International Labour Organisation, household surveys, and the Barro-Lee education dataset.FindingsFrom 1990 to 2016, remarkable shifts in adolescent health occurred. A decrease in disease burden in many countries has been offset by population growth in countries with the poorest adolescent health profiles. Compared with 1990, an additional 250 million adolescents were living in multi-burden countries in 2016, where they face a heavy and complex burden of disease. The rapidity of nutritional transition is evident from the 324·1 million (18%) of 1·8 billion adolescents globally who were overweight or obese in 2016, an increase of 176·9 million compared with 1990, and the 430·7 million (24%) who had anaemia in 2016, an increase of 74·2 million compared with 1990. Child marriage remains common, with an estimated 66 million women aged 20–24 years married before age 18 years. Although gender-parity in secondary school completion exists globally, prevalence of NEET remains high for young women in multi-burden countries, suggesting few opportunities to enter the workforce in these settings.InterpretationAlthough disease burden has fallen in many settings, demographic shifts have heightened global inequalities. Global disease burden has changed little since 1990 and the prevalence of many adolescent health risks have increased. Health, education, and legal systems have not kept pace with shifting adolescent needs and demographic changes. Gender inequity remains a powerful driver of poor adolescent health in many countries.FundingAustralian National Health and Medical Research Council, and the Bill & Melinda Gates Foundation.
Treatment for cervical cancer in Ethiopia: Impact of the optimal radiation dose on survival of 815 patients.
Authors: Aynalem Abraha Woldemariam, Ulrike Moelle, Mathewos Assefa Woldegeorgis, Wondemagegnhu Tigeneh Geberemedhin, Bekuretsion Yonas, Gemechu Tufa, Yirgu Gebrehiwot, Pietro Trocchi, Dirk Vordermark, Christoph Thomssen, Adamu Addissie, Eva Johanna Kantelhardt
Journal: Journal of Clinical Oncology (2015)

e16520 Background: There is little information on treatment and survival of cervical cancer (CC) in developing countries. We evaluated pts who received radiotherapy at Addis Ababa University Hospital, the only center in Ethiopia. Methods: All pts with CC (2008–2012) who received radiotherapy were eligible. Pts received external radiation according to FIGO stage and adapted guidelines (no Brachytherapy). Data was obtained from clinical records and telephone contact. We used multivariable Cox proportional hazards regression to estimate adjusted Hazard Ratios (HR) and corresponding 95% confidence intervals (95% CIs). Statistical analysis was done with SPSS Statistics 22. Results: Of 1009 files 815 (86.7%) pts treated according to guidelines (completed or discontinued) were included. Pts' outcome was better when higher radiation doses were given. Of pts FIGO stage IIa-IIIa (n = 180), 48.9% received the guideline dose 72 Gy. Compared to pts who discontinued, one-year survival probability (OS) was higher (96.1% versus 88.4% HR: 1.43, CI: 0.59-3.47). Of pts FIGO stage IIIb-IVa (n = 416) 82.2% received 44Gy or more. Compared with pts who received less radiation (42Gy), OS was higher (86.1 (44-47Gy) and 72.9% respectively; HR: 3.07, CI 1.44-6.56). Of pts FIGO stage IVb (n = 219) 15.1% received 26-42Gy. OS for those pts and for pts who received less radiation (20Gy compared to 8-10Gy) were 65.5%; 76.3% and 14.4% respectively (HR: 0.64, CI: 0.23-1.77 and HR: 3.67 CI: 1.28-10.51). Conclusions: This study gives an overview of pts with CC who received radiotherapy in Ethiopia. Pts often discontinued and received a non-optimal radiation dose due to limited radiation facilities, socio-economic reasons, side-effects or progression of disease (detailes information was not available in this retrospective study). In general, pts who received radiation doses according to guidelines showed better OS. This may reflect a true effect of the higher radiation doses or possibly discontinuation more often occurred in more aggressive disease. Better supportive medication, a second machine to secure radiation availability and socio-economic support would possibly increase OS of pts.
Recognising women of colour in the NHS
Authors: Shera Chok
Journal: BMJ (2019)

My usual Sunday morning flick through the BMJ Confidential profiles threw up an interesting observation.1 The wonderful women of colour featured in the issues I looked at were in Rwanda (Agnes Binagwaho),2 the United States (Esther Choo),3 Malaysia (Pascale Allotey),4 Australia (Ranjana Srivastava),5 and Scotland (Mahua Chakrabarti).6

We know that around 40% of NHS doctors are people of colour7 …
Inferior Vena Cava Filters in the Management of Venous Thromboembolism
Authors: Eric K. Hoffer
Journal: JAMA (2019)

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A Phase II Trial of the Anti -PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) + Lenalidomide + Dexamethasone As Post Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma
Authors: Noa Biran, Tracy Andrews, Rena Feinman, David H. Vesole, Joshua R Richter, Joshua Zenreich, Palka Anand, Laura McBride, Kristin Ivanovski, Robert Korngold, David Siegel
Journal: Blood (2017)
Identification of novel targets in non-muscle invasive bladder cancer: A systems biology approach.
Authors: Robin Osterhout, Adeela Kamal, Samuel Spigelman
Journal: Journal of Clinical Oncology (2019)

396 Background: Most bladder cancers are diagnosed as non-muscle invasive bladder cancer (NMIBC). Because of the high rate of recurrence and limited treatment options for recurrent disease, there is an urgent need to identify new treatment options. In this study, a network-based drug discovery approach was applied to identify novel targets in NMIBC. Methods: A computational systems-biology framework integrating genomic, transcriptomic, protein-protein, and protein-drug interactions was applied to identify and prioritize potential NMIBC targets and pathways. First, a NMIBC disease network module was constructed from genetic associations augmented with known protein-protein interactions. Independent NMIBC case/control expression data sets were leveraged to develop a phenotypic network module comprising genes differentially expressed in NMIBC. Proteins and pathways linking the disease model with the phenotypic module were identified, ranked, and benchmarked against known NMIBC pathways and drug targets from the literature. Results: NMIBC seed genes cluster significantly within the human interactome, reflecting an underlying disease module. The expanded disease module comprises 103 genes that show functional and literature-based enrichment. Genes differentially expressed in NMIBC were significantly connected to disease module genes compared with random expectation (z = 23.3), and are enriched in several biologically relevant pathways. Based on similarity to disease biology and network topology, 11 NMIBC pathways were identified as bridging genetic predisposition for and phenotypic expression of NMIBC. Within these overlapping pathways, known and novel drug targets were identified. Of these in silico targets, 19 are currently under development for treatment of bladder cancer, validating the approach. To further validate the approach, we observed overlap between in silico targets and hits from a chemogenomic library phenotypic screen. Conclusions: A network-driven systems biology approach identified both known NMIBC targets and novel proteins/pathways that are potential targets for the treatment of NMIBC. Further target validation is required.
Electrochemically Controlled Drug Release from a Conducting Polymer Hydrogel (PDMAAp/PEDOT) for Local Therapy and Bioelectronics
Authors: Carolin Kleber, Karen Lienkamp, Jürgen Rühe, Maria Asplund
Journal: Advanced Healthcare Materials (2019)

Abstract In this study, the release of fluorescein from a photo‐crosslinked conducting polymer hydrogel made from a hydrogel precursor poly(dimethylacrylamide‐ co ‐4‐methacryloyloxy benzophenone (5%)‐ co ‐4‐styrenesulfonate (2.5%)) (PDMAAp) and the conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) is investigated. Fluorescein, here used as a model for a drug, is actively released through application of an electrical trigger signal. The detected quantity is more than six times higher in comparison to that released from a conventional PEDOT/polysterene sulfonate (PSS) system. Release profiles, drug dose, and timing can be tailored by the application of different trigger signals and pretreatments. To demonstrate that the novel drug release system can be used for a drug relevant for local delivery to a neural interface, experiments are furthermore performed with the anti‐inflammatory drug dexamethasone (Dex). The conducting polymer hydrogel facilitates the active release of Dex, in comparison to the previously used PEDOT/Dex. It is suggested that PEDOT/PDMAAp is an interesting alternative for conducting polymer based drug release systems, with the potential to offer more volume for storage, yet retaining the excellent electrochemical properties known for PEDOT electrodes.