tbuckley/cabot-search huggingface dataset:
HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of FcγR-binding functionality
Authors: David M. Richards, Viola Marschall, Katharina Billian-Frey, Karl Heinonen, Christian Merz, Mauricio Redondo Müller, Julian P. Sefrin, Matthias Schröder, Jaromir Sykora, Harald Fricke, Oliver Hill, Christian Gieffers, Meinolf Thiemann
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Glucocorticoid-induced TNFR-related protein (TNFRSF18, GITR, CD357), expressed by T cells, and its ligand (TNFSF18, GITRL), expressed by myeloid populations, provide co-stimulatory signals that boost T cell activity. Due to the important role that GITR plays in regulating immune functions, agonistic stimulation of GITR is a promising therapeutic concept. Multiple strategies to induce GITR signaling have been investigated. The limited clinical efficacy of antibody-based GITR agonists results from structural and functional characteristics of antibodies that are unsuitable for stimulating the well-defined trimeric members of the TNFRSF. <h3>Methods</h3> To overcome limitations of antibody-based TNFRSF agonists, we have developed HERA-GITRL, a fully human <i>hex</i>avalent TNF <i>r</i>eceptor <i>a</i>gonist (HERA) targeting GITR and mimicking the natural signaling concept. HERA-GITRL is composed of a trivalent but single-chain GITRL-receptor-binding-domain (scGITRL-RBD) unit fused to an IgG1 derived silenced Fc-domain serving as dimerization scaffold. A specific mouse surrogate, mmHERA-GITRL, was also generated to examine in vivo activity in respective mouse tumor models. <h3>Results</h3> For functional characterization of HERA-GITRL in vitro, human immune cells were isolated from healthy-donor blood and stimulated with anti-CD3 antibody in the presence of HERA-GITRL. Consistently, HERA-GITRL increased the activity of T cells, including proliferation and differentiation, even in the presence of regulatory T cells. In line with these findings, mmHERA-GITRL enhanced antigen-specific clonal expansion of both CD4+ (OT-II) and CD8+ (OT-I) T cells in vivo while having no effect on non-specific T cells. In addition, mmHERA-GITRL showed single-agent anti-tumor activity in two&nbsp;subcutaneous syngeneic colon cancer models (CT26wt&nbsp;and MC38-CEA). Importantly, this activity is independent of its FcγR-binding functionality, as both mmHERA-GITRL with a functional Fc- and a silenced Fc-domain showed similar tumor growth inhibition. Finally, in a direct in vitro comparison to a bivalent clinical benchmark anti-GITR antibody and a trivalent GITRL, only the hexavalent HERA-GITRL showed full biological activity independent of additional crosslinking. <h3>Conclusion</h3> In this manuscript, we describe the development of HERA-GITRL, a true GITR agonist with a clearly defined mechanism of action. By clustering six receptor chains in a spatially well-defined manner, HERA-GITRL induces potent agonistic activity without being dependent on additional FcγR-mediated crosslinking.
Cervical cytologic screening: Optimal management of atypical squamous cells of undetermined significance in young women
Authors: R. K. Gibb, J. D. Wright, R. Davila, M. A. Powell, J. S. Rader, F. Gao, D. G. Mutch
Journal: Journal of Clinical Oncology (2006)

1019 Background: HPV testing is a cost-effective strategy for the management of ASC-US cytology. However, young women have a high prevalence of transient HPV infections and low incidence high grade cervical lesions which may limit the utility of HPV testing in these women. We sought to determine the utility of HPV testing for young women with ASC-US. Methods: A review of all patients with ASC-US cytology between January, 2003 and December, 2004 was performed. Reflex HPV testing using the Hybrid Capture II system was performed on all samples. Age stratified rates of HPV positivity, rates of high grade dysplasia and sensitivity and specificity were estimated. Results: A total of 1290 women with ASC-US cytology were identified. The percentage of ASC-US samples that were HPV positive was highest in the young women and decreased with advancing age: &lt; 25 yo (55%), 26–40 (36%), 41–50 (13%), &gt; 50 yo (12%) (p&lt;0.0001). Among HPV positive women with ASC-US, the identification of high grade lesions (HSIL, CIN2, CIN3, cancer) was lowest in the young women and increased with age: &lt; 25 (12%), 26–40 (24%), 41–50 (19%), &gt; 50 yo (24%) (p=0.05). A negative HPV test more reliably excluded high disease in the young women. No high grade lesions were detected in the HPV negative women ≤ 25 compared to 3.8% of those &gt; 50 (p=0.04). The sensitivity for detection of high grade disease was higher in women &lt; 25 compared to those &gt; 50 (100% vs. 50%), while specificity was lower (14% vs. 44%). Conclusions: Given the high prevalence of HPV and low occurrence of high grade lesions in young women with ASC-US, an HPV based triage strategy will result in the referral of a large number of women for colposcopy and may limit its cost effectiveness. A program of repeat cytology may be more appropriate for the follow-up of young women with ASC-US. [Table: see text]
The biogenesis of lipid droplets: Lipids take center stage
Authors: Mingming Gao, Xun Huang, Bao-Liang Song, Hongyuan Yang
Journal: Progress in Lipid Research (2019)

Lipid droplets (LDs) are multi-functional cellular organelles that store energy, and regulate many aspects of cell physiology. However, our understanding of the biogenesis of LDs remains very limited. Originating from the endoplasmic reticulum (ER), LDs are highly unique organelles in that each LD is bounded by a monolayer of amphipathic lipids. Recent progress has unveiled critical roles of non-bilayer lipids in LD formation. For instance, non-bilayer lipids such as lysophospholipids, diacylglycerol and phosphatidic acid (PA) can impact the curvature, surface and line tension of the ER, thereby impacting LD biogenesis. Two well-known regulators of LD formation, FIT2/FITM2 and seipin, have both been implicated in controlling the metabolism and/or distribution of non-bilayer lipids. We summarize and integrate these recent advances and propose that non-bilayer lipids may play a critical role in each step of LD biogenesis.
Predicting early relapse in patients with BRAF<sup>V600E</sup> melanoma with a highly sensitive blood BRAF assay.
Authors: Ryan J. Sullivan, Donald P. Lawrence, Keith T. Flaherty, David F. McDermott, Julie Aldridge, Daniel C. Cho, Rachel Simonson, Virginia Jean Seery, F. Stephen Hodi, Michael B. Atkins, James Walter Mier, David J Panka
Journal: Journal of Clinical Oncology (2012)

8516 Background: Many patients (pts) with metastatic melanoma (MM) who progress on BRAF inhibitors (BRAFi) develop rapidly progressive disease (PD) which is difficult to manage. Identification of an early marker of PD may allow for therapeutic intervention prior to clinical deterioration. We have developed a highly sensitive and inexpensive assay in our laboratory which can detect as little as 1 BRAF V600E mutant melanoma cell in 400,000 peripheral blood lymphocytes (PBL). We aimed to determine the utility of our assay as a tool to follow pts with BRAF mutant MM who are being treated with a BRAFi. Methods: Every pt had a BRAF V600E mutation detected from a tumor sample in a CLIA-approved laboratory prior to commencing BRAFi therapy. 20 pts with stage IV BRAF V600E MM underwent serial venopunctures before and every 4 weeks during treatment with a BRAFi. BRAF V600E level was quantified using our proprietary assay (Panka et al Melanoma Research 2010). Serial BRAF V600E levels were generated for every pt and normalized to the pre-treatment value. BRAF V600E level was then correlated with response to therapy and PD. Results: BRAF V600E was detected in the PBL of each pt. To date, 10 pts have had BRAF V600E levels quantified at 3 or more time points (data for all 20 pts will be available at time of presentation). Relative BRAF V600E levels reduced by half following the first and second cycles of treatment in 7 pts, which correlated with disease regression in each pt. Following the third cycle of treatment, the relative BRAF V600E levels varied greatly with a subset of pts having continued suppression while others having a rise in their BRAF V600E levels. In each pt with PD, the BRAF assay showed an increase &gt; 4 wks in advance of clinically or radiographically defined PD. Conclusions: Our assay is able to quantify changes in BRAF V600E levels in the blood of pts with BRAF mutant MM receiving BRAFi therapy. In these pts, the BRAF V600E levels are reduced in the setting of initial disease regression and increase well in advance of clinical or radiographic PD. While further development is necessary, such a test could be used to identify pts who may be selected to receive alternative therapy prior to clinical or radiographic PD.
Drug-eluting coronary stents: insights from preclinical and pathology studies
Authors: Sho Torii, Hiroyuki Jinnouchi, Atsushi Sakamoto, Matthew Kutyna, Anne Cornelissen, Salome Kuntz, Liang Guo, Hiroyoshi Mori, Emanuel Harari, Ka Hyun Paek, Raquel Fernandez, Diljon Chahal, Maria E. Romero, Frank D. Kolodgie, Anuj Gupta, Renu Virmani, Aloke V. Finn
Journal: Nature Reviews Cardiology (2019)
Co-production helps ensure that new technology succeeds
Authors: Juliet Dobson
Journal: BMJ (2019)

Digital technology is a fact of modern life. With the NHS Long Term Plan embracing innovation and technology as a way to improve access to services, doctors will have to adapt to new ways of working. But while we all undergo the digital revolution we must not assume that new technology will work for everyone.

Martin Roland is cautious (doi:10.1136/bmj.l4713). Babylon’s digital service, GP at Hand, provides medical care on a smartphone. A recent evaluation found that …
Identification of Patients with Follicular Lymphoma Patients at Risk of Failing Frontline Immunochemotherapy and Rituximab Maintenance
Authors: Marta Garcia Recio, Sandra Pérez-León, Leyre Bento, Antonio Salar, Blanca Sanchez-Gonzalez, Jordi Gines, Beatriz Robredo, Lucia García, Sara Aida Jiménez-Julià, Jordi Martínez-Serra, Antonia Sampol, Antonio Gutiérrez
Journal: Blood (2018)
Transplanting HCV-Infected Kidneys into Uninfected Recipients
Authors: Fabian Halleck, Klemens Budde, Michael Duerr, Oliver Staeck, Joerg Hofmann, Ute Eisenberger, Kerstin Herzer, Martina Sterneck, Jens Gottlieb, Uwe Schulz
Journal: New England Journal of Medicine (2017)
MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
Authors: Jun-Jiang Chen, Zhi-Jie Xiao, Xiaojing Meng, Yan Wang, Mei Kuen Yu, Wen Qing Huang, Xiao Sun, Hao Chen, Yong-Gang Duan, Xiaohua Jiang, Maria Pik Wong, Hsiao Chang Chan, Fei Zou, Ye Chun Ruan
Journal: Theranostics (2019)

Rationale: Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis.However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive.We explored possible regulation of Wnt/β-catenin signaling by multi-drug resistance protein 4 (MRP4), a potential target in cancer chemotherapy, and investigated the mechanism.Methods: Knockdown of MRP4 was performed in human endometrial cells in vitro or in a mouse embryo-implantation model in vivo.Immunoprecipitation, immunoblotting and immunofluorescence were used to assess protein interaction and stability.Wnt/β-catenin signaling was assessed by TOPflash reporter assay and quantitative PCR array.Normal and endometriotic human endometrial tissues were examined.Data from human microarray or RNAseq databases of more than 100 participants with endometriosis, endometrial cancer or IVF were analyzed.In vitro and in vivo tumorigenesis was performed.Results: MRP4-knockdown, but not its transporter-function-inhibition, accelerates β-catenin degradation in human endometrial cells.MRP4 and β-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium.MRP4-knockdown in mouse uterus reduces β-catenin levels, downregulates a series of Wnt/β-catenin target genes and impairs embryo implantation, which are all reversed by blocking β-catenin degradation.Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with β-catenin and Wnt/β-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers.Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Conclusion:A previously undefined role of MRP4 in stabilizing β-catenin to sustain Wnt/β-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/β-catenin signaling abnormality.
Abstract 15398: Identification of Viral Gene Signatures in Cancer Patients With Reduced Ejection Fraction After Chemotherapy
Authors: Chintan Shah, Jan Moreb, Jovil Kannampuzha, Jordan Yaron, Sriram Ambadapadi, Jiangwei Yao, Stacey Schultz-Cherry, Melanie House, Paul Maranian, Liqiang Zhang, Yan Gong, Carl Pepine, Arvind Varsani, Alexandra Lucas
Journal: Circulation (2018)

Introduction: Viral infections are associated with cardiomyopathy, in particular Coxsackievirus and CMV, among many others. Chemotherapy has also been linked to cardiac toxicity (heart failure, myo...
Machine Learning to Predict Anti–Tumor Necrosis Factor Drug Responses of Rheumatoid Arthritis Patients by Integrating Clinical and Genetic Markers
Authors: Yuanfang Guan, Hongjiu Zhang, Daniel Quang, Ziyan Wang, Stephen C. J. Parker, Dimitrios A. Pappas, Joel M. Kremer, Fan Zhu
Journal: Arthritis & Rheumatology (2019)

Accurate prediction of treatment responses in rheumatoid arthritis (RA) patients can provide valuable information on effective drug selection. Anti-tumor necrosis factor (anti-TNF) drugs are an important second-line treatment after methotrexate, the classic first-line treatment for RA. However, patient heterogeneity hinders identification of predictive biomarkers and accurate modeling of anti-TNF drug responses. This study was undertaken to investigate the usefulness of machine learning to assist in developing predictive models for treatment response.Using data on patient demographics, baseline disease assessment, treatment, and single-nucleotide polymorphism (SNP) array from the Dialogue on Reverse Engineering Assessment and Methods (DREAM): Rheumatoid Arthritis Responder Challenge, we created a Gaussian process regression model to predict changes in the Disease Activity Score in 28 joints (DAS28) for the patients and to classify them into either the responder or the nonresponder group. This model was developed and cross-validated using data from 1,892 RA patients. It was evaluated using an independent data set from 680 patients. We examined the effectiveness of the similarity modeling and the contribution of individual features.In the cross-validation tests, our method predicted changes in DAS28 (ΔDAS28), with a correlation coefficient of 0.405. It correctly classified responses from 78% of patients. In the independent test, this method achieved a Pearson's correlation coefficient of 0.393 in predicting ΔDAS28. Gaussian process regression effectively remapped the feature space and identified subpopulations that do not respond well to anti-TNF treatments. Genetic SNP biomarkers showed small contributions in the prediction when added to the clinical models. This was the best-performing model in the DREAM Challenge.The model described here shows promise in guiding treatment decisions in clinical practice, based primarily on clinical profiles with additional genetic information.
Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma.
Authors: Richard D. Carvajal, Grazia Ambrosini, Jedd D. Wolchok, Paul B. Chapman, Mark Andrew Dickson, Sandra P. D'Angelo, Mark J. Bluth, Daniel Paucar, Anne Fusco, David Bohr, Ruth Ann Roman, Mary Montefusco, L. Austin Doyle, Brian Marr, David H. Abramson, Joanne F. Chou, Katherine Panageas, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2012)

8598 Background: Functionally activating mutations (mut) in Gnaq or Gna11, genes that encode for widely expressed G-protein alpha subunits, are early oncogenic events in uveal melanoma (UM) development and result in activation of the MAPK pathway. We previously demonstrated effective pathway inhibition with selumetinib (AZD6244, ARRY-142866) in UM cell lines, with decreased viability associated with pERK and cyclinD1 suppression (Ambrosini, AACR 2010). Methods: Using paired metastatic tumor biopsies from patients (pts) with radiographically progressing UM treated with selumetinib 75 mg BID on a phase II trial (NCT01143402), we correlated MAPK pathway inhibition with radiographic tumor regression and clinical benefit. Biopsies were performed at baseline and after 14 +/-1 days of treatment. Western blotting was performed for pERK and cyclinD1, and quantitated by densitometry. Response (RECIST 1.1) was assessed at baseline, week (wk) 4, wk 8, and q8wks subsequently. Radiographic regression was defined as greatest percentage shrinkage from baseline. Clinical benefit was defined as RECIST response or stable disease ≥16wks. Results: Paired tumor biopsies were assayed from 18 pts: median age 60 (range 47-81), M:F 11:7, median 1 prior therapy (range 0-2), 17 with liver involvement, Gnaq mut:Gna11 mut:wild-type 8:9:1. Radiographic regression was observed in 5 pts, with 2 achieving partial responses. 4 pts were on study ≥16wks (16+, 20, 25, 31 wks), with one currently on study at 11+ wks. Median pERK and cyclinD1 as measured by densitometry decreased by 48% (p=.03) and 76% (p=.03), respectively. Radiographic regression correlated with suppression of pERK (Spearmen’s rank correlation; p=0.04) but not cyclinD1 (p=0.38). A trend towards pERK suppression correlating with clinical benefit was observed (p=.07) with each of the 5 pts achieving PR or SD ≥16wks having a decrease of ≥30% in pERK from baseline. Conclusions: Selumetinib can inhibit pERK and cyclinD1 in UM and can result in tumor shrinkage. Sustained inhibition of pERK inhibition at day 14 may be predictive of benefit. Further evaluation of MEK inhibition in this disease is warranted.
Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages
Authors: Kylie B.R. Belchamber, Richa Singh, Craig M. Batista, Moira K. Whyte, David H. Dockrell, Iain Kilty, Matthew J. Robinson, Jadwiga A. Wedzicha, Peter J. Barnes, Louise E. Donnelly
Journal: European Respiratory Journal (2019)

Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD.Monocyte-derived macrophages (MDMs) were generated from non-smoker, smoker and COPD subjects, differentiated in either granulocyte macrophage-colony stimulating factor (G-Mφ) or macrophage-colony stimulating factor (M-Mφ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage fluid. Macrophages were incubated in ±200 µM H2O2 for 24 h, then exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, after which phagocytosis, mitochondrial ROS (mROS) and mitochondrial membrane potential (ΔΨm) were measured.Phagocytosis of bacteria was significantly decreased in both G-Mφ and M-Mφ from COPD patients compared with from non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or ΔΨm; however, in COPD, phagocytosis increased early mROS and decreased ΔΨm in both G-Mφ and M-Mφ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages and non-smoker MDMs, associated with reduced mROS production.COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.
Final analysis of efficacy and safety of dose-dense chemotherapy with modified TCF regimen (TCF-dd) in elderly patients (pts) with metastatic gastric cancer (MGC).
Authors: Gianluca Tomasello, Wanda Liguigli, Rossana Poli, Margherita Ratti, Laura Toppo, Matteo Brighenti, Mariangela Maltese, Bruno Perrucci, Stefano Panni, Federica Negri, Silvia Lazzarelli, Chiara Colombi, Alessandra Curti, Maddalena Donini, Mario Martinotti, Massimo Rovatti, Rodolfo Passalacqua
Journal: Journal of Clinical Oncology (2013)

e15086 Background: Gastric cancer is more common in elderly pts with its highest incidence around the seventh decade of life. Most oncologists are reluctant to treat this population with the most active polichemotherapy combinations because of safety concerns. Subgroup analyses of elderly pts enrolled in European studies show limited and conflicting data.We previously reported on the feasibility and high activity of a dose-dense TCF regimen (Tomasello 2010). This is a retrospective analysis of efficacy and safety of this schema in the elderly pts subgroup (≥ 65 years). Methods: From Nov 2004 to Jan 2013, 119 consecutivepts with MGC, PS 0-2, not previously treated, received Docetaxel 70 mg/m 2 d1, Cisplatin 60 mg/m 2 d1, l-Folinic Acid 100 mg/m 2 d1-2, followed by 5-FU 400 mg/m 2 bolus d1-2, and then 600 mg/m 2 22 h c.i. d1-2, every 2 weeks, plus Pegfilgrastim 6 mg on day 3. Pts aged ≥ 65 years (60) received the same schedule with doses reducted by 30%. Results: Overall pts characteristics: 76% male, 24% female; median age: 65, range 31-81. A median of 4 cycles was administered. 102 pts were evaluable for response (86%) and all for toxicity. In pts aged ≥ 65 y, we observed 5 CR (8%), 26 PR (43%), 10 SD (17%) and 7 PD (12%); in younger pts: 3 CR (5%), 32 PR (54%), 9 SD (15%) and 10 PD (17%); ORR by ITT was 56% (95% CI 45-64). Median OS was 11,2 months (95% CI 9,4-14,1); in elderly and younger pts was 11,2 (95% CI 7,3-15,1) and 11,8 (95% CI 9,2-16,2), respectively. Out of 48 evaluable pts aged ≥ 65 years, 24 (50%) were treated at full doses without any delay. In the elderly most frequent grade 3-4 toxicities were: neutropenia (13%, p&lt;0.0001), leucopenia (7%), thrombocytopenia (18%), anemia (3%, p=0.02), febrile neutropenia (8%), asthenia (27%), diarrhea (10%), nausea/vomiting (10%) and hypokalemia (17%); in the younger: neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), febrile neutropenia (15%), asthenia (41%), diarrhea (15%), nausea/vomiting (22%) and hypokalemia (20%). Conclusions: This study shows that elderly pts can be safely treated with a TCF-dd regimen with a 30% dose reduction achieving similar efficacy results as younger pts with lesser toxicity.
Genetically Engineered Pluripotent Cell-Derived Natural Killer Cell Therapy Provides Enhanced Antibody Dependent Cellular Cytotoxicity Against Hematologic Malignancies and Solid Tumors in Combination with Monoclonal Antibody Therapy
Authors: Huang Zhu, Ryan Bjordahl, Svetlana Gaidarova, Paul Rogers, Robert Blum, Dan Kaufman, Bruce Walcheck, Bahram Valamehr
Journal: Blood (2017)
Real‐world versus trial patients with transthyretin amyloid cardiomyopathy
Authors: Marco Canepa, Giacomo Tini, Beatrice Musumeci, Francesco Cappelli, Agnese Milandri, Roberta Mussinelli, Camillo Autore, Federico Perfetto, Claudio Rapezzi, Stefano Perlini
Journal: European Journal of Heart Failure (2019)