tbuckley/cabot-search huggingface dataset:
Abstract 11998: Treatment of Psoriasis With Biologic Therapy is Associated With Regression of Coronary Artery Plaque Necrotic Core and Positive Remodeling: Results From a Prospective, Observational Pilot Study
Authors: Harry Choi, Milena Aksentijevich, Amit K Dey, Colin Scott, Justin A Rodante, Youssef Elnabawi, Noor O Khalil, Danish Akbar, Mina Al Najafi, Paula Anzenberg, Jenis Argueta-Amaya, Andrew Keel, Heather Teague, Martin Playford, Joel Gelfand, Marcus Y Chen, David A Bluemke, Andrew Buckler, Nehal N Mehta
Journal: Circulation (2019)

Introduction: Psoriasis (PSO) is a chronic inflammatory condition associated with elevated non-calcified coronary plaque, high-risk plaque features and increased risk of major cardiovascular events...
Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia
Authors: Tian Zhang, Jiawen Yang, Vijaya P. Vaikari, John S. Beckford, Sharon Wu, Mojtaba Akhtari, Houda Alachkar
Journal: Blood Cancer Discovery (2020)

Abstract Acute myeloid leukemia (AML) is a devastating hematologic malignancy that affects the hematopoietic stem cells. The 5-year overall survival (OS) of patients with AML is less than 30%, highlighting the urgent need to identify new therapeutic targets. Here, we analyze gene expression datasets for genes that are differentially overexpressed in AML cells compared with healthy hematopoietic cells. We report that apolipoprotein C2 (APOC2) mRNA is significantly overexpressed in AML, particularly in patients with mixed-lineage leukemia rearrangements. By multivariate analysis, high APOC2 expression in leukemia blasts is significantly associated with decreased OS (HR: 2.51; 95% CI, 1.03–6.07; P = 0.04). APOC2 is a small secreted apolipoprotein that constitutes chylomicrons, very-low-density lipoproteins, and high-density lipoproteins with other apolipoproteins. APOC2 activates lipoprotein lipase and contributes to lipid metabolism. By gain and loss of function approaches in cultured AML cells, we demonstrate that APOC2 promotes leukemia growth via CD36-mediated LYN–ERK signaling activation. Knockdown or pharmacological inhibition of either APOC2 or CD36 reduces cell proliferation, induces apoptosis in vitro, and delays leukemia progression in mice. Altogether, this study establishes APOC2–CD36 axis as a potential therapeutic target in AML. Significance: The majority of patients with AML die within five years of diagnosis. We reveal that lipid transporter APOC2 is elevated in AML and promotes leukemic cell metabolism and growth via CD36, and provide preclinical evidence that targeting this pathway may be beneficial in AML. This article is highlighted in the In This Issue feature, p. 127
The economic burden of cancer care for Syrian refugees: a population-based modelling study
Authors: Rima A Abdul-Khalek, Ping Guo, Forbes Sharp, Adrian Gheorghe, Omar Shamieh, Tezer Kutluk, Fouad Fouad, Adam Coutts, Ajay Aggarwal, Deborah Mukherji, Ghassan Abu-Sittah, Kalipso Chalkidou, Richard Sullivan
Journal: The Lancet Oncology (2020)

Cancer represents a substantial health burden for refugees and host countries. However, no reliable data on the costs of cancer care for refugees are available, which limits the planning of official development assistance in humanitarian settings. We aimed to model the direct costs of cancer care among Syrian refugee populations residing in Jordan, Lebanon, and Turkey.In this population-based modelling study, direct cost per capita and per incident case for cancer care were estimated using generalised linear models, informed by a representative dataset of cancer costs drawn from 27 EU countries. A range of regression specifications were tested, in which cancer costs were modelled using different independent variables: gross domestic product (GDP) per capita, crude or age-standardised incidence, crude or age-standardised mortality, and total host country population size. Models were compared using the Akaike information criterion. Total cancer care costs for Syrian refugees in Jordan, Lebanon, and Turkey were calculated by multiplying the estimated direct cancer care costs (per capita) by the total number of Syrian refugees, or by multiplying the estimated direct cancer costs (per incident case [crude or age-standardised]) by the number of incident cancer cases in Syrian refugee populations. All costs are expressed in 2017 euros (€).Total cancer care costs for all 4·74 million Syrian refugees in Jordan, Lebanon, and Turkey in 2017 were estimated to be €140·23 million using the cost per capita approach, €79·02 million using the age-standardised incidence approach, and €33·68 million using the crude incidence approach. Under the lowest estimation, and with GDP and total country population as model predictors, the financial burden of cancer care was highest for Turkey (€25·18 million), followed by Lebanon (€6·40 million), and then Jordan (€2·09 million).Cancer among the Syrian refugee population represents a substantial financial burden for host countries and humanitarian agencies, such as the UN Refugee Agency. New ways to provide financial assistance need to be found and must be coupled with clear, prioritised pathways and models of care for refugees with cancer.UK Research and Innovation Global Challenges Research Fund: Research for Health in Conflict-Middle East and North Africa region (R4HC-MENA).
Call to Action to Prevent Venous Thromboembolism in Hospitalized Patients: A Policy Statement From the American Heart Association
Authors: Peter K. Henke, Susan R. Kahn, Christopher J. Pannucci, Eric A. Secemksy, Natalie S. Evans, Alok A. Khorana, Mark A. Creager, Aruna D. Pradhan
Journal: Circulation (2020)

Venous thromboembolism (VTE) is a major preventable disease that affects hospitalized inpatients. Risk stratification and prophylactic measures have good evidence supporting their use, but multiple reasons exist that prevent full adoption, compliance, and efficacy that may underlie the persistence of VTE over the past several decades. This policy statement provides a focused review of VTE, risk scoring systems, prophylaxis, and tracking methods. From this summary, 5 major areas of policy guidance are presented that the American Heart Association believes will lead to better implementation, tracking, and prevention of VTE events. They include performing VTE risk assessment and reporting the level of VTE risk in all hospitalized patients, integrating preventable VTE as a benchmark for hospital comparison and pay-for-performance programs, supporting appropriations to improve public awareness of VTE, tracking VTE nationwide with the use of standardized definitions, and developing a centralized data steward for data tracking on VTE risk assessment, prophylaxis, and rates.
Flow-cytometric microglial sorting coupled with quantitative proteomics identifies moesin as a highly-abundant microglial protein with relevance to Alzheimer’s disease
Authors: Sruti Rayaprolu, Tianwen Gao, Hailian Xiao, Supriya Ramesha, Laura D. Weinstock, Jheel Shah, Duc M. Duong, Eric B. Dammer, James A. Webster, James J. Lah, Levi B. Wood, Ranjita Betarbet, Allan I. Levey, Nicholas T. Seyfried, Srikant Rangaraju
Journal: Molecular Neurodegeneration (2020)

Abstract Background Proteomic characterization of microglia provides the most proximate assessment of functionally relevant molecular mechanisms of neuroinflammation. However, microglial proteomics studies have been limited by low cellular yield and contamination by non-microglial proteins using existing enrichment strategies. Methods We coupled magnetic-activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) of microglia with tandem mass tag-mass spectrometry (TMT-MS) to obtain a highly-pure microglial proteome and identified a core set of highly-abundant microglial proteins in adult mouse brain. We interrogated existing human proteomic data for Alzheimer’s disease (AD) relevance of highly-abundant microglial proteins and performed immuno-histochemical and in-vitro validation studies. Results Quantitative multiplexed proteomics by TMT-MS of CD11b + MACS-enriched ( N = 5 mice) and FACS-isolated ( N = 5 mice), from adult wild-type mice, identified 1791 proteins. A total of 203 proteins were highly abundant in both datasets, representing a core-set of highly abundant microglial proteins. In addition, we found 953 differentially enriched proteins comparing MACS and FACS-based approaches, indicating significant differences between both strategies. The FACS-isolated microglia proteome was enriched with cytosolic, endoplasmic reticulum, and ribosomal proteins involved in protein metabolism and immune system functions, as well as an abundance of canonical microglial proteins. Conversely, the MACS-enriched microglia proteome was enriched with mitochondrial and synaptic proteins and higher abundance of neuronal, oligodendrocytic and astrocytic proteins. From the 203 consensus microglial proteins with high abundance in both datasets, we confirmed microglial expression of moesin (Msn) in wild-type and 5xFAD mouse brains as well as in human AD brains. Msn expression is nearly exclusively found in microglia that surround Aβ plaques in 5xFAD brains. In in-vitro primary microglial studies, Msn silencing by siRNA decreased Aβ phagocytosis and increased lipopolysaccharide-induced production of the pro-inflammatory cytokine, tumor necrosis factor (TNF). In network analysis of human brain proteomic data, Msn was a hub protein of an inflammatory co-expression module positively associated with AD neuropathological features and cognitive dysfunction. Conclusions Using FACS coupled with TMT-MS as the method of choice for microglial proteomics, we define a core set of highly-abundant adult microglial proteins. Among these, we validate Msn as highly-abundant in plaque-associated microglia with relevance to human AD.
β‐Lactamase inhibitors
Authors: S. J. Cartwright, S. G. Waley
Journal: Medicinal Research Reviews (1983)

In summary, Table XVI shows the inhibition profiles of representative beta-lactamases from each major class of Richmond and Sykes. Either resistance (R) or sensitivity (S) is given as a general guide to the type of compounds likely to inhibit each class. Thus the (qualitative) statements regarding the effectiveness of clavulanic acid can be taken to represent those for the penam sulfones and similarly for MM4550 and the other olivanic acids, carpetimycins, PS series, and asparenomycins. This can also be said of cloxacillin and the other aromatic carboxamido penicillins. Compounds are also included which are specifically or particularly inhibitory to certain beta-lactamases.
O-0001 International Experts' Consensus for the Definition of Time to Event Endpoints in Clinical Trials (DATECAN Project): Results for Pancreatic Cancer
Authors: Franck Bonnetain, Adelaide Dousseau, Bonsing Bert, Glimelius Bengt, Karin Haustermans, Thierry Conroy, Jean Luc Van Laethem, Roberto Labianca, Teresa Macarulla, Josep Tabernero, Manfred Lutz, John P. Neoptolemos, Aimery De Gramont, Datecan Group, Laurence Collette
Journal: Annals of Oncology (2012)
Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial
Authors: Lu Xie, Jie Xu, Xin Sun, Wei Guo, Jin Gu, Kuisheng Liu, Bingxin Zheng, Tingting Ren, Yi Huang, Xiaodong Tang, Taiqiang Yan, Rongli Yang, Kunkun Sun, Danhua Shen, Yuan Li
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Results of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy. Methods This open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1. Results 43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths. Conclusions Although the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS. Trial registration number NCT03359018 .
Mild to Moderate Sleep Apnea Is Linked to Hypoxia-induced Motor Recovery after Spinal Cord Injury
Authors: Isabelle Vivodtzev, Andrew Q. Tan, Megan Hermann, Arun Jayaraman, Victoria Stahl, William Zev Rymer, Gordon S. Mitchell, Heather B. Hayes, Randy D. Trumbower
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Allosteric Inhibition of SHP2 Stimulates Antitumor Immunity by Transforming the Immunosuppressive Environment
Authors: Elsa Quintana, Christopher J. Schulze, Darienne R. Myers, Tiffany J. Choy, Kasia Mordec, David Wildes, Nataliya Tobvis Shifrin, Amira Belwafa, Elena S. Koltun, Adrian L. Gill, Mallika Singh, Stephen Kelsey, Mark A. Goldsmith, Robert Nichols, Jacqueline A.M. Smith
Journal: Cancer Research (2020)

Abstract The protein tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of SHP2, induces antitumor immunity, with effects equivalent to or greater than those resulting from checkpoint blockade. In the tumor microenvironment, inhibition of SHP2 modulated T-cell infiltrates similar to checkpoint blockade. In addition, RMC-4550 drove direct, selective depletion of protumorigenic M2 macrophages via attenuation of CSF1 receptor signaling and increased M1 macrophages via a mechanism independent of CD8+ T cells or IFNγ. These dramatic shifts in polarized macrophage populations in favor of antitumor immunity were not seen with checkpoint blockade. Consistent with a pleiotropic mechanism of action, RMC-4550 in combination with either checkpoint or CSF1R blockade caused additive antitumor activity with complete tumor regressions in some mice; tumors intrinsically sensitive to SHP2 inhibition or checkpoint blockade were particularly susceptible. Our preclinical findings demonstrate that SHP2 thus plays a multifaceted role in inducing immune suppression in the tumor microenvironment, through both targeted inhibition of RAS pathway–dependent tumor growth and liberation of antitumor immune responses. Furthermore, these data suggest that inhibition of SHP2 is a promising investigational therapeutic approach. Significance: Inhibition of SHP2 causes direct and selective depletion of protumorigenic M2 macrophages and promotes antitumor immunity, highlighting an investigational therapeutic approach for some RAS pathway–driven cancers.
Association of <i>NOS3</i> and <i>ANGPT2</i> Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study
Authors: Andrea Casadei-Gardini, Giorgia Marisi, Vincenzo Dadduzio, Laura Gramantieri, Luca Faloppi, Paola Ulivi, Francesco Giuseppe Foschi, Emiliano Tamburini, Caterina Vivaldi, Mario Domenico Rizzato, Luca Ielasi, Matteo Canale, Fabio Conti, Britt Rudnas, Lorenzo Fornaro, Nicola Silvestris, Marianna Silletta, Giovanni Gerardo Cardellino, Sara Lonardi, Francesca Fornari, Giulia Orsi, Giulia Rovesti, Vittorina Zagonel, Stefano Cascinu, Mario Scartozzi
Journal: Clinical Cancer Research (2020)

Abstract Purpose: After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of nitric oxide synthase 3 (NOS3) and ANGPT2 polymorphisms in patients with HCC treated with sorafenib [NCT02786342]. Patients and Methods: This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate. Results: A total of 165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; P = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; P &amp;lt; 0.0001) compared with TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; P = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; P = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR = 0.50; P = 0.0128) and OS (HR = 0.29; P = 0.0041). Conclusions: The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.
Meta-analysis of the tumor response in patients treated with rituximab either in combination with chemotherapy or with treatment following chemotherapy in CD20+ B-cell lymphomas.
Authors: Francesco Turturro, Jonathan Glass, Glenn Mills, Ranhua Shi
Journal: Cancer Research (2007)

902  We performed a meta-analysis of the studies that contained two distinct arms of patient population with CD20+ B cell non-Hodgkin’s lymphoma (NHL) undergoing treatment with chemotherapy with and without rituximab (Rituxan®). We identified 9 articles and defined 11 studies within these articles in which data on objective tumor response (OTR) defined by the sum of complete response (CR) and partial response (PR) were available by screening all the studies published on PubMed and Ovid Medline database from June 1966 to October 2006. The total number of patients participating in the 11 studies was 2150 with 1093 patients in the group receiving rituximab/chemotherapy and 1057 in the chemotherapy group. Overall the relative risk (RR) of response to the treatment for using rituximab was 1.20 (95% CI 1.15-1.26) and 1.21 (95% CI 1.09-1.35) based on the fixed effect and random effect model, respectively, translating in an increased response in the order of 20% and 21%. Patients in the follicular cell lymphoma (FCL) group, showed a RR of response to the treatment including rituximab equal to 1.19 (95% CI 1.07-1.17) and 1.20 (95% CI 1.03-1.40) for fixed and random effect model analysis, respectively, equal to an overall response rate increase of 19% and 20%. On the other hand, patients in the mantle cell (MCL) group showed a RR of response to the treatment with rituximab equal to 1.32 (95% CI 1.11-1.56) and 1.28 (95% CI 1.10-1.49) with overall response rate increase of 32% and 28%, respectively. These data indicate that rituximab has a statistically significant additive effect to chemotherapy independently from the lymphoma histotype and that the magnitude of the response to rituximab is higher for MCL than for FCL patients.
Abstract IA03: Control over colorectal tumor growth via bacteria-specific T-cell activation of the local immune response
Authors: Abigail Overacre-Delgoffe, Hannah Bumgarner, Tim Hand
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise, particularly in young people. Therapy for late-stage CRC is often ineffective, and colorectal tumors are most often detected at stage 3 or 4. Immunotherapy is revolutionizing the treatment of many types of cancer but is only effective for a very small subset of CRC patients. Thus, there is a tremendous need for improved therapies for CRC. Colorectal tumors grow from the intestinal epithelium and are therefore subject to interaction with the dense and diverse colonic microbiota. Indeed, CRC has been associated with shifts in the composition of the microbiota that effect inflammation and tumor growth. How the microbiota shapes the CRC immune microenvironment is not fully understood. In general, the microbiota can directly shape T-cell responses, directing the differentiation of CD4 T cells to develop into either regulatory (Treg) or effector (Th1, Th17, etc.) T cells. This is particularly true of those T cells local to the intestine that are often specific to antigens derived from intestinal bacteria. We became interested in how colonization with different bacterial taxa might affect the T-cell immune response and control over colorectal cancer. Using a mouse model of CRC, we show that colonization with a single bacterial taxon, after tumors have already developed, leads to a reduction in tumor burden and size. Bacteria-dependent tumor reduction depended upon CD4 T cells but not CD8 T cells as antibody depletion of CD4 T cells completely abrogated the effect. Accordingly, de novo bacterial colonization was associated with a colorectal tumor environment that possessed fewer Tregs, increased CD4 IFNgamma-producing T cells, and increased CD103+ dendritic cells. We also observed that colonized mice develop increased numbers of organized tertiary lymphoid structures that were adjacent to colonic tumor. Importantly, bacteria-specific CD4 T cells were commonly found in these tertiary lymphoid structures, as were bacteria. Our hypothesis is that microbiota-driven and T cell-dependent development of TLS structures leads to enhanced tumor antigen presentation and augmented antitumor immune responses. This work has the potential to inform CRC therapies via the rational modification of the local microbiota to support TLS formation and antitumor immunity. Citation Format: Abigail Overacre-Delgoffe, Hannah Bumgarner, Tim Hand. Control over colorectal tumor growth via bacteria-specific T-cell activation of the local immune response [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA03.