tbuckley/cabot-search huggingface dataset:
Periodontal inflammation: Integrating genes and dysbiosis
Authors: Shaoping Zhang, Ning Yu, Roger M. Arce
Journal: Periodontology 2000 (2019)

Abstract Biofilm bacteria co‐evolve and reach a symbiosis with the host on the gingival surface. The disruption of the homeostatic relationship between plaque bacteria and the host can initiate and promote periodontal disease progression. Recent advances in sequencing technologies allow researchers to profile disease‐associated microbial communities and quantify microbial metabolic activities and host transcriptional responses. In addition to confirming the findings from previous studies, new putative pathogens and novel genes that have not previously been associated with periodontitis, emerge. For example, multiple studies have reported that Synergistetes bacteria are associated with periodontitis. Genes involved in epithelial barrier defense were downregulated in periodontitis, while excessive expression of interleukin‐17 was associated with a hyperinflammatory response in periodontitis and with a unique microbial community. Bioinformatics‐enabled gene ontology pathway analyses provide a panoramic view of the bacterial and host activities as they shift from periodontal health to disease. Additionally, host innate factors, such as genetic variants identified by either a candidate‐gene approach or genome‐wide association analyses, have an impact on subgingival bacterial colonization. Transgenic mice carrying candidate genetic variants, or with the deletion of candidate genes mimicking the deleterious loss‐of‐function variant effect, provide experimental evidence validating the biologic relevance of the novel markers associated with the microbial phenotype identified through a statistical approach. Further refinement in bioinformatics, data management approaches, or statistical tools, are required to gain insight into host‐microbe interactions by harmonizing the multidimensional “big” data at the genomic, transcriptional, and proteomic levels.
Generating microglia from human pluripotent stem cells: novel in vitro models for the study of neurodegeneration
Authors: Anna M. Speicher, Heinz Wiendl, Sven G. Meuth, Matthias Pawlowski
Journal: Molecular Neurodegeneration (2019)

Microglia play an essential role for central nervous system (CNS) development and homeostasis and have been implicated in the onset, progression, and clearance of numerous diseases affecting the CNS. Previous in vitro research on human microglia was restricted to post-mortem brain tissue-derived microglia, with limited availability and lack of scalability. Recently, the first protocols for the generation of microglia from human pluripotent stem cells have become available, thus enabling the implementation of powerful platforms for disease modeling, drug testing, and studies on cell transplantation. Here we give a detailed and comprehensive overview of the protocols available for generating microglia from human pluripotent stem cells, highlighting the advantages, drawbacks, and operability and placing them into the context of current knowledge of human embryonic development. We review novel insights into microglia biology and the role of microglia in neurological diseases as drawn from the new methods and provide an outlook for future lines of research involving human pluripotent stem cell-derived microglia.
Complete Resolution of Mucosal Neutrophils Associates With Improved Long-Term Clinical Outcomes of Patients With Ulcerative Colitis
Authors: Rish K. Pai, Douglas J. Hartman, Claudia Ramos Rivers, Miguel Regueiro, Marc Schwartz, David G. Binion, Reetesh K. Pai
Journal: Clinical Gastroenterology and Hepatology (2019)
The gut microbiome: an orchestrator of xenobiotic metabolism
Authors: Stephanie L. Collins, Andrew D. Patterson
Journal: Acta Pharmaceutica Sinica B (2019)

Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut via enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell–cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism.
Long-Term Follow-Up of Complete Versus Lesion-Only Revascularization in STEMI and Multivessel Disease
Authors: Anthony H. Gershlick, Amerjeet S. Banning, Emma Parker, Duolao Wang, Charley A. Budgeon, Damian J. Kelly, Peter O. Kane, Miles Dalby, Simon L. Hetherington, Gerry P. McCann, John P. Greenwood, Nick Curzen
Journal: Journal of the American College of Cardiology (2019)
Quantitative distribution of patient-derived leukemia clones in murine xenografts revealed by cellular barcodes
Authors: Sabrina Jacobs, Albertina Ausema, Erik Zwart, Ellen Weersing, Maaike J. Kingma, Yasmine A. S. El Menshawi, Gerald de Haan, Leonid V. Bystrykh, Mirjam E. Belderbos
Journal: Leukemia (2019)
A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies
Authors: Darren C. Phillips, Sha Jin, Gareth P. Gregory, Qi Zhang, John Xue, Xiaoxian Zhao, Jun Chen, Yunsong Tong, Haichao Zhang, Morey Smith, Stephen K. Tahir, Rick F. Clark, Thomas D. Penning, Jennifer R. Devlin, Jake Shortt, Eric D. Hsi, Daniel H. Albert, Marina Konopleva, Ricky W. Johnstone, Joel D. Leverson, Andrew J. Souers
Journal: Leukemia (2019)

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1-dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.
Hemoglobin levels and coronary heart disease risk by age, race, and sex in the reasons for geographic and racial differences in stroke study (REGARDS)
Authors: Damon E. Houghton, Insu Koh, Alicia Ellis, Nigel S. Key, Daniel R. Douce, George Howard, Mary Cushman, Monika Safford, Neil A. Zakai
Journal: American Journal of Hematology (2019)

Higher and lower hemoglobin concentrations are associated with coronary heart disease (CHD), but whether this risk is consistent across age, sex, and race is unclear. The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study is an observational cohort study of 30 239 black, and white, adults aged 45 and older recruited 2003-7. Participants were included if they had hemoglobin measures, were CHD-free at baseline, and had all baseline variables. The primary outcome was incident CHD. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for incident CHD by hemoglobin concentration. This was expressed as a continuous variable and divided into age-, sex-, and race-specific quintiles. The 16 332 participants were included, contributing 114 362 person-years of follow-up and 915 incident CHD events. The mean age was 63 years, 35% were male, 41% were black, and the mean baseline hemoglobin was 13.6 g/dL (SD 1.4). A significant non-linear association between hemoglobin and CHD was identified (P < .001). This association differed significantly by race (P = .025) but not by sex or age. In whites, the risk for incident CHD was higher in the lowest (HR 2.28, 95% CI 1.61, 3.33) and highest (HR 1.94, 95% CI 1.35, 2.79) hemoglobin quintiles relative to the third quintile. For blacks, only those in the lowest hemoglobin quintile had an increased risk for incident CHD events (HR 1.70, 95% CI 1.20, 2.41). Hemoglobin is an independent risk factor for CHD in whites and blacks but with different hemoglobin concentrations conferring different risks.
Asymmetric 67Ga Activity in the Head Related to Prior Head Trauma
Authors: Xia Bai, Xuemei Wang
Journal: Clinical Nuclear Medicine (2019)

Abstract 67 Ga study was performed in a 10-year-old boy who had a history of motor vehicle accident to evaluate occult infection. No abnormal activity typical of active infection was noted. However, there was significantly decreased activity in the right side of the head, which was related to his head trauma.
Initiation of sacubitril/valsartan shortly after hospitalisation for acutely decompensated heart failure in patients with newly diagnosed ( <i>de novo</i> ) heart failure: a subgroup analysis of the TRANSITION study
Authors: Michele Senni, Rolf Wachter, Klaus K. Witte, Ewa Straburzynska‐Migaj, Jan Belohlavek, Candida Fonseca, Christian Mueller, Eva Lonn, Arhit Chakrabarti, Weibin Bao, Adele Noe, Heike Schwende, Dmytro Butylin, Domingo Pascual‐Figal
Journal: European Journal of Heart Failure (2019)
Clinical Development and Research Applications of the Chronic Obstructive Pulmonary Disease Assessment Test
Authors: Hana Müllerová, Mark T. Dransfield, Byron Thomashow, Paul W. Jones, Stephen Rennard, Niklas Karlsson, Malin Fageras, Norbert Metzdorf, Stefano Petruzzelli, Jean Rommes, Frank C. Sciurba, Maggie Tabberer, Debora Merrill, Ruth Tal-Singer
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

The COPD Assessment Test (CAT) was developed by a multidisciplinary group of international experts in chronic obstructive pulmonary disease (COPD) as a short, easy-to-use (paper or digital) tool to...
Will HPV vaccination prevent cervical cancer?
Authors: Claire P Rees, Petra Brhlikova, Allyson M Pollock
Journal: Journal of the Royal Society of Medicine (2020)

Summary We conducted a critical appraisal of published Phase 2 and 3 efficacy trials in relation to the prevention of cervical cancer in women. Our analysis shows the trials themselves generated significant uncertainties undermining claims of efficacy in these data. There were 12 randomised control trials (RCTs) of Cervarix and Gardasil. The trial populations did not reflect vaccination target groups due to differences in age and restrictive trial inclusion criteria. The use of composite and distant surrogate outcomes makes it impossible to determine effects on clinically significant outcomes. It is still uncertain whether human papillomavirus (HPV) vaccination prevents cervical cancer as trials were not designed to detect this outcome, which takes decades to develop. Although there is evidence that vaccination prevents cervical intraepithelial neoplasia grade 1 (CIN1) this is not a clinically important outcome (no treatment is given). Trials used composite surrogate outcomes which included CIN1. High efficacy against CIN1+ (CIN1, 2, 3 and adenocarcinoma in situ (AIS)) does not necessarily mean high efficacy against CIN3+ (CIN3 and AIS), which occurs much less frequently. There are too few data to clearly conclude that HPV vaccine prevents CIN3+. CIN in general is likely to have been overdiagnosed in the trials because cervical cytology was conducted at intervals of 6–12 months rather than at the normal screening interval of 36 months. This means that the trials may have overestimated the efficacy of the vaccine as some of the lesions would have regressed spontaneously. Many trials diagnosed persistent infection on the basis of frequent testing at short intervals, i.e. less than six months. There is uncertainty as to whether detected infections would clear or persist and lead to cervical changes.
A Phase Ib Study of Preoperative, Locoregional IRX-2 Cytokine Immunotherapy to Prime Immune Responses in Patients with Early-Stage Breast Cancer
Authors: David B. Page, Joanna Pucilowska, Katherine G. Sanchez, Valerie K. Conrad, Alison K. Conlin, Anupama K. Acheson, Kelly S. Perlewitz, James H. Imatani, Shaghayegh Aliabadi-Wahle, Nicole Moxon, Staci L. Mellinger, Amanda Y. Seino, Martiza Martel, Yaping Wu, Zhaoyu Sun, William L. Redmond, Venkatesh Rajamanickam, Dottie Waddell, Deborah Laxague, Monil Shah, Shu-Ching Chang, Walter J. Urba
Journal: Clinical Cancer Research (2019)

To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity.Sixteen patients with stage I-III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative locoregional immunotherapy with the IRX-2 cytokine biological (2 mL subcutaneous × 10 days to periareolar skin). The regimen also included single-dose cyclophosphamide (300 mg/m2) on day 1 to deplete T-regulatory cells and oral indomethacin to modulate suppressive myeloid subpopulations. The primary objective was to evaluate feasibility (i.e., receipt of therapy without surgical delays or grade 3/4 treatment-related adverse events). The secondary objective was to evaluate changes in stromal tumor-infiltrating lymphocyte score. The exploratory objective was to identify candidate pharmacodynamic changes for future study using a variety of assays, including flow cytometry, RNA and T-cell receptor DNA sequencing, and multispectral immunofluorescence.Preoperative locoregional cytokine administration was feasible in 100% (n = 16/16) of subjects and associated with increases in stromal tumor-infiltrating lymphocytes (P < 0.001). Programmed death ligand 1 (CD274) was upregulated at the RNA (P < 0.01) and protein level [by Ventana PD-L1 (SP142) and immunofluorescence]. Other immunomodulatory effects included upregulation of RNA signatures of T-cell activation and recruitment and cyclophosphamide-related peripheral T-regulatory cell depletion.IRX-2 is safe in early-stage breast cancer. Potentially favorable immunomodulatory changes were observed, supporting further study of IRX-2 in early-stage breast cancer and other malignancies.
Selective induction of antibody effector functional responses using MF59-adjuvanted vaccination
Authors: Carolyn M. Boudreau, Wen-Han Yu, Todd J. Suscovich, H. Keipp Talbot, Kathryn M. Edwards, Galit Alter
Journal: Journal of Clinical Investigation (2019)

Seasonal and pandemic influenza infection remains a major public health concern worldwide. Driving robust humoral immunity has been a challenge given preexisting, often cross-reactive, immunity and in particular, poorly immunogenic avian antigens. To overcome immune barriers, the adjuvant MF59 has been used in seasonal influenza vaccines to increase antibody titers and improve neutralizing activity, translating to a moderate increase in protection in vulnerable populations. However, its effects on stimulating antibody effector functions, including NK cell activation, monocyte phagocytosis, and complement activity, all of which have been implicated in protection against influenza, have yet to be defined. Using systems serology, we assessed changes in antibody functional profiles in individuals who received H5N1 avian influenza vaccine administered with MF59, with alum, or delivered unadjuvanted. MF59 elicited antibody responses that stimulated robust neutrophil phagocytosis and complement activity. Conversely, vaccination with MF59 recruited NK cells poorly and drove moderate monocyte phagocytic activity, both likely compromised because of the induction of antibodies that did not bind FCGR3A. Collectively, defining the humoral antibody functions induced by distinct adjuvants may provide a path to designing next-generation vaccines that can selectively leverage the humoral immune functions, beyond binding and neutralization, resulting in better protection from infection.
Development of a prognostic composite cytokine signature based on the correlation with nivolumab clearance: translational PK/PD analysis in patients with renal cell carcinoma
Authors: Rui Wang, Junying Zheng, Xiao Shao, Yuko Ishii, Amit Roy, Akintunde Bello, Richard Lee, Joshua Zhang, Megan Wind-Rotolo, Yan Feng
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Although several therapeutic options for patients with renal cell carcinoma (RCC) have been approved over recent years, including immune checkpoint inhibitors, considerable need remains for molecular biomarkers to assess disease prognosis. The higher pharmacokinetic (PK) clearance of checkpoint inhibitors, such as the anti–programmed death-1 (PD-1) therapies nivolumab and pembrolizumab, has been shown to be associated with poor overall survival (OS) across several tumor types. However, determination of PK clearance requires the collection and analysis of post-treatment serum samples, limiting its utility as a prognostic biomarker. This report outlines a translational PK-pharmacodynamic (PD) methodology used to derive a baseline composite cytokine signature correlated with nivolumab clearance using data from three clinical trials in which nivolumab or everolimus was administered. <h3>Methods</h3> Peripheral serum cytokine (PD) and nivolumab clearance (PK) data from patients with RCC were analyzed using a PK-PD machine-learning model. Nivolumab studies CheckMate 009 (NCT01358721) and CheckMate 025 (NCT01668784) (<i>n</i>&nbsp;= 480) were used for PK-PD analysis model development and cytokine feature selection (training dataset). Validation of the model and assessment of the prognostic value of the cytokine signature was performed using data from CheckMate 010 (NCT01354431) and the everolimus comparator arm of CheckMate 025 (test dataset; <i>n</i>&nbsp;= 453). <h3>Results</h3> The PK-PD analysis found a robust association between the eight top-ranking model-selected baseline inflammatory cytokines and nivolumab clearance (area under the receiver operating characteristic curve = 0.7). The predicted clearance (high vs low) based on the cytokine signature was significantly associated with long-term OS (<i>p</i>&nbsp;&lt; 0.01) across all three studies (training and test datasets). Furthermore, cytokines selected from the model development trials also correlated with OS of the everolimus comparator arm (<i>p</i>&nbsp;&lt; 0.01), suggesting the prognostic nature of the composite cytokine signature for RCC. <h3>Conclusions</h3> Here, we report a PK-PD translational approach to identify a molecular prognostic biomarker signature based on the correlation with nivolumab clearance in patients with RCC. This composite biomarker signature may provide improved prognostic accuracy of long-term clinical outcome compared with individual cytokine features and could be used to ensure the balance of patient randomization in RCC clinical trials.
Abstract I01: Mechanisms and consequences of pancreatic cancer stromal evolution
Authors: Mara Sherman
Journal: Cancer Research (2019)

Abstract The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of a fibroinflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type driving the stromal reaction in PDAC. Recent reports suggest that PDAC CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types that support and others that suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas that can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of CAFs in the PDAC microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have taken advantage of a novel mouse model we developed to track PSC differentiation and function during pancreatic tumor progression in vivo. This model leverages the unique lipid-storing origin of PSC-derived CAFs, and enables their distinction from CAFs of non-PSC origin for the first time. We hypothesized that PSC-derived fibroblasts in the PDAC microenvironment are a proinflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. Using our model, we have interrogated PDAC stromal heterogeneity and functional significance, analyzed the distinguishing features of CAF subpopulations from disparate origins, and determined the significance of genetic alterations in the epithelial compartment on stromal cell fate and function. Together, these studies have the potential to lay the foundation for development of stroma-targeted therapies based on careful lineage tracing and molecular data. These findings shed light on mechanisms of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors. Citation Format: Mara Sherman. Mechanisms and consequences of pancreatic cancer stromal evolution [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I01.
68Ga-ZHER2 PET/CT Reveals HER2-Positive Metastatic Gastric Cancer With Better Image Quality Than 18F-FDG
Authors: Nina Zhou, Xiaoyi Guo, Min Yang, Hua Zhu, Zhi Yang
Journal: Clinical Nuclear Medicine (2019)

Abstract A 40-year-old woman with suspected recurrent HER2-positive gastric cancer underwent both 18 F-FDG PET/CT and 68 Ga-ZHER2 PET/CT. Both scans revealed multiple lesions in bones and the left supraclavicular lymph node. Compared with 18 F-FDG, 68 Ga-ZHER2 PET/CT showed better image contrast, especially in the bone lesions.