tbuckley/cabot-search huggingface dataset:
Priming with FLO8-deficient Candida albicans induces Th1-biased protective immunity against lethal polymicrobial sepsis
Authors: Quan-Zhen Lv, De-Dong Li, Hua Han, Yi-Heng Yang, Jie-Lin Duan, Hui-Hui Ma, Yao Yu, Jiang-Ye Chen, Yuan-Ying Jiang, Xin-Ming Jia
Journal: Cellular and Molecular Immunology (2020)

Abstract The morphological switch between yeast and hyphae of Candida albicans is essential for its interaction with the host defense system. However, the lack of understanding of host–pathogen interactions during C. albicans infection greatly hampers the development of effective immunotherapies. Here, we found that priming with the C. albicans FLO8- deficient ( flo8 ) mutant, locked in yeast form, protected mice from subsequent lethal C. albicans infection. Deficiency of Dectin-2, a fungus-derived α-mannan recognition receptor, completely blocked flo8 mutant-induced protection. Mechanistically, the flo8 mutant-induced Dectin-2/CARD9-mediated IL-10 production in DCs and macrophages to block thymus atrophy by inhibiting the C. albicans -induced apoptosis of thymic T cells, which facilitated the continuous output of naive T cells from the thymus to the spleen. Continuous recruitment of naive T cells to the spleen enhanced Th1-biased antifungal immune responses. Consequently, depletion of CD4+ T cells or blockade of IL-10 receptor function using specific antibodies in mice completely blocked the protective effects of flo8 mutant priming against C. albicans infection. Moreover, mannans exposed on the surface of the flo8 mutant were responsible for eliciting protective immunity by inhibiting the C. albicans -induced apoptosis of thymic T cells to sustain the number of naive T cells in the spleen. Importantly, priming with the flo8 mutant extensively protected mice from polymicrobial infection caused by cecal ligation and puncture (CLP) by enhancing Th1-biased immune responses. Together, our findings imply that targeting FLO8 in C. albicans elicits protective immune responses against polymicrobial infections and that mannans extracted from the flo8 mutant are potential immunotherapeutic candidate(s) for controlling infectious diseases.
Abstract IA13: In the light of evolution: Why do we get more cancers in old age?
Authors: Catherine Pham-Danis, Andrii Rozhok, Hannah Scarborough, Nathaniel Little, Curtis Henry, Travis Nemkov, Kirk Hansen, James DeGregori
Journal: Cancer Research (2020)

Abstract Why do we get cancer? Why is cancer highly associated with old age? Of course, aging is associated with the accumulation of more mutations, and some of these mutations can contribute to cancer phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are tissue environmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, cellular (somatic) evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We have been using mouse models of cancer initiation, mathematical models of cellular evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. We have shown that aging and inflammation dependent changes in tissue environments dramatically dictate whether cancer-causing mutations are advantageous to stem cells in our tissues, starting the cells down the path to cancer. Our studies have focused on cancer initiation within the hematopoietic system and the lung. These studies have also uncovered molecular explanations for mutation-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. While we largely cannot prevent mutation accumulation through our lives, we do have the ability to manipulate tissue environments so as to change the evolutionary trajectories of cells with cancer-causing mutations. Citation Format: Catherine Pham-Danis, Andrii Rozhok, Hannah Scarborough, Nathaniel Little, Curtis Henry, Travis Nemkov, Kirk Hansen, James DeGregori. In the light of evolution: Why do we get more cancers in old age? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA13.
PTU-033 Negotiation of the splenic flexure- an observational study of patient characteristics and colonoscopic manoeuvres
Authors: S O’Connor, R Carr, P Dunkley, R Valori, J Anderson
Journal: Gut (2017)

Introduction  Successful negotiation of the splenic flexure (SF) during colonoscopy is essential in achieving caecal intubation. Our aim was to assess patient characteristics and colonoscopic manoeuvres (CM) that facilitate insertion through and beyond the SF.  Method  We conducted a prospective observational study of colonoscopies performed within 2 high volume national training centres in the United Kingdom (UK) where the average caecal intubation rate is 97%. All colonoscopists were certified for colonoscopy within the UK. Data was collected on a pro-forma which was completed by the colonoscopist or an assistant, during or post colonoscopy. Patient sex, age, body mass index (BMI-kg/m²), history of past major abdominal surgery and sedation used were documented. Magnetic endoscope imager (ScopeGuide, Olympus Medical Systems Corporation, Japan) was used for all procedures to determine scope and tip position at the SF. CM employed, patient position, time and success at each SF pass attempt was recorded. The CM that were recorded included, breath in and hold, mid/lower abdominal pressure, left upper quadrant/flank pressure, slowing down, suction and tip deangulation.  Results  10 colonoscopists recorded data on 158 colonoscopies. 140 (88.6%) of these were performed by Gastroenterologists. 43 (27.2%) colonoscopies were unsedated. No patients had more than 3 mg Midazolam or 100mcg Fentanyl. 123 (77.8%) initial attempts at splenic flexure (SF) passes were successful. Of these successful SF passes, the scope stiffener was used in 81 (65.8%) patients. 76 (61.8%) patients were supine and 31 (25.2%) were in the right lateral position. Additional CM was not used in 84 (68.2%) of these patients. Specific slowing of the scope insertion was the most common CM used for successful 1 st pass and was used in 21 (17.1%) patients. Patients with a BMI >30 kg/m² (obese) were more likely to require >1 attempt at negotiation of the SF compared to BMI   Conclusion  Patient satisfaction and comfort are essential, especially where no or minimal sedation is used in colonoscopy. Left upper quadrant pressure can aid passage through the SF in obese patients. Further studies are needed to determine the optimal patient positions and CM to facilitate comfortable, effective and efficient colonoscopy.  Disclosure of Interest  None Declared
A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)
Authors: Kiyomi Morita, Hagop M. Kantarjian, Guillermo Montalban Bravo, Koji Sasaki, Naval Daver, Elias Jabbour, Yesid Alvarado, Kelly S. Chien, Courtney D. DiNardo, Farhad Ravandi, Gautam Borthakur, Prithviraj Bose, Naveen Pemmaraju, Kiran Naqvi, Jorge E. Cortes, Tapan M. Kadia, Marina Konopleva, Caitlin R. Rausch, Yvonne Gasior, Guillermo Garcia-Manero
Journal: Blood (2020)
Retroperitoneal Involvement of Light Chain Amyloidosis-Case Series and Literature Review
Authors: Iuliana Vaxman, Alissa Visram, Oren Pasvolsky, Shaji K. Kumar, Angela Dispenzieri, Francis K. Buadi, David Dingli, Martha Q. Lacy, Suzanne R. Hayman, Robert A. Kyle, Prashant Kapoor, Nelson Leung, Wilson I Gonsalves, Taxiarchis Kourelis, Rahma M Warsame, Abdullah S. Al Saleh, Morie A. Gertz
Journal: Blood (2020)
Characterization of the Blood and Bone Marrow Microbiome of MDS Patients and Associations with Clinical Features
Authors: Jakob Woerner, Yidi Huang, Yimin Huang, Janet Wang, Jesus M Hernández-Sánchez, Jaroslaw P. Maciejewski, Mehmet Koyuturk, Stephan Hutter, Torsten Haferlach, Thomas Laframboise
Journal: Blood (2020)
Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin
Authors: Amany R. Keruakous, George Selby, Sarah A. Schmidt, Jennifer Holter-Chakrabarty, Mohamad O. Khawandanah, Jennifer Steward, Silas Day, Carrie Yuen
Journal: Blood (2020)
Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism
Authors: Sandra Pereira, Daemon L Cline, Maria M Glavas, Scott D Covey, Timothy J Kieffer
Journal: Endocrine Reviews (2020)

The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin's regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.
Invasive Fungal Infections in Pediatric Patients with High-Risk Acute Lymphoblastic Leukemia during Initial Phases of Therapy: A Retrospective Evaluation
Authors: Ksenya Shliakhtsitsava, Jillian Grapsy, Christina Hsu, Mohammad Almatrafi, Michael Sebert, Martha Pacheco, Rong Huang, Paul Sue
Journal: Blood (2020)
GRP78 Is Expressed on the Cell Surface of Pediatric AML Blasts and Can be Targeted with GRP78-CAR T Cells without Toxicity to Hematopoietic Progenitor Cells
Authors: Nikhil Hebbar, Rebecca Epperly, Abishek Vaidya, Sujuan Huang, Cheng Cheng, Stephen Gottschalk, Mireya Paulina Velasquez
Journal: Blood (2020)
Heterogeneity of treatment response in bronchiectasis clinical trials
Authors: Oriol Sibila, Elena Laserna, Amelia Shoemark, Lidia Perea, Diana Bilton, Megan L. Crichton, Anthony De Soyza, Wim G. Boersma, Josje Altenburg, James D. Chalmers
Journal: European Respiratory Journal (2021)

Background Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QoL) and lung function are the most common end-points evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis. Methods We evaluated treatment response in three randomised clinical trials that evaluated mucoactive therapy (inhaled mannitol), an oral anti-inflammatory/antibiotic (azithromycin) and an inhaled antibiotic (aztreonam). Treatment response was defined by an absence of exacerbations during follow-up, an improvement of QoL above the minimum clinically important difference and an improvement in forced expiratory volume in 1 s (FEV 1 ) of ≥100 mL from baseline. Results Cumulatively the three trials included 984 patients. Changes in FEV 1 , QoL and exacerbations were heterogeneous in all trials analysed. Improvements in QoL were not correlated to changes in FEV 1 in the azithromycin and aztreonam trials (r= −0.17, p=0.1 and r=0.04, p=0.4, respectively) and weakly correlated in the mannitol trial (r=0.22, p&lt;0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QoL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV 1 is not a responsive measure in bronchiectasis. Conclusions Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV 1 is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response, suggesting the need to develop biomarkers to identify responders.
Gut Microbiota-Induced Regulatory T Cells in Patients with Hematological Malignancies Receiving Allogeneic Hematopoietic Stem Cell Transplantation: Towards Deciphering a Role for These Tregs in aGVHD
Authors: Emmanuelle Godefroy, Patrice Chevallier, Thierry Guillaume, Pierre Peterlin, Alice Garnier, Amandine Le Bourgeois, Annabelle Pédron, Frédéric Altare, Francine Jotereau
Journal: Blood (2020)
Mortality and Associated Comorbidities Among Patients Hospitalized for Deep Vein Thrombosis and Pulmonary Embolism in the United States: Results from a Nationally Representative Database
Authors: Ashwin Gupta, Jonathan R Day, Michael B. Streiff, Clifford Takemoto, Kyungsuk Jung, Calvin Abro, Eric Gehrie, Evan Bloch, Aaron Tobian, Ruchika Goel
Journal: Blood (2020)
Reticular Dysgenesis-Associated Adenylate Kinase 2 Deficiency Impairs Hematopoietic Stem and Progenitor Cell Function through Reductive Stress
Authors: Wenqing Wang, Andrew Devilbiss, Thomas Mathews, Martin Arreola, Misty Martin, Zhiyu Zhao, Avni Awani, Daniel P. Dever, Matthew H. Porteus, Sean Morrison, Katja G Weinacht
Journal: Blood (2020)
Correlation between the Degree of Bone Marrow Involvement and the Results of NGS in Plasma Cell Neoplasms
Authors: Ekaterina Rebmann Chigrinova, Naomi A. Porret, Gertrud Wiedemann, Martin Andres, Yara Banz, Myriam Legros, Matthias Pollak, Elisabeth Oppliger Leibundgut, Thomas Pabst, Ulrike Bacher
Journal: Blood (2020)
Inflammatory syndromes associated with SARS-CoV-2 infection: dysregulation of the immune response across the age spectrum
Authors: Jill E. Weatherhead, Eva Clark, Tiphanie P. Vogel, Robert L. Atmar, Prathit A. Kulkarni
Journal: Journal of Clinical Investigation (2020)

Coronavirus disease 2019 (COVID-19) has devastated the global community since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in late 2019.Most COVID-19 cases occur in adults, and a subset develop COVID-19-associated hyperinflammatory syndrome (1), resulting in progressive respiratory illness and multiorgan dysfunction.Progression to severe COVID-19 after SARS-CoV-2 exposure is less common in young adults and children.However, since March 2020, areas with high community SARS-CoV-2 transmission have reported increasing cases of a pediatric inflammatory syndrome that occurs weeks to months after initial asymptomatic or mild SARS-CoV-2 infection (2).The US CDC termed this condition multisystem inflammatory syndrome in children (MIS-C, also known as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 [PIMS-TS] in Europe, where it was first recognized).Since June 2020, a similar syndrome (MIS-A) has been recognized in adults (3).The pathology of MIS-C/A and its relationship to SARS-CoV-2 infection are not yet known.Available evidence suggests significant heterogeneity in the human immune response to SARS-CoV-2.In this Viewpoint, we examine the spectrum of SARS-CoV-2-associated clinical inflammatory syndromes identified in adult and pediatric populations to date.A better understanding of the immunopathologies and related clinical manifestations of these syndromes is necessary to improving their diagnosis and management.
Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and future prospects
Authors: Zahid Hussain, Hnin Ei Thu, Ibrahim Elsayed, Mohammed A.S. Abourehab, Shahzeb Khan, Mohammad Sohail, Rai Muhammad Sarfraz, Muhammad Asim Farooq
Journal: Journal of Controlled Release (2020)
Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States
Authors: Daniel Jacobs, Huang Huang, Kelly Olino, Sarah Weiss, Harriet Kluger, Benjamin L. Judson, Yawei Zhang
Journal: JAMA Dermatology (2020)

Merkel cell carcinoma is an aggressive, cutaneous, neuroendocrine cancer that is increasing in incidence. Understanding why the incidence of Merkel cell carcinoma is increasing through underlying factors, such as age effects, calendar period of diagnosis effects, and birth cohort effects, can help guide resource allocation and design of screening programs.To evaluate the associations of patient age, calendar period of diagnosis, and birth cohort with the increasing incidence of Merkel cell carcinoma and to provide new incidence projections to 2030.A cross-sectional retrospective study with age-period-cohort analysis and incidence projection modeling using data from the Surveillance, Epidemiology, and End Results Program database of 9 registries from 1987 to 2016 was conducted among 3720 patients with Merkel cell carcinoma. Statistical analysis was conducted from October 20, 2019, to July 29, 2020.Age effects (ie, physiology), period of diagnosis effects (ie, changes in diagnostics and clinical awareness), and birth cohort effects (ie, environmental risk factors) over time were assessed.Incidence rates of Merkel cell carcinoma.Among the 3720 patients in the study (2200 male patients [59.1%]; median age, 77 years [interquartile range, 68-84 years]), during the period from 2012 to 2016, the age-adjusted Merkel cell carcinoma incidence rate was 0.66 per 100 000 (95% CI, 0.62-0.70), which represented a 3.5-times (95% CI, 3.0-4.2) increase from 1987 to 1991. The incidence of Merkel cell carcinoma increased with patient age across calendar periods and birth cohorts; the highest incidence rate was observed for those aged 85 years or older, with an age-adjusted rate from 2012 to 2016 of 14.6 per 100 000 for men and 5.5 per 100 000 for women. Although the birth cohort effect has continued to increase over time, the calendar period of diagnosis effect has started to plateau. It is projected that there will be 3023 new cases of Merkel cell carcinoma in 2020 and 5130 new cases in 2030, increased from an estimated 1933 cases in 2010.The slowing down of the period effect (ie, changes in diagnostics and awareness) found in this longitudinal cohort study suggests that part of the initial increased incidence of Merkel cell carcinoma was associated with increased detection. However, the projected increase in incidence rate is likely associated with the aging population and increasing risk factor exposure in more recent birth cohorts.
Abstract 376: Functional Significance of Anatomically Heterogeneous Distribution of Transversal-axial Tubule System in Mouse and Human Atrial Myocardium
Authors: Roman Y Medvedev, Lucas Ratajczyk, Frank C Deguire, Alexander R Vasquez, Di Lang, Alexey Glukhov
Journal: Circulation Research (2020)

Background: In cardiac myocytes, efficient and synchronous excitation-contraction coupling (ECC) occurs through a specialized network of membrane invaginations called transverse-axial tubule system (TATS). In contrast to an extensive TATS in ventricular myocytes, atrial cells show a significantly heterogeneous organization of TATS, varying from a ventricular-like organized TATS to absent/irregular TATS. However, anatomical distribution of atrial TATS and its functional significance remains unknown. We hypothesized that atrial myocytes with a different TATS organization have a specific anatomical location within the atria that determines their impact on atrial ECC and contraction. Methods and Results: In order to avoid the potential bias associated with cell isolation, we applied a mosaic imaging protocol at the whole-mount isolated mouse atrial preparation stained with a membrane dye RH-237. We developed an algorithm that can automatically remove the outer membrane and analyze TATS organization. This analysis showed that myocytes located within the inter-caval region (ICR, i.e., between the superior and inferior vena cava and between the crista terminalis in atrioventricular junction) have a lower TATS organization than cells located within the right atrial appendage (RAA): 0.21±0.01 A.U. vs. 0.50±0.02 A.U. in ICR vs. RAA, respectively, P&lt;0.01. Fluorescent optical mapping of Ca 2+ transients from isolated mouse atrial preparations revealed that ICR region has a longer Ca 2+ transient rise up time compared to RAA (7.8±0.3 ms vs. 6.3±0.3 ms, P&lt;0.01). Moreover, a similar region-specific TATS organization was found in human non-failing (donor) atrial tissue samples. The analysis of TATS density in specimens selected from ICR and RAA regions of the human hearts (n=4) showed a significantly lower density of TATS in ICR compared to RAA region (5.8±0.2% vs. 10.6±0.4%, P&lt;0.01). Conclusion: Our findings show a region-specific structural and functional differences of myocytes from RAA and ICR regions of mouse and human heart that could represent a general organization of the mammalian atria. It may have important implications into establishment of different functional roles of cells with a specific TATS structure in atrial physiology and pathology.
Mgta-145, in Combination with Plerixafor in a Phase 1 Clinical Trial, Mobilizes Large Numbers of Human Hematopoietic Stem Cells and a Graft with Immunosuppressive Effects for Allogeneic Transplant
Authors: Kevin A. Goncalves, Sharon L. Hyzy, Katelyn J. Hammond, Patrick C. Falahee, Haley Howell, Jan Pinkas, Veit Schmelmer, Jonathan G. Hoggatt, David T. Scadden, Steven M Devine, John F. DiPersio, Will J. Savage, John C. Davis
Journal: Blood (2020)
Heterogeneity of <i>MYC</i> Abnormalities in Multiple Myeloma
Authors: Neeraj Sharma, James B Smadbeck, Nadine Abdallah, Kathryn E. Pearce, Yan Asmann, Jess Peterson, Rhett P. Ketterling, Patricia Greipp, P. Leif Bergsagel, S. Vincent Rajkumar, Shaji K. Kumar, Linda B Baughn
Journal: Blood (2020)
Evaluation of Maternal Safety Following Prenatal Cell and Gene Therapy for Hemophilia a in a Large Animal Model Demonstrates Absence of Maternal Exposure to the Cells or Gene Products Infused into the Fetus
Authors: Quan DM Pham, Martin Rodriguez, Ritu M Ramamurthy, Sunil George, Jorge Figueroa, Anthony Atala, Christopher B Doering, H. Trent Spencer, Christopher D Porada, M. Graca Almeida-Porada
Journal: Blood (2020)