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Surveillance of Gastric Intestinal Metaplasia.
Shah SC, Gawron AJ, Li D
(2020) Am J Gastroenterol 115: 641-644
MeSH Terms: Cause of Death, Gastric Mucosa, Global Health, Humans, Morbidity, Patient Selection, Population Surveillance, Precancerous Conditions, Risk Assessment, Stomach Neoplasms, Survival Rate
Added March 3, 2020
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11 MeSH Terms
Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.
Katholnig K, Schütz B, Fritsch SD, Schörghofer D, Linke M, Sukhbaatar N, Matschinger JM, Unterleuthner D, Hirtl M, Lang M, Herac M, Spittler A, Bergthaler A, Schabbauer G, Bergmann M, Dolznig H, Hengstschläger M, Magnuson MA, Mikula M, Weichhart T
(2019) JCI Insight 4:
MeSH Terms: Animals, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Colitis, Ulcerative, Colon, Colorectal Neoplasms, Dextran Sulfate, Disease Models, Animal, Female, Humans, Intestinal Mucosa, Kaplan-Meier Estimate, Macrophages, Male, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Transgenic, Morpholines, Osteopontin, Primary Cell Culture, Prognosis, Survival Rate
Show Abstract · Added November 6, 2019
The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
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24 MeSH Terms
Phosphorylated Hexa-Acyl Disaccharides Augment Host Resistance Against Common Nosocomial Pathogens.
Hernandez A, Luan L, Stothers CL, Patil NK, Fults JB, Fensterheim BA, Guo Y, Wang J, Sherwood ER, Bohannon JK
(2019) Crit Care Med 47: e930-e938
MeSH Terms: Analysis of Variance, Animals, Blotting, Western, Cross Infection, Cytokines, Disaccharides, Disease Models, Animal, Hexosaminidase A, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Peritoneal Cavity, Random Allocation, Staphylococcal Infections, Statistics, Nonparametric, Survival Rate
Show Abstract · Added December 1, 2020
OBJECTIVES - To determine whether synthetic phosphorylated hexa-acyl disaccharides provide antimicrobial protection in clinically relevant models of bacterial infection.
DESIGN - Laboratory study.
SETTING - University laboratory.
SUBJECTS - BALB/c, C57BL/10J, and C57BL/10ScNJ mice.
INTERVENTIONS - Mice were treated with lactated Ringer's (vehicle) solution, monophosphoryl lipid A, or phosphorylated hexa-acyl disaccharides at 48 and 24 hours prior to intraperitoneal Pseudomonas aeruginosa or IV Staphylococcus aureus infection. Leukocyte recruitment, cytokine production, and bacterial clearance were measured 6 hours after P. aeruginosa infection. In the systemic S. aureus infection model, one group of mice was monitored for 14-day survival and another for S. aureus tissue burden at 3 days postinfection. Duration of action for 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide was determined at 3, 10, and 14 days using a model of intraperitoneal P. aeruginosa infection. Effect of 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide on in vivo leukocyte phagocytosis and respiratory burst was examined. Leukocyte recruitment, cytokine production, and bacterial clearance were measured after P. aeruginosa infection in wild-type and toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide or vehicle to assess receptor specificity.
MEASUREMENTS AND MAIN RESULTS - During intraperitoneal P. aeruginosa infection, phosphorylated hexa-acyl disaccharides significantly attenuated infection-induced hypothermia, augmented leukocyte recruitment and bacterial clearance, and decreased cytokine production. At 3 days post S. aureus infection, bacterial burden in lungs, spleen, and kidneys was significantly decreased in mice treated with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides, which was associated with improved survival. Leukocyte phagocytosis and respiratory burst functions were enhanced after treatment with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides. A time course study showed that monophosphoryl lipid A- and 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide-mediated protection against P. aeruginosa lasts for up to 10 days. Partial loss of augmented innate antimicrobial responses was observed in toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide.
CONCLUSIONS - Phosphorylated hexa-acyl disaccharides significantly augment resistance against clinically relevant Gram-negative and Gram-positive infections via enhanced leukocyte recruitment, phagocytosis, and respiratory burst functions of innate leukocytes. Improved antimicrobial protection persists for up to 10 days and is partially mediated through toll-like receptor 4.
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Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.
Ahmed IA, Farooqi MS, Vander Lugt MT, Boklan J, Rose M, Friehling ED, Triplett B, Lieuw K, Saldana BD, Smith CM, Schwartz JR, Goyal RK
(2019) Biol Blood Marrow Transplant 25: 2186-2196
MeSH Terms: Allografts, Child, Preschool, Disease-Free Survival, Female, Genetic Diseases, Inborn, Germ-Line Mutation, Hematopoietic Stem Cell Transplantation, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Myelodysplastic Syndromes, Retrospective Studies, Survival Rate, Syndrome, Tumor Suppressor Proteins
Show Abstract · Added September 19, 2019
Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
High prevalence of antibiotic allergies in cladribine-treated patients with hairy cell leukemia - lessons for immunopathogenesis and prescribing.
Meher-Homji Z, Tam CS, Siderov J, Seymour JF, Holmes NE, Chua KYL, Phillips EJ, Slavin MA, Trubiano JA
(2019) Leuk Lymphoma 60: 3455-3460
MeSH Terms: Adult, Aged, Anti-Bacterial Agents, Antineoplastic Combined Chemotherapy Protocols, Australia, Case-Control Studies, Cladribine, Drug Hypersensitivity, Female, Follow-Up Studies, Humans, Leukemia, Hairy Cell, Male, Middle Aged, Prevalence, Prognosis, Retrospective Studies, Survival Rate, Vidarabine
Show Abstract · Added March 30, 2020
The relationship between hematological malignancy and chemotherapy on the prevalence of antibiotic allergy label (AAL) is ill-defined. We performed a multicenter retrospective case-control study comparing AAL rates among cladribine-treated hairy cell leukemia (C-HCL) cases, non-HCL cladribine-treated controls (control-1), and fludarabine-treated controls (control-2). The prevalence of AALs in C-HCL patients was 60%, compared with control-1 (14%,  < .01) and control-2 patients (25%,  < .01). The predominant phenotype was maculopapular exanthem (92%). The drugs implicated in AAL causality in C-HCL patients included beta-lactams (81%), trimethoprim-sulfamethoxazole (58%), and allopurinol (69%). C-HCL patients demonstrate high rates of AAL, potentially due to immune dysregulation, impacting beta-lactam utilization.
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19 MeSH Terms
Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic Syndromes.
Iams WT, Shiuan E, Meador CB, Roth M, Bordeaux J, Vaupel C, Boyd KL, Summitt IB, Wang LL, Schneider JT, Warner JL, Zhao Z, Lovly CM
(2019) J Thorac Oncol 14: 1970-1981
MeSH Terms: Aged, B7-H1 Antigen, Biomarkers, Tumor, Female, Humans, Lung Neoplasms, Lymphocytes, Tumor-Infiltrating, Male, Middle Aged, Paraneoplastic Syndromes, Nervous System, Prognosis, Retrospective Studies, Small Cell Lung Carcinoma, Survival Rate, Tumor Microenvironment
Show Abstract · Added September 10, 2020
BACKGROUND - Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition.
METHODS - We queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards models.
RESULTS - We evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival compared to patients with endocrinologic PNS and controls (median overall survival of 24 months versus 12 months versus 13 months, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p = 0.033) and PD-1/PD-L1 interaction (p = 0.014) compared to tumors from patients with endocrinologic PNS or controls.
CONCLUSIONS - Tumor tissue from patients with SCLC with neurologic PNS showed increased tumor-infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus.
Liu M, Frej C, Langefeld CD, Divers J, Bowden DW, Carr JJ, Gebre AK, Xu J, Larsson B, Dahlbäck B, Freedman BI, Parks JS
(2019) J Lipid Res 60: 1425-1431
MeSH Terms: African Americans, Apolipoproteins M, Biomarkers, Diabetes Mellitus, Type 2, Disease-Free Survival, Female, Humans, Lysophospholipids, Male, Middle Aged, Sphingosine, Survival Rate
Show Abstract · Added January 10, 2020
apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, = 0.01] and plasma apoM (OR = 0.10, = 0.02), but not HDL apoM ( = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.
Copyright © 2019 Liu et al.
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12 MeSH Terms
Early onset oral tongue squamous cell carcinoma: Associated factors and patient outcomes.
Campbell BR, Sanders CB, Netterville JL, Sinard RJ, Rohde SL, Langerman A, Mannion K, Kim YJ, Murphy BA, Lewis JS, Warner JL, Smith DK, Lang Kuhs KA
(2019) Head Neck 41: 1952-1960
MeSH Terms: Adult, Age of Onset, Aged, Carcinoma, Squamous Cell, Combined Modality Therapy, Female, Health Behavior, Humans, Incidence, Logistic Models, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Survival Rate, Tobacco, Smokeless, Tongue Neoplasms
Show Abstract · Added March 20, 2020
BACKGROUND - Incidence of oral tongue squamous cell carcinoma (OTC) is rising among those under age 50 years. The etiology is unknown.
METHODS - A total of 395 cases of OTC diagnosed and/or treated at Vanderbilt University Medical Center between 2000 and 2017 were identified. Of those, 113 (28.6%) were early onset (age < 50 years). Logistic regression was used to identify factors associated with early onset OTC. Cox proportional hazards models evaluated survival and recurrence.
RESULTS - Compared to typical onset patients, patients with early onset OTC were more likely to receive multimodality treatment (surgery and radiation; adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2-6.3) and report a history of snuff use (aOR, 5.4; 95% CI, 1.8-15.8) and were less likely to report a history of cigarette use (aOR, 0.5; 95% CI, 0.2-0.9). Early onset patients had better overall survival (adjusted hazard ratio, 0.6).
CONCLUSIONS - This is the largest study to evaluate factors associated with early onset OTC and the first to report an association with snuff.
© 2019 Wiley Periodicals, Inc.
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17 MeSH Terms
Continued Poor Survival in Metastatic Uveal Melanoma: Implications for Molecular Prognostication, Surveillance Imaging, Adjuvant Therapy, and Clinical Trials.
Johnson DB, Daniels AB
(2018) JAMA Ophthalmol 136: 986-988
MeSH Terms: Combined Modality Therapy, Humans, Melanoma, Survival Rate, Uveal Neoplasms
Added March 30, 2020
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Minimal clinically important differences for measures of treatment efficacy in Stevens-Johnson syndrome and toxic epidermal necrolysis.
Kim WB, Worley B, Holmes J, Phillips EJ, Beecker J
(2018) J Am Acad Dermatol 79: 1150-1152
MeSH Terms: Clinical Trials as Topic, Dermatologists, Disease Progression, Humans, Length of Stay, Minimal Clinically Important Difference, Professional Practice, Re-Epithelialization, Research Design, Stevens-Johnson Syndrome, Surgeons, Surveys and Questionnaires, Survival Rate, Treatment Outcome
Added March 30, 2020
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