tbuckley/cabot-search huggingface dataset:
The gut-liver axis in liver disease: Pathophysiological basis for therapy
Authors: Agustín Albillos, Andrea de Gottardi, María Rescigno
Journal: Journal of Hepatology (2019)

The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.
Vaccination Coverage by Age 24 Months Among Children Born in 2015 and 2016 — National Immunization Survey-Child, United States, 2016–2018
Authors: Holly A. Hill, James A. Singleton, David Yankey, Laurie D. Elam-Evans, S. Cassandra Pingali, Yoonjae Kang
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

The Advisory Committee on Immunization Practices (ACIP) recommends that children be vaccinated against 14 potentially serious illnesses during the first 24 months of life (1). CDC used data from the National Immunization Survey-Child (NIS-Child) to assess vaccination coverage with the recommended number of doses of each vaccine at the national, state, territorial, and selected local levels* among children born in 2015 and 2016. Coverage by age 24 months was at least 90% nationally for ≥3 doses of poliovirus vaccine, ≥1 dose of measles, mumps, and rubella vaccine (MMR), ≥3 doses of hepatitis B vaccine (HepB), and ≥1 dose of varicella vaccine, although MMR coverage was <90% in 20 states. Children were least likely to be up to date by age 24 months with ≥2 doses of influenza vaccine (56.6%). Only 1.3% of children born in 2015 and 2016 had received no vaccinations by the second birthday. Coverage was lower for uninsured children and for children insured by Medicaid than for those with private health insurance. Vaccination coverage can be increased by improving access to vaccine providers and eliminating missed opportunities to vaccinate children during health care visits. Increased use of local vaccination coverage data is needed to identify communities at higher risk for outbreaks of measles and other vaccine-preventable diseases.
18f-FDG PET/CT and the Revised International Staging System Are More Discriminating of Survival Outcomes in Newly Diagnosed Multiple Myeloma
Authors: Sung-Hoon Jung, Seong Young Kwon, Jung-Joon Min, Hee Seung Bom, Seo-Yeon Ahn, Seung-Yeon Jung, Seung-Shin Lee, Moo-Rim Park, Deok-Hwan Yang, Jae-Sook Ahn, Hyeoung-Joon Kim, Je-Jung Lee
Journal: Blood (2018)
Reply to Mengxin Lu, Yi Zhang, Yu Xiao’s Letter to the Editor, re: Kimmo Kettunen, Peter J. Boström, Tarja Lamminen, et al. Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells. Eur Urol 2019;76:430–4
Authors: Kimmo Kettunen, Peter J. Boström, Pekka Taimen
Journal: European Urology (2019)
A Prospective Study Comparing 99mtc-Sestamibi SPECT/CT with 18f-FDG PET/CT in Multiple Myeloma Staging: A Potential Resource-Constraint Image Alternative for MM Bone Evaluation
Authors: Camila Mosci, Fernando Vieira Pericole, Allan de Oliveira Santos, Mariana Cunha Lima, Elba Cristina Camargo Etchebehere, Barbara Juarez Amorim, Gislaine Borba Duarte, Marcia Torresan Delamain, Carmino Antonio Souza, Irene Lorand-Metze, Celso Dario Ramos
Journal: Blood (2018)
Hematopoietic Cell Lines and Patient Samples Show a Correlation Between Upregulated MSI2 and BCR-ABL Expression
Authors: Jaspal S. Kaeda, Rolf Schwarzer, Robert K. Slany, Thomas Burmeister, Elisabetta Vagge, Leila Amini, Frauke Ringel, Katarina Pardon, Michaela Schwarz, Bernd Dörken, Franziska Jundt, Philipp le Coutre
Journal: Blood (2013)
Abstract 526: A Transcriptomic Analysis of Cardiac Myofibroblasts Reveals Novel Anti-fibrotic and Immunomodulatory Genes Modulated by CDC-Derived Exosomes
Authors: Everett J Sinibaldi, Fraser J Sim, Jennifer K Lang
Journal: Circulation Research (2019)

Background: Cardiac fibroblasts are the most prevalent cell in the heart and play an important role in both the healthy and diseased myocardium. Following myocardial infarction, TGF-β secretion promotes a phenotype transition of fibroblasts to activated myofibroblasts. We have previously shown that CDC-derived exosomes promote cardiomyocyte proliferation and survival, stimulate angiogenesis, and polarize cardiac macrophages to a unique Arg1-high phenotype. We hypothesized that CDC-derived exosomes modulate the gene expression of myofibroblasts to attenuate fibrosis in the remodeling heart. Methods: We took a genomics-based approach to investigate CDC-exosome mediated differential gene expression and regulation of operant signaling pathways in TGF-β induced ventricular myofibroblasts. Cardiac fibroblasts were isolated from C57BL/6 mice (n=3) using a Langendorff-free method of in situ enzymatic dissociation. Cells were plated at 1x10 5 cells/mL, serum depleted to induce cell cycle arrest and exposed to 4 different conditions: media alone, TGF-β (4 ng/ml) “myofibroblasts”, CDC-exosomes (20 μg/ml), or TGF-β and CDC-exosomes. After 24 hours, RNA was extracted and analyzed by RNA-seq. Results/Conclusions: Gene ontology analysis showed attenuation of a pro-fibrotic gene expression profile in the TGF-β + CDC-exo group relative to TGF-β treatment alone. Genes involved in blunting of the pro-fibrotic response ( Mmp14 and Qsox1) , as well those implicated in attenuating the transition of fibroblasts to myofibroblasts ( Gsto1 ) were also upregulated in CDC-exosome treated myofibroblasts (edgeR; FDR-corrected p&lt;0.05). Interesting, we found a highly significant enrichment of genes involved in macrophage migration ( Kars , Mmp14 , and Tnfsf18 ) in the CDC-exosome treated myofibroblasts relative to the TGF-β group (GO:1905523, p=8.42x10 -6 ). These data suggest active cross talk between myofibroblasts and macrophages and highlight a novel immunomodulatory role of CDC-derived exosomes on myofibroblasts post MI.
Abstract 521: Cardiac Fibroblasts are Activated During Postnatal Extracellular Matrix Remodeling
Authors: Luis Hortells, Iñigo Valiente, Nivedhitha Velayutham, Katherine E Yutzey
Journal: Circulation Research (2019)

Objectives: During the postnatal period, P0 to P30 in the mouse, the myocardial extracellular matrix (ECM) transitions to a mature profile necessary for increased cardiac output. We hypothesize that, during the postnatal period, cardiac fibroblasts (CF) become activated, as indicated by Periostin (Postn) expression, and remodel the ECM, followed by quiescence in the mature heart. Our goal is to study CF activation and its role in postnatal heart development. Methods: CF activation was monitored by Postn MerCreMer(MCM) ;Rosa GFP lineage analysis and the resident CF were studied using a TCF21 MCM ;R26 GFP model. Tamoxifen induction of Cre MCM was initiated in the postnatal period and lineage-specific CF were quantified. Cardiac ECM maturation and CF proliferation, together with bone marrow-derived and endothelial cells, were assessed by Immunofluorescence (IF). TCF21 , Postn , Col1a1 , TnnI and CD31 transcripts were examined by RNAscope, and Fibronectin (FN) compartmentalization, an indicator of ECM maturation, also was examined. Results: FN, Postn, and Postn MCM R26 GFP lineage cells were more prominent at P0-7 than at P30. Postn -expressing cells also co-express Tcf21 and Col1a1 , but not TnnI (myocytes) or PECAM (endothelial cells), as determined by RNAscope. In agreement, Postn MCM R26 GFP CF do not express CD31, CD45, or the myofibroblast marker alphaSMA at P7. At P30, Postn, FN, and Col1a1 expression is reduced in CF, but TCF21 MCM ;R26 GFP is maintained, suggesting a transient period of CF activation followed by quiescence. Similarly, proliferation rates of the Postn MCM R26 GFP cells are higher than TCF21 MCM ;R26 GFP CF at P7, followed by decreased proliferation at P30. Conclusions: Activation and proliferation of CFs and ECM gene expression is increased in the week after birth relative to quiescent CFs at P30. Postn+ cells also peak at P7 but are not detected in appreciable numbers at P30, suggesting a critical role in ECM remodeling and myocardial maturation in the postnatal period. Studies are ongoing to determine the codependence of postnatal activated CF, ECM maturation and myocardial regeneration.
Pharmacy involvement in an oral anticancer management program: Drug acquisition and safety in an ambulatory comprehensive care center.
Authors: Audrea H Szabatura, Marina D. Kaymakcalan, Cathy Cao, Phuong Nguyen
Journal: Journal of Clinical Oncology (2019)

85 Background: Oral anticancer agents (OACA) offer benefits of convenience, flexibility and quality of life; however, similar to intravenous therapy, OACA can be prone to medication ordering errors, drug-interactions, and administration errors. Additionally, they carry unique challenges such as treatment delay due to acquisition barriers and errors related to self-administration and monitoring. An oral anticancer management program was implemented to address vulnerable aspects of the outpatient OACA medication use process. Pharmacy benefit specialists (PBS) assist with prior authorizations (PA) and drug acquisitions; while, clinical pharmacists perform medication assessments and patient education. Methods: A retrospective review of patients prescribed OACAs between January 1 - March 31, 2019 was performed. A review of all PAs facilitated by our PBS was conducted and included date of prescription, date of submission to insurance, and date of PA approval. An assessment of pharmacist interventions on the prevention of medication-related errors and toxicity was conducted and was defined by any clarification or recommendation regarding medication dose, administration instructions, drug interactions, symptom management, medication reconciliation, and/or medication monitoring. Results: A total of 567 PAs were processed. Twenty-eight PA requests were denied and 539 were approved. The average time to approval was 1.5 days (range 0-13 days). 299 of the 567 patients were prescribed a new OACA and were enrolled into our education program. Pharmacists educated 191 patients. Pharmacists intervened 175 times for the 191 patients counseled. Interventions included recommendations/clarifications for symptom management (21.5%), medication reconciliation (19.5%), drug administration (16.2%), drug interactions (13.6%), and medication monitoring (7.3%). Conclusions: Pharmacy staff can make a valuable contribution to drug acquisition and overall clinical care of patients receiving OACAs. Our PBS reduced delays in acquisition and clinical pharmacists minimized medication-related errors and toxicity.
Abstract 531: Urolithin a Suppress Cardiac Fibrosis via Autophagy Pathway in the Diabetic Cardiomyopathy
Authors: Xiaoqian Wu, Xiaoyan Zhu, You Zhou
Journal: Circulation Research (2019)

Objective: The cardiovascular protective effect of Urolithins remains poorly understood, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which is found in the pomegranate fruit. We identified Urolithin A (UA) as a natural compound that induces mitophagy and protects against diabetic cardiomyopathy both in vivo and in vitro. Healthy male C57BL/6 mice were fed with a High-fat diet for 6 months combined with a small dose of STZ injection to establish the T2DM model. Compared with the control, the diabetic mice suffered from cardiac dysfunction characterized by decrease EF, FS and E/A ratio, which was reversed with UA treatment. Masson staining and collagen marker Immunoblots showed that cardiac fibrosis was also decreased with UA treatment in the diabetic mice both in vivo and in vitro. Interestingly, we found UA significantly activated mitophagy and increased the co-localization of Myto-tracker and Lysotracker. However, we found UA increased Drp1 expression but not PINK1 or Parkin phosphorylation indicating a non-canonical mitophagy pathway. We treated the cardiac fibroblast with Drp1 siRNA and found the protective effect of UA against cardiac fibrosis was abolished. Conclusion: UA protected against diabetic cardiomyopathy by activating mitophagy vias a non-canonical pathway. Keywords: Diabetic cardiomyopathy; Cardiac fibrosis; Urolithin A; Autophagy; Mitophagy
Rescue of Lethal Hypophosphatasia Mice by Neonatal Ex Vivo Gene Therapy Using Lentivirally Transduced Bone Marrow Cells.
Authors: Osamu Iijima, Koichi Miyake, Hanako Sugano-Tajima, Tsutomu Igarashi, Chizu Kanokoda, Atsushi Watanabe, Takashi Shimada
Journal: Blood (2012)
FLT3mutation Assay Laboratory Cross Validation: Results from the CALGB 10603/Ratify Trial in Patients with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML)
Authors: Christian Thiede, Thomas W Prior, Serena Lavorgna, Jürgen Krauter, Eva Barragán, Josep Nomdedeu, Joop H. Jansen, Andrew H Wei, Weiqiang Zhao, Xiaohong Li, Celine Pallaud, Eva Tiecke, Richard A. Larson, Clara D. Bloomfield, Hartmut Döhner, Gerhard Ehninger, Richard M. Stone, Konstanze Döhner
Journal: Blood (2018)
Perioperative Risk Calculators and the Art of Medicine
Authors: Nidhi Rohatgi
Journal: JAMA Internal Medicine (2019)

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CD19 CAR T Cell Product Exhibits High Remission Rate in Adult Relapsed and/or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Zhitao Ying, Wen Wang, Xiaopei Wang, Wen Zheng, Ningjing Lin, Meifeng Tu, Yan Xie, Lingyan Ping, Chen Zhang, Weiping Liu, Lijuan Deng, Ming Hao, Su Yang, Yan Zhou, James Li, Yuqin Song, Jun Zhu
Journal: Blood (2018)
ELN Genetic Risk Stratification Not Affect the Mid-Term Survival in Childhood AML: Report from Southern China Childhood AML Group
Authors: Xiaoqin Feng, Jian Li, Xiangling He, Honggui Xu, Mincui Zheng, Hong Wen, Yingyi He, Sixi Liu, Yongsheng Ruan, Chunfu Li
Journal: Blood (2018)
Abstract 469: Genomic Context Predicts Dilated but Not Hypertrophic Cardiomyopathy
Authors: Megan J Puckelwartz, Lorenzo L Pesce, Lisa M Dellefave-Castillo, Matthew T Wheeler, Tess D Pottinger, Avery C Robinson, Anthony M Gacita, Zachary J Schoppen, Wenyu Pan, Gene Kim, Jane E Wilcox, Allen S Anderson, Euan A Ashley, Sharlene M Day, Thomas Cappola, Gerald W Dorn, Elizabeth M McNally
Journal: Circulation Research (2019)

Rationale: Cardiomyopathies are a major cause of heart failure and have a strong heritable component. Objective: Determine the role of both common and rare nonsynonymous genetic variation in hypertrophic (HCM) and dilated familial cardiomyopathy (DCM). Methods and Results: Whole genome sequencing was used to determine common and rare nonsynonymous genetic variation in familial cases of HCM (n=56) or DCM (n=71). Variation was evaluated in 102 cardiomyopathy genes routinely assayed in clinical and commercial gene testing panels. We used cardiac gene expression data from GTEx (Genotype-Tissue Expression database) to define additional genes expressed in the heart. The number of nonsynonymous single nucleotide variants (nsSNVs), the majority of which were missense variants, was correlated with echocardiographic measurements. Principal component analysis (PCA) of left ventricular measures separated HCM and DCM. Regression of the first principal component using all nonsynonymous single nucleotide variants (nsSNVs) in cardiomyopathy genes showed the number of nsSNVs predicted DCM but not HCM. DCM probability in the cohort significantly increased as the number of cardiomyopathy gene nsSNVs increased (p&lt;0.02). The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter in DCM. Resampling methods identified genes with deviant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions: DCM subjects carry a greater burden of nsSNVs in cardiomyopathy genes. This genomic burden translates to impaired systolic cardiac function in DCM. In contrast, nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support a complex inheritance for DCM where increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity. The distinct genetic landscapes of HCM and DCM suggest that greater genetic variation in cardiac genes provokes unfavorable ventricular remodeling with reduced systolic function.
A cost-effectiveness analysis of primary prophylaxis (PP) versus secondary prophylaxis (SP) with biosimilar myeloid growth factors (MGFs) for preventing chemotherapy-induced febrile neutropenia (FN) in non-Hodgkin lymphoma (NHL) patients at intermediate risk.
Authors: Gary H. Lyman, Dylan Mezzio, Edward C. Li, Kim Campbell, Sanjeev Balu
Journal: Journal of Clinical Oncology (2019)

107 Background: Historically, PP with a MGF was recommended in patients with a ≥40% risk for developing chemotherapy-induced FN, based on clinical and regimen-related factors. Previous economic studies provided evidence to lower the threshold to 20%, the current high-risk threshold listed by practice guidelines. Biosimilar MGFs, such as filgrastim-sndz or LA-EP2006 (a proposed pegfilgrastim biosimilar), offer an opportunity to evaluate whether it is cost-effective to further lower the threshold for intermediate-risk regimens (i.e., 10-20% FN risk). Methods: A Markov model was constructed to evaluate the total costs and clinical outcomes of biosimilar or reference MGFs when used as PP vs. SP in patients 55 years old with NHL receiving 6 cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with no additional FN risk factors. Model inputs, including MGF efficacy and acquisition costs, were estimated from publically available data and literature, as were FN hospitalization costs and clinical utilities. Incremental cost-effectiveness ratios (ICERs) were calculated for cost per FN event avoided, life-year saved (LYS), and quality-adjusted life-year (QALY) gained from a payer perspective within the United States. Deterministic and probabilistic sensitivity analyses were conducted. Results: Use of filgrastim-sndz as PP vs. SP provided an additional 0.130 QALYs (0.144 LYS) at an incremental cost of $5,999. The ICERs were $50,676, $41,761, and $46,207 for cost per FN event avoided, cost per LYS, and cost per QALY gained, respectively. Using LA-EP2006 as PP vs. SP provided an additional 0.166 QALYs (0.184 LYS) at an incremental cost of $17,648. The ICERs were $123,840, $95,963, and $106,265 for cost per FN event avoided, cost per LYS, and cost per QALY gained, respectively. Conclusions: Within NHL patients receiving R-CHOP at an intermediate risk for FN, PP with filgrastim-sndz and LA-EP2006 are cost-effective compared to their respective use as SP based on a cost-effectiveness threshold of $150,000/QALY.
Loss of Heterozygosity and Possible Loss of Allele Amplification in Homozygous Short Tandem Repeats Loci in Two ALL Patients with Central Nervous System and Bone Marrow Relapses
Authors: Natalya Risinskaya, Julia Chabaeva, Elena Nikulina, Anna Yushkova, Vera Vasilyeva, Zoya Konova, Larisa Kuzmina, Andrey Sudarikov, Sergei M. Kulikov, Elena Parovichnikova, Valery G. Savchenko
Journal: Blood (2018)