tbuckley/cabot-search huggingface dataset:
Interplay of Liver–Heart Inflammatory Axis and Cannabinoid 2 Receptor Signaling in an Experimental Model of Hepatic Cardiomyopathy
Authors: Csaba Matyas, Katalin Erdelyi, Eszter Trojnar, Suxian Zhao, Zoltan V. Varga, Janos Paloczi, Partha Mukhopadhyay, Balazs T. Nemeth, György Haskó, Resat Cinar, Robim M. Rodrigues, Yeni Ait Ahmed, Bin Gao, Pal Pacher
Journal: Hepatology (2019)

Background and Aims Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)–induced liver fibrosis, by monitoring echocardiography and intracardiac pressure–volume relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid‐2 receptor (CB 2 ‐R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation and fibrosis on cardiac function. Approach and Results BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines, and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic, and macrovascular functions; cardiac inflammation (increased macrophage inflammatory protein 1, interleukin‐1, P‐selectin, cluster of differentiation 45–positive cells); and oxidative stress (increased malondialdehyde, 3‐nitrotyrosine, and nicotinamide adenine dinucleotide phosphate oxidases). CB 2 ‐R up‐regulation was observed in both livers and hearts of mice exposed to BDL. CB 2 ‐R activation markedly improved hepatic inflammation, impaired microcirculation, and fibrosis. CB 2 ‐R activation also decreased serum tumor necrosis factor‐alpha levels and improved cardiac dysfunction, myocardial inflammation, and oxidative stress, underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy. Conclusions We propose BDL‐induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similar to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension and impaired macrovascular and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver–heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g., with selective CB 2 ‐R agonists) may delay or prevent the development of cardiomyopathy in severe liver disease.
Overexpression of EphA4 gene and reduced expression of EphB2 gene: Correlation with liver metastasis in colorectal cancer
Authors: T. Oshima, N. Yamamoto, T. Sato, Y. Nagano, S. Fujii, C. Kunisaki, M. Shiozawa, M. Akaike, Y. Rino, M. Masuda, T. Imada
Journal: Journal of Clinical Oncology (2009)

e15129 The Eph receptors, members of a large family of transmembrane receptor tyrosine kinases, play important roles in a variety of biologic functions. Recent studies have suggested that EphA4 and EphB2 participate in the growth and development of various carcinomas. This study examined the relations of EphA4 and EphB2 gene expression to clinicopathological factors, especially metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal cancer. The relative expression levels of EphA4 and EphB2 mRNA in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of EphA4 mRNA was higher in the presence than in the absence of liver metastasis, whereas the relative expression levels of EphB2 mRNA were similar. Analysis of the relations between clinicopathological features and gene expression showed that high expression of the EphA4 gene and low expression of the EphB2 gene correlated with liver metastasis. There was no correlation between EphA4 and EphB2 gene expression. Our results suggest that over-expression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer. Over-expression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer. No significant financial relationships to disclose.
Inactivation of TFEB and NF-κB by marchantin M alleviates the chemotherapy-driven pro-tumorigenic senescent secretion
Authors: Huanmin Niu, Lilin Qian, Bin Sun, Wenjian Liu, Fang Wang, Qian Wang, Xiaotian Ji, Yanhai Luo, Effat Un Nesa, Hongxiang Lou, Huiqing Yuan
Journal: Acta Pharmaceutica Sinica B (2019)

It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-κB (NF-κB) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy.
CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis
Authors: Guanhua Song, Tingting Feng, Ru Zhao, Qiqi Lu, Yutao Diao, Qingwei Guo, Zhaoxia Wang, Yuang Zhang, Luna Ge, Jihong Pan, Lin Wang, Jinxiang Han
Journal: Annals of the Rheumatic Diseases (2019)

Objective The aim of this study was to investigate the role of CD109 in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and to evaluate its potential as a therapeutic target. Methods CD109 expression was examined in synovial tissues and FLSs from RA patients and collagen-induced arthritis (CIA) model mice. CD109-deficient mice were developed to evaluate the severity of CIA. Small interfering RNAs and a neutralising antibody against CD109 (anti-CD109) were designed for functional or treatment studies in RA FLSs and CIA. Results CD109 was found to be abundantly expressed in the synovial tissues from RA patients and CIA mice. CD109 expression in RA FLSs was upregulated by inflammatory stimuli, such as interleukin-1β and tumour necrosis factor-α. Silencing of CD109 or anti-CD109 treatment reduced proinflammatory factor production, cell migration, invasion, chemoattractive potential and osteoclast differentiation, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. Mice lacking CD109 were protected against arthritis in the CIA model. Anti-CD109 treatment prevented the onset and ameliorated the severity of CIA lesions. Conclusion Our study uncovers an antiarthritic role for CD109 and suggests that CD109 inhibition might serve as a promising novel therapeutic strategy for RA.
Inborn Errors of Folate Metabolism
Authors: Richard W. Erbe
Journal: New England Journal of Medicine (1975)

Inborn Errors of Folate MetabolismThe established and putative inborn errors of folate metabolism and the total number of patients described with each are shown in Table 1 and Figure 3. The disorders can be classified according to whether the primary defect is thought to involve the uptake, interconversion or utilization of folates.Congenital Malabsorption of FolateA congenital disorder involving folate was identified in 196147 in a three-month-old girl with severe megaloblastic anemia. Subsequently, three additional patients, one a sister of the original patient, have been described.48 49 50 51 All four of these patients have shown low serum folate levels, . . .
Treatments for the Prevention and Management of Suicide
Authors: Kristen E. D'Anci, Stacey Uhl, Gina Giradi, Constance Martin
Journal: Annals of Internal Medicine (2019)

Background: Suicide is a growing public health problem, with the national rate in the United States increasing by 30% from 2000 to 2016. Purpose: To assess the benefits and harms of nonpharmacologic and pharmacologic interventions to prevent suicide and reduce suicide behaviors in at-risk adults. Data Sources: MEDLINE, EMBASE, PsycINFO, and other databases from November 2011 through May 2018. Study Selection: Systematic reviews (SRs) and randomized controlled trials (RCTs) that assessed nonpharmacologic or pharmacologic therapies for adults at risk for suicide. Data Extraction: One investigator abstracted data and assessed study quality, and a second investigator checked abstractions and assessments for accuracy. Data Synthesis: Eight SRs and 15 RCTs were included. The evidence for psychological interventions suggests that cognitive behavioral therapy (CBT) reduces suicide attempts, suicidal ideation, and hopelessness compared with treatment as usual (TAU). Limited evidence suggests that dialectical behavior therapy (DBT) reduces suicidal ideation compared with wait-list control or crisis planning. The evidence for pharmacologic treatments suggests that ketamine reduces suicidal ideation with minimal adverse events compared with placebo or midazolam. Lithium reduces rates of suicide among patients with unipolar or bipolar mood disorders compared with placebo. However, no differences were observed between lithium and other medications in reducing suicide. Limitation: Qualitative synthesis of new evidence with existing meta-analyses, methodological shortcomings of studies, heterogeneity of nonpharmacologic interventions, and limited evidence for pharmacologic treatments and harms. Conclusion: Both CBT and DBT showed modest benefit in reducing suicidal ideation compared with TAU or wait-list control, and CBT also reduced suicide attempts compared with TAU. Ketamine and lithium reduced the rate of suicide compared with placebo, but there was limited information on harms. Limited data are available to support the efficacy of other nonpharmacologic or pharmacologic interventions. Primary Funding Source: U.S. Department of Veterans Affairs Veterans Health Administration. (PROSPERO: CRD42018104978)
Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Polycythemia Vera or Essential Thrombocythemia Transformed to Myelofibrosis or Acute Myeloid Leukemia: a Single Center Experience
Authors: Paolo Bernasconi, Anna Amelia Colombo, Daniela Caldera, Virginia Valeria Ferretti, Silvia Mangiacavalli, Marta Ubezio, Daniela Pietra, Elisa Rumi, Ilaria Carola Casetti, Matteo Davià, Marina Boni, Irene Dambruoso, Rita Zappatore
Journal: Blood (2017)
Clinical outcomes of sunitinib (Su) for patients (pts) with desmoid tumors (DT).
Authors: Salvatora tindara Miano, Guido Francini, Serenella Civitelli, Roberto Petrioli, Edoardo Francini
Journal: Journal of Clinical Oncology (2019)

11052 Background: The incidence of DT is steadily increasing in pts affected by familial adenomatous polyposis (FAP) and represents the first cause of death for pts who underwent preventive proctocolectomy. Currently, there is no standard therapy for DT and Tamoxifen (20 mg once daily) + Meloxicam (15 mg once daily) (TM) is the most commonly used regimen in clinical routine. We sought to evaluate the efficacy of Su, the most active PDGFR TKI, as first-line therapy for pts with DT. Methods: In this phase II IRB approved prospective study, pts with progressive, symptomatic, or recurrent DT were randomized to receive either Su (52 mg once daily) or TM. The primary end point was progression-free survival, defined as time from treatment start to clinical or radiological progression, whichever came first, at 2 years (2yr-PFS). Secondary endpoints were rates of objective response (OR), evaluated per RECIST criteria version 1.1, time to OR (ttOR), and toxicity. Adverse events (AE) were assessed per NCI-CTCAE version 4.02. Results: Of the 32 pts enrolled, 22 received Su and 10 TM. In both groups, median age at diagnosis was 43.5 years No OR was observed in the TM group. In the Su group, 17 pts had a partial response and 5 stable disease and the ORR was 75% (95% CI, 50 to 100). At a median follow-up of 27 months, the 2yr-PFS was 81% (95% CI, 69-96) and 36% (95% CI, 22-57) in the Su cohort and TM cohort, respectively (HR = 0.13; 95% CI, 0.05- 0.31; P&lt;0.001). The median ttOR among pts who had an OR was 24 months. In the TM group, no toxicity was observed. The most frequently reported AE in the Su group were grade 1 or 2 hypothyroidism (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). (HR: 0.260; p = 0.0035). All AE responded to dose reduction (37.5 mg). Conclusions: In a cohort of pts with progressive, recurrent, or symptomatic DT, Su seems to be well tolerated and improve 2yr-PFS and OR rate compared with TM therapy. Further prospective studies with larger samples are needed to verify these results.
Author Correction: Immune-orthogonal orthologues of AAV capsids and of Cas9 circumvent the immune response to the administration of gene therapy
Authors: Ana M. Moreno, Nathan Palmer, Fernando Alemán, Genghao Chen, Andrew Pla, Ning Jiang, Wei Leong Chew, Mansun Law, Prashant Mali
Journal: Nature Biomedical Engineering (2019)
Combined Azacitidine and High Dose Lenalidomide Therapy Is Well Tolerated and Clinically Active in Patients Who Relapse after Allogeneic Stem Cell Transplantation for Actue Myeloid Leukemia: Results of the Uk Trials Acceleration Programme Viola Trial
Authors: Charles Craddock, Wendy Ingram, Daniel Slade, Andrea Hodgkinson, Francis J. Mussai, Carmela De Santo, Jamie Cavenagh, Michael Dennis, Ram Malladi, Shamyla Siddique, Yap Christina
Journal: Blood (2017)
Adoptive T-cell therapy combined with intra-lesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients.
Authors: Amir Khammari, Jean-Marc Limacher, Jean-Michel NGuyen, Melanie Saint-Jean, Gaelle Quereux, Anabelle Brocard, Lucie Peuvrel, Anne-Chantal Knol, Soraya Saiagh, Vincent Bataille, Brigitte Dreno
Journal: Journal of Clinical Oncology (2013)

e20022 Background: The purpose of this study was to evaluate the feasibility, safety and efficacy of adding intra-tumoral injections of TG1042 (Adenovirus 5 expressing Interferon-γ) to adoptive T cell therapy in patients with advanced stage melanoma. Methods: This was a monocentric phase I/II study. The main inclusion criteria were: stage IIIc/IV melanoma, age 18 to 75, at least one injectable metastasis. Tumor infiltrating lymphocytes (TILs) produced from a surgical biopsy of a lesion were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x10 10 viral particles per lesion (in up to 6 lesions) every 2 weeks from day -15 to month 2 and then every month up to month 11 or progression. Primary objective was the safety of the procedure; secondary objectives included response according to RECIST and translational research. Results: Eighteen patients have been included. The TILs production was successful in 16 of them. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections were the most frequent adverse events observed. No grade 3 or 4 treatment related adverse events was recorded. Among the 13 patients evaluable for tumor response 4 patients (31%) had an overall objective response (2 complete, 2 partial), 1patient had a stable disease and 8 progressed. When considering only the injected lesions 6 (46%) had an objective response (3 complete, 3 partial), 3 had a stable disease and 4 progressed. Distant responses in non-injected lesions were observed for 2 patients. Translational research on cutaneous biopsies before and after injections (3 months) showed an increase of CD8 T lymphocytes, IFN-γ and STAT 1 expression in 3 patients. Conclusions: This study demonstrates that co-delivery of TILs and intra lesional TG1042 is feasible and safe. Stimulation of innate immunity by adenovirus expressing interferon-γ could contribute to reverse the immunotolerant profile of the tumour environment. These results support to further explore combined immunotherapies in the treatment of melanoma. Clinical trial information: NCT01082887.
External Societal Costs of Antimicrobial Resistance in Humans Attributable to Antimicrobial Use in Livestock
Authors: Gabriel K. Innes, Pranay R. Randad, Anton Korinek, Meghan F. Davis, Lance B. Price, Anthony D. So, Christopher D. Heaney
Journal: Annual Review of Public Health (2020)

Antimicrobial use (AMU) in animal agriculture contributes to antimicrobial resistance (AMR) in humans, which imposes significant health and economic costs on society. Economists call these costs negative externalities, societal costs that are not properly reflected in market prices. We review the relevant literature and develop a model to quantify the external costs of AMU in animal agriculture on AMR in humans. Parameters required for this estimate include (
Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies
Authors: Elizabeth A Comen, Robert L Bowman, Pier Selenica, Maria Kleppe, Noushin R Farnoud, Fresia Pareja, Britta Weigelt, Corinne E Hill, Abigail Alon, Felipe C Geyer, Guray Akturk, Jorge S Reis-Filho, Larry Norton, Ross L Levine
Journal: JNCI Journal of the National Cancer Institute (2019)

Chemotherapy and radiation therapy are the foundations of adjuvant therapy for early-stage breast cancer. As a complication of cytotoxic regimens, breast cancer patients are at risk for therapy-related myeloid neoplasms (t-MNs). These t-MNs are commonly refractory to antileukemic therapies and result in poor patient outcomes. We previously demonstrated that somatic mutations in leukemia-related genes are present in the tumor-infiltrating leukocytes (TILeuks) of a subset of early breast cancers. Here, we performed genomic analysis of microdissected breast cancer tumor cells and TILeuks from seven breast cancer patients who subsequently developed leukemia. In four patients, mutations present in the leukemia were detected in breast cancer TILeuks. This finding suggests that TILeuks in the primary breast cancer may harbor the ancestor of the future leukemogenic clone. Additional research is warranted to ascertain whether infiltrating mutant TILeuks could constitute a biomarker for the development of t-MN and to determine the functional consequences of mutant TILeuks.
Umbilical Cord Blood Mononuclear Cells for Ex-Vivo Gene Therapy
Authors: Farid V. Bashirov, Ilnur I. Salafutdinov, Michail E. Sokolov, Andrew A. Izmailov, Vage A. Markosyan, Filip O. Fadeev, Albert Rizvanov, Rustem I. Islamov
Journal: Blood (2018)
Impact of health behavior change on health utility (HU) and financial toxicity in head and neck cancer (HNC) survivors.
Authors: Lawson Eng, Katrina Hueniken, M. Catherine Brown, Andrew Hope, Meredith Elana Giuliani, Peter Selby, Kelvin K. Chan, Nicole Mittmann, Wei Xu, David Paul Goldstein, Geoffrey Liu, John R. de Almeida
Journal: Journal of Clinical Oncology (2019)

11561 Background: Health behavior changes including tobacco cessation and increasing physical activity (PA) are important aspects of cancer survivorship. Understanding how these behaviours impact on HU and financial toxicity will help when evaluating survivorship programs. We evaluated the impact of tobacco cessation and PA on HU, function and financial toxicity among HNC patients (pts). Methods: HNC pts from Princess Margaret Cancer Centre completed questionnaires at baseline (diagnosis) and 12 months between 2014-2018 evaluating tobacco use, PA with the Godin questionnaire, cancer related monthly out of pocket costs (OOPC), HU using HU Index Mark 3, function using Lawton Brody Scale (LBS) and lost annual income. Multivariable linear regression analyses evaluated the impact of health behaviour change on OOPC, HU, LBS and lost income. Results: Among 296 pts, mean age 61, 76% male; 29% smoked at diagnosis, 60% quit 1 year after; 26% met PA guidelines at diagnosis, 52% continued to meet guidelines at 1 year. 19% of those not meeting PA guidelines at diagnosis, met them at 1 year. Among all, mean HU [SEM] was 0.84 [0.01] (baseline), 0.80 [0.01] (12 months); mean monthly OOPC [SEM] were $171 [27] (12 months); mean annual lost individual income was $25897 [2945]. Among smokers at diagnosis, those continuing to smoke at 1 year lost a mean of $21272 (95% CI [$2783-39761] P= 0.03) more in individual annual income compared to pts who quit, adjusted for baseline income and education. Current smokers who quit smoking at 1 year had an adjusted mean increase in HU of 0.15 ([0.00-0.30] P= 0.05) greater than pts continuing to smoke. Pts who continued meeting PA guidelines at 1 year had an adjusted mean increase in HU scores of 0.11 ([0.02-0.20], P= 0.02) compared to those reducing PA levels after diagnosis. Changes in PA and tobacco were not associated with change in function or OOPC; improving to meet PA guidelines after diagnosis was not associated with HU or lost income ( P&gt; 0.05). Conclusions: Quitting smoking and maintaining PA levels after diagnosis were associated with improvements in HU scores; quitting smoking reduced lost income. Cancer survivors should be made aware of the potential economic impact of behaviour change.