tbuckley/cabot-search huggingface dataset:
Deoxyribozymes as Catalytic Nanotherapeutic Agents
Authors: Levon M. Khachigian
Journal: Cancer Research (2019)

RNA-cleaving deoxyribozymes (DNAzymes) are synthetic single-stranded DNA-based catalytic molecules that can be engineered to bind to and cleave target mRNA at predetermined sites. These have been used as therapeutic agents in a range of preclinical cancer models and have entered clinical trials in Europe, China, and Australia. This review surveys regulatory insights into mechanisms of disease brought about by use of catalytic DNA in vitro and in vivo, including recent uses as nanosensors, nanoflowers, and nanosponges, and the emerging role of adaptive immunity underlying DNAzyme inhibition of cancer growth. DNAzymes represent a promising new class of nucleic acid-based therapeutics in cancer. This article discusses mechanistic and therapeutic insights brought about by DNAzyme use as nanotools and reagents in a range of basic science, experimental therapeutic and clinical applications. Current limitations and future perspectives are also discussed.
Comparison of Topical N-Acetylaspartylglutamic Acid (Naabak®) Efficacy Versus Topical Fluorometholone (Flucon®) in Allergic Conjunctivitis Related To Birch Pollen in ALYATEC Environmental Exposure Chamber (EEC)
Authors: Tristan Bourcier, Alina Gherasim, Ibrahim Choual, Nicole Beck, Audrey Jacob, Florian Schoettel, Nathalie Domis, Frederic J. De Blay De Gaix
Journal: Journal of Allergy and Clinical Immunology (2019)
Antibody-dependent cellular cytotoxicity mediated by Cetuximab against colon cancer cell lines is inhibited by membrane expression of HLA-E on target cells
Authors: Michele Bianchini, Estrella Levy, Gabriela Sycz, Marcela Barrio, Juan Martin Arriaga, Erika von Euw, Ines Bravo, Jose Mordoh
Journal: Cancer Research (2008)

3996  Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in Western nations. Cytotoxic agents have increased the median survival of patients, and promising studies in CRC therapy have emerged using new agents such as Cetuximab, a chimeric IgG1 monoclonal antibody (mAb) that binds to the extracellular domain of EGFR. Direct growth inhibition, apoptosis induction, complement-dependent cytotoxicity (CDC) and Ab-dependent cellular cytotoxicity (ADCC) are the modes of action of Ab therapies. In a previous work, we demonstrated that the expression of HLA-E, a non-polymorphic MHC class Ib molecule, is significantly increased in primary human CRC, perhaps contributing to tumor escape from immune surveillance. Accordingly, we found that CRC patients with a high percentage of tumor HLA-E positive cells had a shorter disease-free survival. To establish if HLA-E could be a factor that renders CRC cells less susceptible to Cetuximab-mediated ADCC, in the present study we performed a detailed analysis of ADCC activity against five CRC cell lines, expressing or not HLA-E at the cell surface. We first observed that CRC cells treated with Cetuximab (1μg/ml) were killed more efficiently by ADCC, as measured by calcein-AM release from target cells. Interestingly, recombinant human- β2microglobulin treatment of target cells inhibits Ab-mediated ADCC activity, probably through HLA-E membrane stabilization; this result confirms that HLA-E at the cell surface can reliably suppress the ADCC effect of the mAb. Furthermore, Cetuximab induced a direct growth inhibition (measured by MTT assay) but only at high antibody concentrations (at 100μg/ml inhibits proliferation 93.7 %); in contrast, CDC effect was quite moderate (observed only in one cell line at 100μg/ml), and we failed to observe a pro-apoptotic effect, as measured by the annexin-V assay. Taking into account that our findings suggest that ADCC activity is the main anti-tumour effect observed at clinically achievable concentrations of Cetuximab (1μg/ml) at the tumor site, we believe that the characterization of new biologic markers of potential responsiveness to ADCC-inducing agents could be relevant. Considering the immunomodulatory function assigned to HLA-E molecule, its expression in malignant cells may represent one of various mechanisms used by the tumor cells to escape immune surveillance and constitute a reliable determinant of ADCC inhibition. We believe that our data justify further studies using samples from Cetuximab-treated patients to establish if high HLA-E levels could be a bad prognosis marker for antibody therapy in primary CRC.
FOLFOX versus POF (paclitaxel plus FOLFOX) versus IP PAC (intraperitoneal paclitaxel plus FOLFOX) as a first-line treatment in advanced gastric cancer (AGC): A multicenter, randomized phase II trial, FNF-004 trial.
Authors: Rongbo Lin, Hui Li, Yigui Chen, Jinfeng Zhu, Peicheng Lin, Wujin Chen, Wenzheng Fang, Jie Liu, Shen Zhao, Nanfeng Fan
Journal: Journal of Clinical Oncology (2019)

6 Background: Double regimens are commonly accepted for AGC in East Asia. However, triple regimens are recommended in west countries. POF regimen (reported in 2007, 2008, 2009, 2010 ASCO) appeared to be of good efficacy and was well tolerated in patients with AGC. Intraperitoneal paclitaxel showed high local concentration in abdominal cavity and low systemic toxicity. The aims of this study were to find out if the POF and IP PAC was more effective with manageable side effects than FOLFOX in AGC (reported in 2017 ASCO-GI for feasibility analysis). Methods: The patients with AGC were randomized to three groups. The POF consisted of a 3-hour infusion of paclitaxel 135 mg/m 2 , followed by FOLFOX omitted 5-Fu bolus. The IP PAC consisted of paclitaxel 80 mg/m2 intraperitoneally plus FOLFOX. Every 14 days repeated for all three regimens. Up to 9 cycles of treatment were administered, followed by S-1 until disease progression. The primary endpoint was PFS. Results: Between Nov 2015 and May 2018, 89 pts (30 POF, 29 IP PAC, 30 FOLFOX) were randomly allocated. PFS, OS and RR were seen in the table below. POF was better in PFS and RR than FOLFOX, although no statistically significant difference in RR. IP PAC was trend to be better in PFS than FOLFOX, but not in RR. OS was unmatured. The most common adverse events of grade 3 or 4 were neutropenia and neuropathy, but no significant difference among three groups. Conclusions: Both POF and IP PAC improved survival compared to FOLFOX. Only POF, not IP PAC, improved response rate compared to FOLFOX. Clinical trial information: NCT02845908. [Table: see text]
Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer
Authors: Sheng-Jia Shi, Li-Juan Wang, Dong-Hui Han, Jie-Heng Wu, Dian Jiao, Kai-Liang Zhang, Jiang-Wei Chen, Yu Li, Fa Yang, Jing-Liang Zhang, Guo-Xu Zheng, An-Gang Yang, Ai-Zhi Zhao, Wei-Jun Qin, Wei-Hong Wen
Journal: Theranostics (2019)

: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC
Abstract 15004: 4D Flow MRI Pressure Mapping in Patients With Bicuspid Aortic Valve: Feasibility Study With Comparison to Pressure Gradient Quantification
Authors: Fiona Burns, Julio Garcia, Cody Wu, Michael S Bristow, Xuexin Gao, Bobak Heydari, Carmen Lydell, Andrew G Howarth, Paul Fedak, James A White
Journal: Circulation (2017)

Introduction: Aortic valve disease is typically evaluated by trans-valvular velocities and Pressure Gradients (PG). 4D Flow MRI allows for Pressure Mapping (PM), a novel and alternate hemodynamic m...
No Clear Evidence for an Effect of Sofosbuvir Against Hepatitis E Virus in Organ Transplant Patients
Authors: Nassim Kamar, Qiuwei Pan
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: Recently, Drinane et al. presented the case of a kidney–pancreas transplant patient with chronic hepatitis E virus (HEV) infection who failed to clear HEV after two courses of ribavirin and who thereafter eradicated HEV when ribavirin was combined with sofosbuvir.1 The authors claimed that sofosbuvir has a therapeutic activity against HEV. Unfortunately, they do not provide any robust data to support their conclusion. Indeed, the patient was initially treated with ribavirin (600 mg/day) for 4 months. Treatment was stopped without confirming that HEV RNA became undetectable in the serum and the stools. It has been recently confirmed that the persistence of HEV shedding in the stools at the end of therapy is associated with a higher risk of relapse and that prolonging the duration of ribavirin therapy allows for eradication of HEV.2 In the presented case, HEV replication was observed again 18 months after ribavirin cessation. Because HEV genotype was not assessed, it is unknown whether HEV was still replicating for 18 months or if the patient was reinfected. A phylogenetic analysis of both strains and HEV RNA polymerase mutations had to be provided. The patient was retreated with ribavirin (600 mg/day) for 9 months. Treatment was stopped while the patient still had HEV replication. Sixteen months later, he was given ribavirin at double dose (1,200 mg/day) and sofosbuvir (400 mg/day) for 3 months. This allowed for a sustained virological response. There is no evidence that adding sofosbuvir to ribavirin was responsible for the HEV eradication. During the third course of ribavirin its dose was doubled compared to the two previous courses. Because ribavirin trough levels and kidney function were not provided, one could speculate that the patient was not receiving an optimal dose of ribavirin during the two first courses. In addition, because the 50% inhibitory concentration of sofosbuvir for HEV is 10‐fold higher than that for hepatitis C virus, one could wonder how a standard dose of sofosbuvir can be effective against HEV. Previous reports have failed to find a beneficial effect of sofosbuvir against HEV.3 Finally, the HEV genome, levels of immunosuppressants, and immunological parameters during follow‐up are unknown. Hence, there is still no evidence for an antiviral effect of sofosbuvir against HEV.
Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: A Randomized Controlled Study
Authors: David Jayne, Daniel Blockmans, Raashid Luqmani, Sergey Moiseev, Beulah Ji, Yulia Green, Leanne Hall, David Roth, Robert B. Henderson, Peter A. Merkel
Journal: Arthritis & Rheumatology (2019)

Objective To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody ( ANCA )–associated vasculitis ( AAV ). Methods In this multicenter, double‐blind, placebo‐controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low‐dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol‐specified event ( PSE ), with first PSE defined as a Birmingham Vasculitis Activity Score ( BVAS ) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 ( PR 3) or myeloperoxidase ( MPO )], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results The intent‐to‐treat population totaled 105 patients with AAV , of whom 52 (40 with PR 3‐ ANCA s, 12 with MPO ‐ ANCA s) received placebo and 53 (41 with PR 3‐ ANCA s, 12 with MPO ‐ ANCA s) received belimumab; 27 of the patients were in rituximab‐induced disease remission, while 78 were in cyclophosphamide‐induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [ HR ] 1.07, 95% confidence interval [95% CI ] 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSE s was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR 3‐ ANCA –associated vasculitis with cyclophosphamide‐induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.
Association Between Push-up Exercise Capacity and Future Cardiovascular Events Among Active Adult Men
Authors: Justin Yang, Costas A. Christophi, Andrea Farioli, Dorothee M. Baur, Steven Moffatt, Terrell W. Zollinger, Stefanos N. Kales
Journal: JAMA Network Open (2019)

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Robust evidence indicates an association of increased physical fitness with a lower risk of CVD events and improved longevity; however, few have studied simple, low-cost measures of functional status.To evaluate the association between push-up capacity and subsequent CVD event incidence in a cohort of active adult men.Retrospective longitudinal cohort study conducted between January 1, 2000, and December 31, 2010, in 1 outpatient clinics in Indiana of male firefighters aged 18 years or older. Baseline and periodic physical examinations, including tests of push-up capacity and exercise tolerance, were performed between February 2, 2000, and November 12, 2007. Participants were stratified into 5 groups based on number of push-ups completed and were followed up for 10 years. Final statistical analyses were completed on August 11, 2018.Cardiovascular disease-related outcomes through 2010 included incident diagnoses of coronary artery disease and other major CVD events. Incidence rate ratios (IRRs) were computed, and logistic regression models were used to model the time to each outcome from baseline, adjusting for age and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared). Kaplan-Meier estimates for cumulative risk were computed for the push-up categories.A total of 1562 participants underwent baseline examination, and 1104 with available push-up data were included in the final analyses. Mean (SD) age of the cohort at baseline was 39.6 (9.2) years, and mean (SD) BMI was 28.7 (4.3). During the 10-year follow up, 37 CVD-related outcomes (8601 person-years) were reported in participants with available push-up data. Significant negative associations were found between increasing push-up capacity and CVD events. Participants able to complete more than 40 push-ups were associated with a significantly lower risk of incident CVD event risk compared with those completing fewer than 10 push-ups (IRR, 0.04; 95% CI, 0.01-0.36).The findings suggest that higher baseline push-up capacity is associated with a lower incidence of CVD events. Although larger studies in more diverse cohorts are needed, push-up capacity may be a simple, no-cost measure to estimate functional status.
Association Between Hidradenitis Suppurativa and Lymphoma
Authors: Rachel Tannenbaum, Andrew Strunk, Amit Garg
Journal: JAMA Dermatology (2019)

Between Hidradenitis Suppurativa and LymphomaThe chronic inflammatory state in hidradenitis suppurativa (HS) may result in development of clonal immune cell populations which give rise to malignant lymphomas.Our objective was to investigate prevalence of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and cutaneous T-cell lymphoma (CTCL) among patients with HS.Methods | This cross-sectional cohort analysis used standardized electronic health record information of the IBM Explorys database for 55 million patients from 27 integrated health systems across the United States. 1 The analysis was limited to adults aged at least 18 years with active status between July 16, 2013, and July 16, 2018, who had complete information on sex and age.The Systemized Nomenclature of Medicine-Clinical Terms hidradenitis, non-Hodgkin's lymphoma, Hodgkin's disease, and primary cutaneous T-cell lymphoma were used to identify cohorts. 2 Use of electronic health data to identify lymphoma cohorts has been performed in prior studies evaluating associations between lymphoma and other conditions, including psoriasis. 3,4We assessed overall lymphoma prevalences among patients with and without HS, and within demographic subgroups.Prevalences were compared using a logistic regression model controlling for age and sex.All hypothesis tests were 2-tailed and conducted at the .05significance level.
ABL Tyrosine Kinase Inhibitors (TKIs) Are Associated with Increased Rho-Associated Kinase (ROCK) Activity That May Contribute to Vascular Toxicity in Patients with Chronic Myeloid Leukemia (CML)
Authors: Afaf Osman, Brian Yu, Nancy Glavin, Tamar S. Polonsky, James K. Liao, Richard A. Larson
Journal: Blood (2018)
Identification of a First-in-Class SETD2 Inhibitor That Shows Potent and Selective Anti-Proliferative Activity in t(4;14) Multiple Myeloma: T(4;14) Multiple Myeloma Cells Are Dependent on Both H3K36 Di and Tri-Methylation
Authors: Michael J Thomenius, Jennifer Totman, Kat Cosmopoulos, Dorothy Brach, Lei Ci, Neil Farrow, Jesse J Smith, Richard Chesworth, Kenneth W. Duncan, Cuyue Tang, Thomas Riera, John Lampe
Journal: Blood (2018)
TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer
Authors: Min Chen, Xiu-Jie Sheng, Yuan-Yi Qin, Song Zhu, Qing-Xia Wu, Liqing Jia, Nan Meng, Yu-Tian He, Guang-Rong Yan
Journal: Theranostics (2019)

Cancer cells undergo metabolic reprogramming to support their energy demand and biomass synthesis. However, the mechanisms driving cancer metabolism reprogramming are not well understood. Methods: The differential proteins and interacted proteins were identified by proteomics. Western blot, qRT-PCR and IHC staining were used to analyze TBC1D8 levels. In vivo tumorigenesis and metastasis were performed by xenograft tumor model. Cross-Linking assays were designed to analyze PKM2 polymerization. Lactate production, glucose uptake and PK activity were determined. Results: We established two aggressive ovarian cancer (OVCA) cell models with increased aerobic glycolysis. TBC1D8, a member of the TBC domain protein family, was significantly up-regulated in the more aggressive OVCA cells. TBC1D8 is amplified and up-regulated in OVCA tissues. OVCA patients with high TBC1D8 levels have poorer prognoses. TBC1D8 promotes OVCA tumorigenesis and aerobic glycolysis in a GAP activity-independent manner in vitro and in vivo. TBC1D8 bound to PKM2, not PKM1, via its Rab-GAP TBC domain. Mechanistically, TBC1D8 binds to PKM2 and hinders PKM2 tetramerization to decreases pyruvate kinase activity and promote aerobic glycolysis, and to promote the nuclear translocation of PKM2, which induces the expression of genes which are involved in glucose metabolism and cell cycle. Conclusions:TBC1D8 drives OVCA tumorigenesis and metabolic reprogramming, and TBC1D8 serves as an independent prognosis factor for OVCA patients.
Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications
Authors: Sandra P. Susanibar Adaniya, Adam D. Cohen, Alfred L. Garfall
Journal: American Journal of Hematology (2019)

Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients despite significant improvements achieved with modern therapy. Tumor evasion is a key process in the pathogenesis of MM and a compromised immune system is associated with more aggressive forms of the disease. In contrast, the emergence of myeloma‐specific immune responses after both autologous and allogeneic stem cell transplantation is associated with better prognosis. Adoptive T cell therapies may improve specific anti‐myeloma immunity resulting in long‐lasting remissions. CAR T cell therapies for MM are at an early stage of clinical development. To date, anti‐BCMA CAR T cells have shown the greatest results in early‐phase clinical trials. Toxicities have included cytokine release syndrome (CRS) and neurotoxicity. Current areas of research in CAR T cell therapies include the use of gene‐editing to enhance their effectiveness and safety, the integration of CAR T cells with other therapies (immunomodulatory drugs, checkpoint inhibitors) and CAR T cells to target multiple antigens.
Abstract MP040: Comparative-Effectiveness of Implementation Strategies on Blood Pressure Control among Hypertensive Patients: a Meta-Analysis
Authors: Katherine T Mills, Katherine M Obst, Wei Shen, Sandra Molina, Huijie Zhang, Jiang He
Journal: Circulation (2017)

Introduction: Globally, only 13.8% of adults with hypertension have controlled blood pressure (BP). Effective strategies are needed to overcome barriers to BP control. The overall objective is to determine the comparative-effectiveness of implementation strategies to reduce BP in adults with hypertension. Methods: We searched Medline and Embase (through November 2015) for randomized controlled trials of implementation strategies targeting barriers to hypertension control compared to usual care. One hundred trials with 48,070 hypertensive participants met our eligibility criteria and were included in this analysis. These trials were grouped by intervention strategy, and the effects of the intervention on BP change were combined using random effects models. Results: Multi-component team-based care with and without non-physician providers titrating medications had the greatest reduction in systolic and diastolic BP. Health coaching, home BP monitoring, and a combination of the two also resulted in significant reductions in BP. Few studies of BP audit and feedback and clinical decision support systems were available, and they did not result in significant reductions in systolic BP. Provider training did not significantly reduce BP. Conclusions: Team-based collaborative care is the most effective strategy for BP control among patients with hypertension. In addition, health coaching and home BP monitoring are useful patient-level strategies for hypertension control. These strategies should be prioritized in future BP control efforts.