tbuckley/cabot-search huggingface dataset:
Novel Paracrine Functions of Smooth Muscle Cells in Supporting Endothelial Regeneration Following Arterial Injury
Authors: Jun Ren, Ting Zhou, Vijaya Satish Sekhar Pilli, Noel Phan, Qiwei Wang, Kartik Gupta, Zhenjie Liu, Nader Sheibani, Bo Liu
Journal: Circulation Research (2019)

Regeneration of denuded or injured endothelium is an important component of vascular injury response. Cell-cell communication between endothelial cells and smooth muscle cells (SMCs) plays a critical role not only in vascular homeostasis but also in disease. We have previously demonstrated that PKCδ (protein kinase C-delta) regulates multiple components of vascular injury response including apoptosis of SMCs and production of chemokines, thus is an attractive candidate for a role in SMC-endothelial cells communication.To test whether PKCδ-mediated paracrine functions of SMCs influence reendothelialization in rodent models of arterial injury.Femoral artery wire injury was performed in SMC-conditional Prkcd knockout mice, and carotid angioplasty was conducted in rats receiving transient Prkcd knockdown or overexpression. SMC-specific knockout of Prkcd impaired reendothelialization, reflected by a smaller Evans blue-excluding area in the knockout compared with the wild-type controls. A similar impediment to reendothelialization was observed in rats with SMC-specific knockdown of Prkcd. In contrast, SMC-specific gene transfer of Prkcd accelerated reendothelialization. In vitro, medium conditioned by AdPKCδ-infected SMCs increased endothelial wound closure without affecting their proliferation. A polymerase chain reaction-based array analysis identified Cxcl1 and Cxcl7 among others as PKCδ-mediated chemokines produced by SMCs. Mechanistically, we postulated that PKCδ regulates Cxcl7 expression through STAT3 (signal transducer and activator of transcription 3) as knockdown of STAT3 abolished Cxcl7 expression. The role of CXCL7 in SMC-endothelial cells communication was demonstrated by blocking CXCL7 or its receptor CXCR2, both significantly inhibited endothelial wound closure. Furthermore, insertion of a Cxcl7 cDNA in the lentiviral vector that carries a Prkcd shRNA overcame the adverse effects of Prkcd knockdown on reendothelialization.SMCs promote reendothelialization in a PKCδ-dependent paracrine mechanism, likely through CXCL7-mediated recruitment of endothelial cells from uninjured endothelium.
Abstract A081: Activation of sphingosine kinase 1 by lipopolysaccharide promotes prostate cancer cell invasion via matriptase
Authors: Cheng-Fan Lee, Benjamin Chen, Jer-Tsong Hsieh, Ming-Shyue Lee
Journal: Cancer Research (2018)

Abstract A 15-year cohort study indicates that bacterial-induced prostatitis is correlated to prostate cancer (PCa) incidence. Several gram-negative bacteria have been identified in PCa patient specimens and inflammatory cytokines derived from bacterial infection have been involved in PCa tumorigenesis. However, the direct effect of lipopolysaccharide (LPS), a potent inflammatory substance from gram-negative bacteria, on PCa development is not well studied. In this study, we examine the effect of LPS on the growth (MTT assay) and invasion (Transwell assay) of several PCa cells lines including LNCaP, PC3, and DU145. Although LPS does not change the cell growth, our results reveal that LPS can enhance the PCa cell invasiveness and increase pericellular proteolytic activities. Using protease inhibitor screening and proteolytic analyses, we have identified that matriptase (MTX), a member of the membrane-anchored serine protease family, plays a key role in LPS-induced PCa cell invasiveness. The activated levels of MTX can be detected in the cells and the conditioned medium (CM) from LPS-treated cells. Indeed, the elevation of MTX expression is associated with high-grade PCa in archival specimens. Knowing LPS as a ligand for toll-like receptor 4 (TLR4), specific antagonists and shRNA knockdown methodology were used to delineate the mechanism by which TLR4/sphingosine kinase 1 (SphK1) signaling cascade plays a role in LPS-induced PCa cell invasion. The results show that SphK1 was important for MTX activation and PCa cell invasion. Moreover, we found that LPS could induce the activation of SphK1 based on an elevated phosphorylation level and SphK1 translocation to plasma membrane for the production of sphingosine 1-phosphate (S1P). S1P can subsequently induce MTX activation and PCa cell invasion through S1P receptor 4 (S1PR4) in a paracrine or autocrine manner. S1PR4 is further identified as an important receptor for S1P to mediate MAPK signaling. Furthermore, there is a significant correlation between the elevated expression of SphK1 and the Gleason scores of PCa specimens. The phenomenon was further corroborated by the fact that LPS could induce SphK1 activation in patient-derived explant model (PDeX). Taken together, we have unveiled a novel LPS-elicited pathway leading to PCa cell invasion. Our results provide not only the potential impact of bacterial infection on PCa progression but also several therapeutic target(s) against PCa metastasis. Citation Format: Cheng-Fan Lee, Benjamin Chen, Jer-Tsong Hsieh, Ming-Shyue Lee. Activation of sphingosine kinase 1 by lipopolysaccharide promotes prostate cancer cell invasion via matriptase [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A081.
Cognate Nonlytic Interactions between CD8+ T Cells and Breast Cancer Cells Induce Cancer Stem Cell–like Properties
Authors: Roland G. Stein, Stefan Ebert, Laura Schlahsa, Claus J. Scholz, Matthias Braun, Petra Hauck, Evi Horn, Camelia-Maria Monoranu, Vincent J. Thiemann, Michael P. Wustrow, Sebastian F. Häusler, Itsaso Montalbán del Barrio, Tanja N. Stüber, Matthias Wölfl, Johannes Dietl, Andreas Rosenwald, Joachim E. Diessner, Achim Wöckel, Jörg Wischhusen
Journal: Cancer Research (2019)

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8+ T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with nonlytic CD8+ T cells also increased the proportion of stem cell-like cancer cells in a cell-to-cell contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell-like properties was confirmed by enhanced tumor-forming capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after nonlytic cognate interactions with CD8+ T cells enables increased tumor growth and metastasis in BALB/cnu/nu mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy. SIGNIFICANCE: This study shows that ineffective immune responses not only fail to clear a malignancy, but can also activate pathways in cancer cells that promote stemness and tumor-seeding capacity.
Abstract P1-13-10: Comparison of overall and recurrence-free survival between four and six cycles of adjuvant docetaxel and cyclophosphamide in early stage breast cancer
Authors: I Mehmi, CE Wight, JL Hill
Journal: Cancer Research (2019)

Abstract Background: The ABC trials and the WSG Plan B trial demonstrated that certain early stage breast cancer patients can be appropriately treated with docetaxel and cyclophosphamide (TC) rather than doxorubicin and cyclophosphamide (AC); however both of these trials utilized six cycles of TC as the comparator. TC is given for 4 cycles based on the US Oncology 9735 trial. To our knowledge, there is no available data that has compared adverse events or outcomes of four versus six cycles of TC. Methods: This was a single-center, retrospective study evaluating recurrence-free survival, overall survival, and occurrence of toxicities between four and six cycles of docetaxel and cyclophosphamide adjuvant chemotherapy for early stage breast cancer at West Virginia University Cancer Institute. Results: 112 patients were included; 81 received four cycles and 31 received six. Recurrence free survival rates of patients that received four and six cycles of chemotherapy were 94% and 90%, respectively, at three years (P=0.68). Overall survival at three years was 99% versus 97% (P=0.49), respectively. The incidence of peripheral neuropathy requiring treatment was 42% in patients that received six cycles and 19% in patients that received four (P=0.015). Conclusion: The addition of two cycles of docetaxel and cyclophosphamide adjuvant chemotherapy for early stage breast cancer provides no additional recurrence-free or overall survival benefit but does increase the incidence of peripheral neuropathy requiring treatment. Table 1.Baseline Characteristics 4 Cycles (n=81)6 Cycles (n=31)P-valueAge, median years (range)57 (37-75)48 (32-71)0.001Receptor status, n (%) 0.63HR positive, HER2 negative61 (75)25 (81) Triple negative20 (25)6 (19) Cancer stage, n (%) 0.031I39 (48)9 (29) II39 (48)17 (55) III3 (4)5 (16) Lymph node involvement, n (%)24 (30)20 (65)0.001Ki67 (%), median (range)23 (2-99)23.5 (4-99)0.99Tumor grade, n (%) 0.07212 (2)4 (13) 242 (52)12 (39) 337 (46)15 (48) Surgery, n (%) Breast conservation35 (43)14 (45)0.99Unilateral mastectomy32 (40)9 (29)0.38Bilateral mastectomy14 (17)8 (26)0.43 Table 2.Adverse Events 4 Cycles (n=81)6 Cycles (n=31)P-valueDose reductions, n (%)17 (21)8 (26)0.62Dose delay, n (%)3 (4)1 (3)0.99Inpatient admissions, n (%)22 (27)8 (26)0.99Treatment for peripheral neuropathy, n (%)15 (19)13 (42)0.015 Citation Format: Mehmi I, Wight CE, Hill JL. Comparison of overall and recurrence-free survival between four and six cycles of adjuvant docetaxel and cyclophosphamide in early stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-10.
Degradable Nanoparticles Restore Lysosomal pH and Autophagic Flux in Lipotoxic Pancreatic Beta Cells
Authors: Jialiu Zeng, Orian S. Shirihai, Mark W. Grinstaff
Journal: Advanced Healthcare Materials (2019)

Abstract Chronic exposure to high levels of fatty acids (lipotoxicity) in pancreatic beta cells (β‐cells) decreases lysosomal acidity and inhibits autophagic flux. Today, there are a lack of approaches to modify lysosomal acidity to determine whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions. Biodegradable poly(lactic‐ co ‐glycolic acid) (PLGA) nanoparticles (NPs) with diameters of ≈100 nm localize to lysosomes and serve as an ideal method to deliver lactic and glycolic acid to lysosomes upon NP polymer degradation. In this study, the ability of PLGA NPs to lower lysosomal pH and restore autophagic flux is investigated in pancreatic insulin secreting (INS1) β‐cells. PLGA NPs display a concentration dependent performance with higher concentrations of PLGA NPs, lowering lysosomal pH, as well as restoring autophagic flux and insulin secretion in pancreatic β‐cells. These results document that acidifying the lysosome, via an external perturbation, in lipotoxic pancreatic β‐cells affords a specific biological outcome of improved cellular degradative activity.
Pharmacologic Management of Aneurysms
Authors: Jan H. Lindeman, Jon S. Matsumura
Journal: Circulation Research (2019)

Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic aneurysm identified hundreds of candidate strategies for stabilization, and data from preoperative clinical intervention studies show that interventions in the pathways of the activated inflammatory and proteolytic cascades in enlarging abdominal aortic aneurysm are feasible. Similarly, the concept of pharmaceutical aorta stabilization in Marfan syndrome is supported by a wealth of promising studies in the murine models of Marfan syndrome-related aortapathy. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and aortic root stabilization in Marfan syndrome, these claims are not consistently confirmed in larger and controlled studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models of aneurysm disease and perhaps incomplete understanding of the pathological processes involved in later stages of aortic aneurysm progression. Preclinical models more reflective of human pathophysiology, identification of biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance the opportunities in this important field.
Subgroup Analysis of Patients with Biochemical or Symptomatic Relapse at the Time of Enrollment in the Endeavor Study
Authors: Philippe Moreau, David S Siegel, Hartmut Goldschmidt, Ruben Niesvizky, Sara Bringhen, Robert Z Orlowski, Julie Blaedel, Zhao Yang, Meletios A Dimopoulos
Journal: Blood (2018)
Microsatellite instability detection from plasma of colorectal cancer patients.
Authors: Jing Sun, Zhenghao Cai, Songbing He, Chengliu Liu, Minhua Zheng, Xinguo Zhu, Jian Zhou, Yizhou Yao, Han Han-Zhang, Hao Liu
Journal: Journal of Clinical Oncology (2019)

515 Background: MSI, detected in 15% of colorectal cancer (CRC) patients, is a hypermutable phenotype caused by deficiency in DNA mismatch repair system. Currently, MSI detection is limited to tissue samples. Detection of MSI from blood samples has been explored but confounded by low sensitivity due to the trace amount of ctDNA present. In this study, we developed a NGS read-count based algorithm-bMSISEA (blood MSI signature enriched analysis) to detect MSI from blood samples. Methods: Matched tumor and adjacent normal tissues were obtained from 50 MSI-H CRC patients to establish a microsatellite pattern for MSI-H tumors. White blood cells (WBCs) from 100 CRC patients were used to establish a microsatellite pattern for MSS. Plasma samples were obtained from 75 CRC patients with known MSI status assessed by IHC (38 MSI-H and 37 MSS) to validate the algorithm. Results: To establish features for MSI-H and MSS tumors, 51 microsatellite loci covered by ColonCore panel with mononucleotide repeats longer than 10bp were scanned using paired tumor and adjacent normal tissues and 8 loci with significant differential read length distribution were identified. MSI signature enrichment analysis was performed using WBCs to establish a microsatellite signature for MSS tumors. For each locus, the numbers of total reads supporting either MSI-H (denoted as K in the equation) or MSS (N-K, where N refers to the total number of reads supporting either MSI-H or MSS at a specific locus) were counted. The MSI signature enrichment analysis was performed using hypergeometric test. The log-transformed p values were used to calculate z scores. The final microsatellite status was reflected by MS score, which was the sum of z scores of all loci. A MS score of 15 was derived to differentiate MSS and MSI-H tumors. Both simulation data and data generated using clinical samples revealed more than 98% sensitivity and 100% specificity with ctDNA percentage greater than 1%. This method is still reliable if the ctDNA percentage drops to 0.4%, yielding sensitivity of 93.3% and specificity of 100%. Conclusions: We developed a sensitive algorithm which can reliably detect MSI status with ctDNA fraction greater than 0.4% with sensitivity of 93.3% and specificity of 100%.
Silk Fibroin-Coated Nanoagents for Acidic Lysosome Targeting by a Functional Preservation Strategy in Cancer Chemotherapy
Authors: Mixiao Tan, Weiwei Liu, Fengqiu Liu, Wei Zhang, Hui Gao, Juan Cheng, Yu Chen, Zhigang Wang, Yang Cao, Haitao Ran
Journal: Theranostics (2019)

Background: Premature drug leakage and inefficient cellular uptake are stand out as considerable hurdles for low drug delivery efficiency in tumor chemotherapy.Thus, we established a novel drug delivery and transportation strategy mediated by biocompatible silk fibroin (SF)-coated nanoparticles to overcome these therapeutic hurdles.Methods: we first synthesised a TME-responsive biocompatible nanoplatform constructed of amorphous calcium carbonate (ACC) cores and SF shells for enhanced chemotherapy by concurrently inhibiting premature drug release, achieving lysosome-targeted explosion and locally sprayed DOX, and monitoring via PAI, which was verified both in vitro and in vivo. Results:The natural SF polymer first served as a "gatekeeper" to inhibit a drug from prematurely leaking into the circulation was demonstrated both in vitro and in vivo.Upon encountering TMEs and targeting to the acidic pH environments of lysosomes, the sensitive ACC nanoparticles were gradually degraded, eventually generating a large amount of Ca 2+ and CO 2 , resulting in lysosomal collapse, thus preventing both the efflux of DOX from cancer cells and the protonation of DOX within the lysosome, releasing multiple hydrolytic enzyme to cytoplasm, exhibiting the optimal therapeutic dose and remarkable synergetic therapeutic performance.In particular, CO 2 gas generated by the pH response of ACC nanocarriers demonstrated their imaging capability for PAI, providing the potential for quantifying and guiding drug release in targets. Conclusion:In this work, we constructed TME-responsive biocompatible NPs by coating DOX-preloaded ACC-DOX clusters with SF via a bioinspired mineralization method for efficient therapeutics.This functional lysosome-targeted preservation-strategy-based therapeutic system could provid novel insights into cancer chemotherapy.
One Step Closer to Precision Medicine Strategies Based on Genetic Information
Authors: Benjamin P. George, Guido J. Falcone
Journal: JAMA Neurology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Abstract 15624: Resting Amygdalar Activity Independently Predicts Diabetes Risk Across Levels of Adiposity: A Mechanism Linking Chronic Stress and Metabolic Disease
Authors: Michael T Osborne, Amorina Ishai, Basma Hammad, Brian Tung, Ying Wang, Amos Baruch, Jon T Giles, Janet Lo, Zahi A Fayad, Lisa M Shin, Karestan C Koenen, Steven K Grinspoon, Roger K Pitman, Ahmed Tawakol
Journal: Circulation (2017)

Introduction: While stress associates with poor glycemic control, its relationship to incident diabetes (DM) risk is unclear. We imaged activity of the amygdala (AA: a validated measure of neural t...
FRI0069 Efficacy and safety of remicade (infliximab) plus arava (leflunomide) in rheumatoid arthritis (ra)
Authors: S Patel, B Bergen, A Kraemer, G Keenan
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Leflunomide is a new disease-modifying antirheumatic drug (DMARD) approved for the treatment of active RA as an alternative to methotrexate (MTX) therapy. Infliximab is approved for the treatment of RA when used in combination with MTX. However, in patients either intolerant of or refractory to MTX therapy, combination therapy with leflunomide is sometimes utilised. <h3>Objectives</h3> To assess the efficacy and safety of infliximab plus leflunomide in patients with RA. <h3>Methods</h3> Select community practices were surveyed about the use of infliximab in combination with leflunomide for the treatment of RA. Demographic data and information on prior and concomitant medications were documented. Further data regarding efficacy (numbers of swollen and tender joints, functional class, ESR/CRP) and safety (occurrence of nausea, vomiting, alopecia, or any other symptoms) are being collected at baseline (prior to start of the combination) and after 4 to 5 doses of the combination. <h3>Results</h3> Twenty-one community practices were included in the survey; 31 patients were identified who recently started on the combination of infliximab plus leflunomide. The patient population consisted of 20 (65%) women and 11 (35%) men. Patients ranged in age from 29 to 80 yrs (mean of 56.3 yrs). The duration of RA ranged from 2 to 50 yrs (mean of 10.6 yrs). Twenty-six (84%) patients had received MTX at a mean dose of 18.2 mg/wk. 42% of the population developed intolerance to MTX. MTX was ineffective in 45% of patients and contraindicated in 16% of patients. Patients were generally started on leflunomide at 20 mg QD. Rheumatologists added infliximab (3 mg/kg q 8 wks after loading doses at Weeks 0, 2, and 6 in the majority of patients) due to an incomplete response achieved with leflunomide. 71% of these patients also continued to receive concomitant prednisone at 2.5 to 20 mg/day. While patients had only received a few doses each, no serious adverse experiences were reported. This population will continue to be followed over time for both safety and efficacy of the infliximab/leflunomide combination. <h3>Conclusion</h3> Infliximab has been used in combination with leflunomide in select RA patients in whom MTX has not been tolerated, is ineffective, or is contraindicated. The ongoing clinical experience of these and similar patients will be monitored.