Preliminary Consequences of Blood Pressure Management and Blood Homocysteine Levels with Perindopril in Newly Diagnosed Hypertensive Patients in the Vietnamese Population.

Background: Perindopril is an ACE inhibitor that aids in both blood pressure regulation and homocysteine reduction. Objectives: Our study aimed to evaluate the results of controlling blood pressure and blood homocysteine levels by perindopril in patients with primary hypertension. Materials and Methods: A cross-sectional descriptive study with a longitudinal follow-up was conducted on 105 primary hypertensive patients treated with perindopril. Results: The results of our study showed that after 6 weeks of treatment with perindopril, the proportion of patients with the target blood pressure (BP) level accounted for 70.5%, the rate of grade 1 hypertension decreased from 61.0% to 25.7%, grade 2 blood pressure decreased from 17.1% to 3.8%, and there was no case of grade 3 hypertension. At the same time, we also found that the rate of BP control in the group of patients who controlled Hcy below a threshold of 15 µmol/L was significantly higher than in the other group (p < 0.05). Concerning the efficacy of decreasing homocysteine in blood, we discovered that after 6 weeks of treatment with perindopril, the proportion of patients with elevated homocysteine reduced considerably from 74.3% to 40% (p < 0.05). In addition, the homocysteine concentration was 4.33 mol/L lower after treatment than before treatment (95% CI: 3.69-4.97) (p < 0.05). Conclusion: Perindopril helps control blood pressure and reduces blood homocysteine levels in patients with primary hypertension.

Robotic animal-assisted therapy as a complementary therapy in clinical practice: Exploring animal-assisted intervention professional perspectives.

BACKGROUND: and Purpose: Animal-Assisted Therapy (AAT) is a therapy that incorporates animals to improve the motor, social, behavioral, and/or cognitive functioning of participants. AAT has been shown to be a beneficial intervention for a wide range of populations. Although, researchers have suggested concerns in implementing AAT. The purpose of this study is to gain insight into the perspectives of therapists who incorporate AAT into their programs and to explore benefits and ethical considerations within the field of AAT. This study also aims to seek possible implications for robotic animal-assisted therapy (RAAT). MATERIALS AND METHODS: Professionals from the Association of Animal-Assisted Intervention Professionals (AAAIP) were recruited, along with members from multiple AAT private and public Facebook groups. Participants completed an anonymous online semi-structured survey, exploring their experience with and perspectives on both AAT and RAAT. Fourteen participants' responses were analyzed using Dedoose software to identify common themes in the responses. RESULTS: The results of this study provide various perspectives from professionals in different settings on the benefits of AAT, concerns about AAT, and the implication for the utilization of RAAT. The data indicated that most of the participants have not incorporated RAAT into practice. However, many of the participants believed that RAAT can be an alternative or preparatory intervention when interaction with live animals is not possible. The data collected further contributes to an emerging niche setting.

Avelumab in Men With Metastatic Castration-Resistant Prostate Cancer, Enriched for Patients Treated Previously With a Therapeutic Cancer Vaccine.

Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T . Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

Videos of Sipuleucel-T Programmed T Cells Lysing Cells That Express Prostate Cancer Target Antigens.

Sipuleucel-T, an autologous cellular immunotherapy, was approved to treat metastatic castration-resistant prostate cancer in 2010 in the United States. Treatment with sipuleucel-T primes the immune system to target prostate acid phosphatase, which is expressed by prostate cancer cells, potentially leading to lysis of cancer cells. Expanding on previously reported indirect evidence of cell killing with sipuleucel-T treatment, we sought to provide direct evidence of cell lysis through visualization. We used advanced video technology and available samples of peripheral blood mononuclear cells from subjects enrolled in the STAMP trial (NCT01487863). Isolated CD8+ T cells were used as effector cells and cocultured with autologous monocytes pulsed with control or target antigens. Differentially stained effector and target cells were then video recorded during coculture. Here, we present video recordings and analyses of T cells from sipuleucel-T-treated subjects showing-for the first time-direct lysis of cells that express prostate cancer target antigens, prostate acid phosphatase, or prostate-specific antigen.

Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival.

Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood.Patients and Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T-induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T-treated patient and healthy volunteer samples.Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post-sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P < 0.0001; N = 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P = 0.013) or PA2024 (Pearson R, 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90; P = 1.53E-08).Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res; 24(19); 4662-71. ©2018 AACR.

Self-aggregation of water-dispersible nanocollagen helices.

Inspired by nature, collagen is an outstanding polypeptide utilized to exploit its bioactivity and material design for healthcare technologies. In this study, we describe the self-aggregation of water-dispersible nanocollagen helices upon solidification to fabricate different forms of natural collagen materials. Chemically extracted native collagen fibrils are uniform anisotropic nanoparticles with an average diameter of about 50 nm and a high aspect ratio. The as-prepared collagen nanofibrils are soluble in sodium acetate-acetic acid buffer and are dispersible in water, thus generating collagen liquids that are used as distinct biopolymer precursors for materials development. Our interesting findings indicate that water-dispersible collagen-derived alcogels undergo critical point drying to self-arrange hierarchical nanofibrils into helix bundles in collagen sponge-like aerogels. Notably, using lyophilization to remove water in the biopolymer dispersion, a full regeneration of solidified fibers is achieved, producing collagen aerogels with lightweight characteristics similar to natural cottons. The self-aggregation of water-dispersible collagen occurs under freeze-drying conditions to turn individual nanofibrils into sheets with layered structures in the aerogel networks. The development of transparent, water resistant collagen bioplastic-like membranes was achieved by supramolecular self-assembly of water-dispersible collagen nanofibrils. Our efforts present a reliable concept in soft matter for creating promising collagen examples of liquids, hydrogels, aerogels, and membranes to increase utilization value of native collagen for biomedicine, pharmaceuticals, cosmetics, and nutrients.

Water-soluble chitosan-derived sustainable materials: towards filaments, aerogels, microspheres, and plastics.

Bioinspired materials have aroused great interest as their inherent biocompatible and structural characteristics have given rise to sustainable applications. In this work, we have reported the phase and morphology transformation of chitosan from crystalline nanofibrils into amorphous sheets for fabricating sustainable materials. Acetylation-induced aqueous dissolution of native chitosan nanofibrils affords water-soluble chitosan as a biopolymeric liquid. Water-soluble chitosan macromolecules self-aggregate into amorphous sheets on solidification, presenting an interesting way to inspire new structures of chitosan assemblies. Through control over gelation, lyophilization, and self-assembled confinement of water-soluble chitosan, we have fabricated novel chitosan materials including filaments, aerogels, microspheres, and plastics that are promising for sustainable use.

Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome.

PURPOSE: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). EXPERIMENTAL DESIGN: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. RESULTS: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05). CONCLUSIONS: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.

A dual-targeting PDGFRbeta/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo.

Targeting angiogenesis is a promising approach to the treatment of solid tumors and age-related macular degeneration (AMD). Inhibition of vascularization has been validated by the successful marketing of monoclonal antibodies (mAbs) that target specific growth factors or their receptors, but there is considerable room for improvement in existing therapies. Combination of mAbs targeting both the VEGF and PDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy without the accompanying toxicities of tyrosine kinase inhibitors and the inability to combine efficiently with traditional chemotherapeutics. However, development costs and regulatory issues have limited the use of combinatorial approaches for the generation of more efficacious treatments. The concept of mediating disease pathology by targeting two antigens with one therapeutic was proposed over two decades ago. While mAbs are particularly suitable candidates for a dual-targeting approach, engineering bispecificity into one molecule can be difficult due to issues with expression and stability, which play a significant role in manufacturability. Here, we address these issues upstream in the process of developing a bispecific antibody (bsAb). Single-chain antibody fragments (scFvs) targeting PDGFRbeta and VEGF-A were selected for superior stability. The scFvs were fused to both termini of human Fc to generate a bispecific, tetravalent molecule. The resulting molecule displays potent activity, binds both targets simultaneously, and is stable in serum. The assembly of a bsAb using stable monomeric units allowed development of an anti-PDGFRB/VEGF-A antibody capable of attenuating angiogenesis through two distinct pathways and represents an efficient method for rapid engineering of dual-targeting molecules.

Engineering of stable bispecific antibodies targeting IL-17A and IL-23.

Bispecific antibodies (bsAbs) present an attractive opportunity to combine the additive and potentially synergistic effects exhibited by combinations of monoclonal antibodies (mAbs). Current challenges for engineering bsAbs include retention of the binding affinity of the parent mAb or antibody fragment, the ability to bind both targets simultaneously, and matching valency with biology. Other factors to consider include structural stability and expression of the recombinant molecule, both of which may have significant impact on its development as a therapeutic. Here, we incorporate selection of stable, potent single-chain variable fragments (scFvs) early in the engineering process to assemble bsAbs for therapeutic applications targeting the cytokines IL-17A/A and IL-23. Stable scFvs directed against human cytokines IL-23p19 and IL-17A/A were isolated from a human Fab phage display library via batch conversion of panning output from Fabs to scFvs. This strategy integrated a step for shuffling V regions during the conversion and permitted the rescue of scFv molecules in both the V(H)V(L) and the V(L)V(H) orientations. Stable scFvs were identified and assembled into several bispecific formats as fusions to the Fc domain of human IgG1. The engineered bsAbs are potent neutralizers of the biological activity of both cytokines (IC(50) < 1 nM), demonstrate the ability to bind both target ligands simultaneously and display stability and productivity advantageous for successful manufacture of a therapeutic molecule. Pharmacokinetic analysis of the bsAbs in mice revealed serum half-lives similar to human mAbs. Assembly of bispecific molecules using stable antibody fragments offers an alternative to reformatting mAbs and minimizes subsequent structure-related and manufacturing concerns.