Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: To use or not to use?

Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens.     

DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses

Plasmid DNA serves as a simple and easily modifiable form of antigen delivery for vaccines. The USDA approval of DNA vaccines for several non-human diseases underscores the potential of this type of antigen delivery method as a cost-effective approach for the treatment or prevention of human diseases, including cancer. However, while DNA vaccines have demonstrated safety and immunological effect in early phase clinical trials, they have not consistently elicited robust anti-tumor responses. Hence many recent efforts have sought to increase the immunological efficacy of DNA vaccines, and we have specifically evaluated several target antigens encoded by DNA vaccine as treatments for human prostate cancer. In particular, we have focused on SSX2 as one potential target antigen, given its frequent expression in metastatic prostate cancer. We have previously identified two peptides, p41-49 and p103-111, as HLA-A2-restricted SSX2-specific epitopes. In the present study we sought to determine whether the efficacy of a DNA vaccine could be enhanced by an altered peptide ligand (APL) strategy wherein modifications were made to anchor residues of these epitopes to enhance or ablate their binding to HLA-A2. A DNA vaccine encoding APL modified to increase epitope binding elicited robust peptide-specific CD8+ T cells producing Th1 cytokines specific for each epitope. Ablation of one epitope in a DNA vaccine did not enhance immune responses to the other epitope. These results demonstrate that APL encoded by a DNA vaccine can be used to elicit increased numbers of antigen-specific T cells specific for multiple epitopes simultaneously, and suggest this could be a general approach to improve the immunogenicity of DNA vaccines encoding tumor antigens.     

In vitro assays of the antibacterial and antioxidant activity of aqueous leaf extracts from different Prunus salicina Lindl. cultivars

The growing interest in the substitution of synthetic food antioxidants and antimicrobial additives by natural ones has fostered research on vegetable sources and on the screening of raw materials, for identifying new antioxidants and antimicrobial natural agents. The aim of the present study was to assess total phenolic contents and determine polyphenolic composition, related antioxidative and antimicrobial properties of plum leaves extracts from six cultivars. It was observed that the content of total phenolic compounds was cultivar dependent. High antioxidant capacity has been observed and related to the relative amounts of polyphenolic compounds with good antioxidant properties. The antimicrobial activity was confirmed against Listeria innocua and Escherichia coli, and it has found to be related with the high phenolic contents. Our results suggest that the use of plum leaf extracts is a feasible alternative as antibacterial and antioxidant agents to prevent the deterioration of stored foods by bacteria and oxidation.     

JTE-522, a cyclooxygenase-2 inhibitor,is an effective chemopreventive agent against rat experimental liver fibrosis1

BACKGROUND & AIMS: The aim of this study was to assess the effects of cyclooxygenase (COX)-2 inhibition on rat experimental liver fibrogenesis. METHODS: We investigated the inhibitory effects of a selective COX-2 inhibitor, JTE-522, on liver fibrosis induced by a choline-deficient, l-amino acid-defined diet (CDAA). Inhibitory effect was also tested in a second model of thioacetamide (TAA)-induced liver fibrosis. RESULTS: CDAA induced liver fibrosis and preneoplastic foci at 12 weeks and cirrhosis at 36 weeks. Hepatocellular carcinoma was noted in 13 of 15 rats (87%). JTE-522 significantly inhibited fibrosis and development of preneoplastic lesions in a dose-dependent manner and completely inhibited generation of cirrhosis and hepatocellular carcinoma at both low and high doses (10 and 30 mg/kg body wt/day, respectively). JTE-522 administrated only from 12 weeks to 36 weeks also prevented cirrhosis and formation of hepatocellular carcinoma. JTE-522 itself did not cause local or systemic gross or histopathologic changes at 36 weeks. Mechanistic studies indicated that the CDAA model displayed up-regulation of several biomarkers, including COX-2, arachidonate metabolite (prostaglandin E(2)), serum aspartate aminotransferase, and c-myc expression. The model also showed an increased proportion of activated hepatic stellate cells, proliferating cell nuclear antigen index, and CD45-positive inflammatory cells in the liver. JTE-522 effectively diminished these changes. JTE-522 exhibited similar antifibrosis effects in the TAA model. CONCLUSIONS: Our results suggest that COX-2 is involved in CDAA- and TAA-induced liver fibrosis. Our data also indicate that JTE-522 is a potent chemopreventive agent of rat liver fibrosis with low toxicity.     

Height alone,rather than body surface area,suffices for risk estimation in ascending aortic aneurysm

Background

In international guidelines, risk estimation for thoracic ascending aortic aneurysm (TAAA) is based on aortic diameter. We previously introduced the aortic size index (ASI), defined as aortic size/body surface area (BSA), as a predictor of aortic dissection, rupture, and death. However, weight might not contribute substantially to aortic size and growth. We seek to evaluate the height-based aortic height index (AHI) versus ASI for risk estimation and revisit our natural history calculations.

Positive and negative factors for the treatment outcomes following total ankle arthroplasty? A systematic review

BackgroundPatient selection, surgeon’s experience and implant design play an integral role and affect the treatment outcomes of total ankle arthroplasty (TAA). The aims of this study were to investigate the positive and negative attributes that correlate with different clinical and radiographic outcomes.MethodsEight-nine studies matched the inclusion criteria: (1) studies of primary TAA with uncemented prosthesis; (2) mean follow-up of no less than 2-year; (3) reports of clinical and radiographic outcomes, and exclusion criteria: (1) non-English study; (2) more than one type of prosthesis without separated data; (3) kin studies with shorter follow-up or smaller cohort. Age, etiology, preoperative deformity, surgeon’s experience, follow-up duration and prosthetic type were studied with respect to different outcomes by mixed-effects logistic regression analysis.ResultsPatients factor: older patients reported less pain or stiffness and demonstrated less radiographic loosening which did not require additional surgical intervention. More traumatic arthritis experienced adjacent joints degeneration after TAA. Surgeon factor: less experienced surgeons had more intraoperative complications. Lack of experience for complications management without implant retrieval during early period might result in more revisions or fusion was done. Prosthetic factor: updated instrumentation decreased malalignment. If the polyethylene (PE) insert was significantly narrower than the metal components more implant instability and subsequent severe particulate wear was seen. Designs with flat-on-flat articulation and ridge at the center of the talar component associated with more PE fracture. Minimal bone resection reduced postoperative fractures. A flat cut of the tibial component and a flat undersurface with press-fit by two screws or pegs of the talar component demonstrated less postoperative fractures, whereas a syndesmosis fusion and a small triangular shape with one central fin of the talar component experienced more loosening which did not require additional surgery. Anatomic conical shape of the talar component seemed to reduce adjacent joint degeneration. Finally, fewer failures were found in patients who received HINTEGRA and Salto Talaris.ConclusionsBased on our investigation, some positive and negative factors for different clinical and radiographic outcomes were found, which should be taken into consideration in clinical practice and ankle implant design.     

A comparison of thoracoabdominal aortic aneurysms open repair in patients with or without “shaggy aorta”

ObjectiveIn the field of thoracoabdominal aortic aneurysm (TAAA) open surgical repair (OSR), some preoperative characteristics are established risk factors for adverse outcomes, whereas others are supposed to be relevant, but their role still need to be defined; among them, the presence of “shaggy aorta” (SA), an extensive and irregular atheroma within the aorta. The aim of this study is to report the results of a single-center large cohort of patients treated with OSR for TAAA with SA, comparing the outcomes with patients affected by TAAA without SA, and analyzing the impact of the scores for SA on the outcomes.MethodsAll consecutive patients receiving OSR for TAAA between 2012 and 2021 were retrospectively analyzed. Clinical data from patients with degenerative TAAA were included and analyzed for preoperative characteristics and postoperative outcomes; patients with ruptured TAAA, and patients with aortic dissection were excluded from the analysis. Patients with degenerative aortic aneurysm, thrombus measurement in non-aneurysmal aortic segments (≤40 mm), atheroma thickness ≥5 mm, and finger-like thrombus projection were included in the SA group, whereas the others were included in the non-shaggy aorta group (NSA group). The SA group and NSA group were compared using a propensity-matched comparison. Preoperative computed tomography scans of patients in the SA group were also stratified according to SA grading scores.ResultsA total of 58 patients with SA were identified (male, n = 43 [74.1%], mean age 70.1 ± 7.8 years) among 497 patients with TAAA treated with open surgical repair. After propensity matching, there were 57 patients in the SA group and 57 in the NSA group with correction of all differences in baseline characteristics. Patients in the SA group presented significantly higher in-hospital mortality (SA group, 14.0% vs NSA group, 3.5%; P = .047), postoperative acute renal failure (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease [RIFLE], 3-5) (SA group, 21.1% vs NSA group, 5.3%; P = .013), and postoperative embolization (SA group, 28.1% vs NSA group, 8.8%; P = .008). Spinal cord ischemia and stroke rate were not significantly influenced by the presence of SA. In the SA group, 16 patients (27.6%) with end-organ embolization were compared with 42 patients (72.4%) without a documented embolization considering the grade of aortic “shagginess” and no significant difference was identified (P = .546).ConclusionsDespite a better knowledge of the SA disease, new classifications, and intraoperative adjuncts, TAAA patients with SA treated with OSR have worse postoperative outcomes if compared with patients without SA. The presence of SA is a risk factor itself, whereas the grade of “shagginess” seems not to impact on postoperative outcomes.