We report the experimental generation of highly energetic carbon ions up to 48 MeV per nucleon by shooting double-layer targets composed of well-controlled slightly underdense plasma and ultrathin ...foils with ultraintense femtosecond laser pulses. Particle-in-cell simulations reveal that carbon ions are ejected from the ultrathin foils due to radiation pressure and then accelerated in an enhanced sheath field established by the superponderomotive electron flow. Such a cascaded acceleration is especially suited for heavy ion acceleration with femtosecond laser pulses. The breakthrough of heavy ion energy up to many tens of MeV/u at a high repetition rate would be able to trigger significant advances in nuclear physics, high energy density physics, and medical physics.
Summary
New variants of porcine epidemic diarrhoea virus (PEDV), which emerged in Taiwan in late 2013, have caused a high morbidity and mortality in neonatal piglets. To investigate the molecular ...characteristics of the spike (S) gene of the emerging Taiwan PEDV strains for a better understanding of the genetic diversity and relationship among the Taiwan new variants and the global PEDVs, full‐length S genes of PEDVs from nine 1–7 day‐old piglets from three pig farms in the central and southern Taiwan were sequenced and analysed. The result of phylogenetic analysis of the S gene showed that all the Taiwan PEDV strains were closely related to the non‐S INDEL strains from US, Canada and China, suggesting a common ancestor for these strains. As compared with the historic PEDVs and CV777‐based vaccine strains, the nine Taiwan PEDV variants shared almost the same genetic signatures as the global non‐S INDEL strains, including a series of insertions, deletions and mutations in the amino terminal as well as identical mutations in the neutralizing epitopes of the S gene. The high similarity of the S protein among the Taiwan and the globally emerged non‐S INDEL PEDV strains suggests that the Taiwan new variants may share similar pathogenesis and immunogenicity as the global outbreak variants. The development of a novel vaccine based on the Taiwan or the global non‐S INDEL strains may be contributive to the control of the current global porcine epidemic diarrhoea outbreaks.
In vaccine design, antigens are often arrayed in a multivalent nanoparticle form, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. We ...compared the fates of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized envelope trimer, in protein nanoparticle or "free" forms after primary immunization. Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network and then concentrated in germinal centers in a complement-, mannose-binding lectin (MBL)-, and immunogen glycan-dependent manner. Loss of FDC localization in MBL-deficient mice or via immunogen deglycosylation significantly affected antibody responses. These findings identify an innate immune-mediated recognition pathway promoting antibody responses to particulate antigens, with broad implications for humoral immunity and vaccine design.
Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering ...antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.
Background and purpose
Statin therapy is beneficial for primary and secondary prevention of ischaemic stroke, but its influence in patients with intracerebral hemorrhage (ICH) is unclear. An ...assessment was made of the effect of early statin therapy on patients with acute ICH.
Methods
Taiwan's National Health Insurance Research Database was screened for patients without prior statin therapy admitted from January to December 2008 for newly diagnosed ICH. Patients taking statins during hospitalization or within 3 months post‐discharge were the early statin group (n = 749); patients who were not were the control group (n = 7583). The study end‐points were recurrent ICH and all‐cause mortality during follow‐up.
Results
All eligible patients were followed up until 31 December 2010. During the follow‐up, 69 (9.2%) patients in the early statin group and 677 (8.9%) control group patients had recurrent ICH. Cox proportional hazards analyses showed that early statin use did not increase the risk of recurrent ICH (adjusted hazard ratio 1.044; 95% confidence interval 0.812–1.341). During the same period, 90 (12.0%) of the early statin group and 1519 (20.0%) control group patients died. All‐cause mortality was lower in the early statin group (adjusted hazard ratio 0.742; 95% confidence interval 0.598–0.919) than in the control group. Matched propensity score analyses were consistent with findings in Cox proportional hazards analyses.
Conclusions
Early statin group patients with acute ICH did not have a higher recurrent risk of ICH and might have lower all‐cause mortality during follow‐up. It is concluded that statin therapy might be beneficial for patients with ICH.
Summary
Background
Although ultraviolet (UV) phototherapy is an effective treatment for vitiligo, its effect on the risk of skin cancer remains controversial.
Aim
To investigate the association ...between UV phototherapy and skin cancer risk in patients with vitiligo.
Methods
A systematic review was performed for studies published before 5 May 2021 in the PubMed, Embase, Web of Science and Cochrane Library databases. The primary outcome was the association of UV phototherapy with the risk of skin cancer in patients with vitiligo. A meta‐analysis with a random‐effects model was conducted.
Results
Five retrospective cohort studies covering a total of 228 607 patients with vitiligo (110 038 who had been treated with UV phototherapy and 118 569 patients who had not) were included in the meta‐analysis. The risk of nonmelanoma skin cancer Mantel–Haenszel risk ratio (MHRR) = 0.95; 95% CI 0.44–2.05 and melanoma (MHRR = 1.11; 95% CI 0.33–3.82) did not significantly increase after phototherapy in patients with vitiligo. In the subgroup analysis, we also found no significant association between phototherapy with narrowband UVB phototherapy specifically and risk of skin cancer in patients with vitiligo. There was no significant difference in risk of skin cancer between patients from Europe and those from East Asia and the risk was not affected by the number of narrowband UVB phototherapy sessions.
Conclusions
The findings of this systematic review and meta‐analysis suggest that UV phototherapy is a safe treatment for vitiligo with no significant risk of skin cancer.
This systematic review and meta‐analysis demonstrates that patients with vitiligo do not have a significantly increased risk of skin cancer after ultraviolet phototherapy compared with those not receiving phototherapy.
Summary
Although primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur ...following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well‐known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2‐octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2‐OA–BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2‐OA–BSA in the presence or absence of α‐galactosylceramide (α‐GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock‐out mice immunized with 2‐OA–BSA/PBS or 2‐OA–BSA/α‐GalCer develop anti‐mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α‐GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways.
Chimeric antigen receptor-T cell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an ...approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-T expansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non-human leukocyte antigen-restricted approach to enhanced CAR-T functionality to be applied to existing CAR-T designs.
Summary Objective To study the effect of intra-articular injection of meloxicam (Mobic) on the development of osteoarthritis (OA) in rats and examine concomitant changes in nociceptive behavior and ...the expression of mitogen-activated protein kinases (MAPKs) in articular cartilage chondrocytes. Methods OA was induced in Wistar rats by right anterior cruciate ligament transection (ACLT); the left knee was not treated. The OA + meloxicam (1.0 mg) group was injected intra-articularly in the ACLT knee with 1.0 mg of meloxicam once a week for 5 consecutive weeks starting 5 weeks after ACLT. The OA + meloxicam (0.25 mg) group was treated similarly with 0.25 mg meloxicam. The sham group underwent arthrotomy only and received vehicle of 0.1 mL sterile 0.9% saline injections, whereas the naive rats in meloxicam-only groups were treated similarly with 1.0- and 0.25-mg meloxicam. Nociception was measured as secondary mechanical allodynia and hind paw weight-bearing distribution at before (pre-) and 5, 10, 15, and 20 weeks post-ACLT. Histopathology of the cartilage and synovia was examined 20 weeks after ACLT. Immunohistochemical analysis was performed to examine the effect of meloxicam on MAPKs (p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)) expression in the articular cartilage chondrocytes. Results OA rats receiving intra-articular meloxicam treatment showed significantly less cartilage degeneration and synovitis than saline-treated controls. Nociception were improved in the OA + meloxicam groups compared with the OA group. Moreover, meloxicam attenuated p38 and JNK but enhanced ERK expression in OA-affected cartilage. Conclusions Intra-articular injection of meloxicam (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cellular p38 and JNK, but enhances ERK expression.
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