Minimization of the buckling load of a clamped plate with perimeter constraint

We look for minimizers of the buckling load problem with perimeter constraint in any dimension. In dimension 2, we show that the minimizing plates are convex; in higher dimension, by passing through a weaker formulation of the problem, we show that any optimal set is open and connected. For higher eigenvalues, we prove that minimizers exist among convex sets with prescribed perimeter

Effects of balloon injury on neointimal hyperplasia in steptozotocin-induced diabetes and in hyperinsulinemic nondiabetic pancreatic islet-transplanted rats.

BACKGROUND: The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown. METHODS AND RESULTS: Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-ras-negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed. CONCLUSIONS: In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals

Preliminary Analysis of the Effects of Ad26.COV2.S Vaccination on CT Findings and High Intensive Care Admission Rates of COVID-19 Patients

On 27 February 2021, the Food and Drug Administration(FDA) authorized the administration of the adenovirus-based Ad26.COV2-S vaccine (J&J-Janssen) for the prevention of COVID-19, a viral pandemic that, to date, has killed more than 5.5 million people. Performed during the early phase of the COVID-19 4th wave, this retrospective observational study aims to report the computerized tomography (CT) findings and intensive care unit admission rates of Ad26.COV2-S-vaccinated vs. unvaccinated COVID-19 patients. From the 1st to the 23rd of December 2021, all confirmed COVID-19 patients that had been subjected to chest non-contrast CT scan analysis were enrolled in the study. These were divided into Ad26.COV2.S-vaccinated (group 1) and unvaccinated patients (group 2). The RSNA severity score was calculated for each patient and correlated to CT findings and type of admission to a healthcare setting after CT-i.e., home care, ordinary hospitalization, sub-intensive care, and intensive care. Descriptive and inference statistical analyses were performed by comparing the data from the two groups. Data from a total of 71 patients were collected: 10 patients in group 1 (4M, 6F, mean age 63.5 years, SD ± 4.2) and 61 patients in group 2 (32M, 29F, mean age 64.7 years, SD ± 3.7). Statistical analysis showed lower values of RSNA severity in group 1 compared to group 2 (mean value 14.1 vs. 15.7, p = 0.009, respectively). Furthermore, vaccinated patients were less frequently admitted to both sub-intensive and high-intensive care units than group 2, with an odds ratio of 0.45 [95%CI (0.01; 3.92)]. Ad26.COV2.S vaccination protects from severe COVID-19 based on CT severity scores. As a result, Ad26.COV2.S-vaccinated COVID-19 patients are more frequently admitted to home in comparison with unvaccinated patients

Understanding the Biological Significance of Anti-DFS70 Antibodies: Effect of Biologic Therapies on Their Occurrence in Inflammatory Arthritis

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Molecular Phylogeny of the Myxobolus and Henneguya Genera with Several New South American Species

The present study consists of a detailed phylogenetic analysis of myxosporeans of the Myxobolus and Henneguya genera, including sequences from 12 Myxobolus/Henneguya species, parasites of South American pimelodids, bryconids and characids. Maximum likelihood and maximum parsimony analyses, based on 18 S rDNA gene sequences, showed that the strongest evolutionary signal is the phylogenetic affinity of the fish hosts, with clustering mainly occurring according to the order and/or family of the host. of the 12 South American species studied here, six are newly described infecting fish from the Brazilian Pantanal wetland. Henneguya maculosus n. sp. and Myxobolus flavus n. sp. were found infecting both Pseudoplatystoma corruscans and Pseudoplatystoma reticulatum; Myxobolus aureus n. sp. and Myxobolus pantanalis n. sp. were observed parasitizing Salminus brasiliensis and Myxobolus umidus n. sp. and Myxobolus piraputangae n. sp. were detected infecting Brycon hilarii.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Centro Nacional de Pesquisa e Conservacao de Peixes Continentais of the Instituto Chico Mendes de Conservacao da BiodiversidadeConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Fac Zootecnia & Engn Alimentos, Dept Vet Med, Pirassununga, SP, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, Diadema, SP, BrazilUniv Estadual Campinas, Inst Biol, Dept Biol Anim, Campinas, SP, BrazilInst Chico Mendes Conservacao Biodiversidade, Ctr Nacl Pesquisa & Conservacao Peixes Continenta, Pirassununga, SP, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, Diadema, SP, BrazilFAPESP: 06/59075-6FAPESP: 2009/03320-0CNPq: 477658/2010-5Web of Scienc

Phylogeny, ultrastructure, histopathology and prevalence of Myxobolus oliveirai sp. nov., a parasite of Brycon hilarii (Characidae) in the Pantanal wetland, Brazil

This paper presents the morphological, histological and ultrastructural characteristics of Myxobolus oliveirai sp. nov., a parasite of the gill filaments in Brycon hilarii from the Brazilian Pantanal. Out of 216 B. hilariispecimens examined (126 wild and 90 cultivated), 38.1% of wild specimens (n = 48) were infected. The parasites form elongated plasmodia primarily in the tip of gill filaments, reaching about 3 mm in length. A thorough comparison with all the Myxobolus species described from South American hosts, as well as nearly all the Myxobolus species described so far is provided. Partial sequencing of the 18S rDNA gene revealed a total of 1,527 bp. The Myxobolus species parasite of B. hilarii did not match any of the Myxozoa available in GenBank. In the phylogenetic analysis, M. oliveirai sp. nov. composed a monophyletic group with eight other species: five species of Myxobolus parasites of mugilid fishes, two parasites of pangasiid and one of centrarchid. Infection prevalence values of the parasite revealed no significant differences between wet and dry seasons or between males and females. The importance of the infection to the farming of the host species is emphasized1056762769sem informaçã

AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment

Background: Aurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment. Methods: A human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology. Total protein extracts were examined for p53 and c-Myc protein expression by Western blot analysis. Drug anti-tumor effects were further assessed using a 3D-human melanoma skin reconstruction model, in which tissues were incubated with serum-free medium containing control, B-RAF plus MEK inhibitor, MEK plus AurkA inhibitor or the triple combination. Results: AurkA inhibitor plus B-RAF inhibitor, AurkA inhibitor plus MEK inhibitor or triple combination had a markedly greater anti-proliferative effect on A375 (BRAFV600E) melanoma cells than single agents. In the 3D human skin model, the triple combination had a greater anti-tumor effect at the epidermal/dermal junction than control or either double combination. However, S-100 and Ki-67 positively stained spindle-shaped cells were detected in the dermal stratum, suggesting the presence of alive and proliferating melanoma cells. Conclusions: These findings provide new prospects for melanoma research, including combined B-RAF/AurkA inhibition for B-RAF mutated melanomas and MEK/AurkA inhibitor combination for patients without B-RAF mutations. Moreover, for the first time, we have shown that a B-RAF, MEK and AurkA inhibitor triple drug combination offers increased efficacy against melanoma cell growth and might be considered as a potential treatment strategy for enhancing clinical response in melanoma. However, although this triple drug combination was more effective at the epidermal/dermal junction, the suggested presence of alive and proliferating melanoma cells in the dermal stratum could result in drug resistance and disease recurrence. Molecular characterization of these dermal cells may be critical for the development of novel therapeutic strategies

Structure-based design of an urokinase-type plasminogen activator receptor–derived peptide inhibiting cell migration and lung metastasis

The urokinase-type plasminogen activator receptor (uPAR) plays a central role in sustaining the malignant phenotype and promoting tumor metastasis. The Ser88-Arg-Ser-Arg-Tyr92 is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as its ligand uPA. Here, we describe the generation of new peptide inhibitors of cell migration and invasion derived from SRSRY by a drug design approach. Ac-Arg-Glu-Arg-Phe-NH2 (i.e., RERF), which adopts a turned structure in solution, was selected for its ability to potently prevent SRSRY-directed cell migration. Fluorescein-RERF associates with very high affinity to RBL-2H3 rat basophilic leukemia cells expressing the human formyl peptide receptor (FPR). Accordingly, femtomolar concentrations of RERF prevent agonist-dependent internalization of FPR and inhibit N-formyl-Met-Leu-Phe–dependent migration in a dose-dependent manner. In the absence of FPR, fluorescein-RERF binds to cell surface at picomolar concentrations in an αv integrin–dependent manner. The involvement of vitronectin receptor is further supported by the findings that 100 pmol/L RERF selectively inhibits vitronectin-dependent RBL-2H3 cell migration and prevents SRSRY-triggered uPAR/αv association. Furthermore, RERF reduces the speed of wound closure and the extent of Matrigel invasion by human fibrosarcoma HT1080 cells without affecting cell proliferation. Finally, a 3- to 5-fold reduction of lung metastasis number and size in nude mice following i.v. injection of green fluorescent protein–expressing HT1080 cells in the presence of 3.32 mg/kg RERF is observed. Our findings indicate that RERF effectively prevents malignant cell invasion in vivo with no signs of toxicity and may represent a promising prototype drug for anticancer therapy

Four-year real-world experience of secukinumab in a large Italian cohort of axial spondyloarthritis

Objectives: This study aims to evaluate in a real-life Italian multicenter cohort of axial spondyloarthritis (axSpA) (1) the 4-year effectiveness and safety of secukinumab, (2) the drug retention rate (DRR), and (3) the impact of the line of bDMARDs treatment, subtype of axSpA, and sex on achieving low disease activity (LDA) and very low disease activity (VLDA). Methods: Consecutive axSpA patients receiving secukinumab between 2016 and 2023 were prospectively evaluated. Data on disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were collected. Treatment response was evaluated at 6 and 12 months after initiation and yearly up to 48 months (T48). DRR and effectiveness outcomes were evaluated according to bDMARDs treatment, axSpA subtype, and sex. Infections and adverse events (AEs) were recorded. Results: We enrolled 272 patients (48.2% male; median age, 51; 39.7% HLA-B27+; 40.4% nr-axSpA), of whom 30.9% were naïve to secukinumab. Overall, secukinumab yielded improvement in effectiveness outcomes; the naïve patients maintained lower disease activity vs. the non-naïve ones. At T48, the LDA and VLDA rates were higher in naïve patients and in male individuals. Treatment was discontinued in 104 patients due to primary/secondary loss of effectiveness and in 34 patients due to AEs. The DRR at T48 was 67.4% in the whole population, regardless of treatment line, axSpA subtype, and sex. Conclusions: Secukinumab was safe and effective in all axSpA patients irrespective of treatment line, disease subtype, and sex. The patients achieved sustained 4-year remission and DRR