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A method of metal matrix composites processing consists of injecting a liquid metal through a fibrous preform. The metal flow through the porous preform is associated with phase-change phenomena which imply modifications of the porous medium permeability and disturb the metal flow. A finite-volume model was developed to simulate the injection of a pure metal through a fibrous preform placed between two plane walls of a metal mold. This model is based on the simultaneous resolutions of the heat equation, Darcy's law, and an advection equation to follow the evolution of the metal front geometry during the infiltration. [ABSTRACT FROM AUTHOR]

Artemisinin, a natural product isolated from Artemisia annua, contains an endoperoxide group that can be activated by intracellular iron to generate toxic radical species. Cancer cells over-express transferrin receptors (TfR) for iron uptake while most normal cells express nearly undetectable levels of TfR. We prepared a series of artemisinin-tagged transferrins (ART-Tf) where different numbers of artemisinin units are attached to the N-glycoside chains of transferrin (Tf). The Tf bearing approximately 16 artemisinins retains the functionality of both Tf and artemisinin. Reduction of TfRs by TfR siRNA transfection significantly impaired the ability of ART-Tf, but not dihydroartemisinin, to kill cells. We also demonstrate that the ART-Tf conjugate kills the prostate carcinoma cell line DU 145 by the mitochondrial pathway of apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: McClean, ZJ, Pasanen, K, Lun, V, Charest, J, Herzog, W, Werthner, P, Black, A, Vleuten, RV, Lacoste, E, and Jordan, MJ. A biopsychosocial model for understanding training load, fatigue, and musculoskeletal sport injury in university athletes: A scoping review. J Strength Cond Res 38(6): 1177-1188, 2024-The impact of musculoskeletal (MSK) injury on athlete health and performance has been studied extensively in youth sport and elite sport. Current research examining the relationship between training load, injury, and fatigue in university athletes is sparse. Furthermore, a range of contextual factors that influence the training load-fatigue-injury relationship exist, necessitating an integrative biopsychosocial model to address primary and secondary injury prevention research. The objectives of this review were (a) to review the scientific literature examining the relationship between training load, fatigue, and MSK injury in university athletes and (b) to use this review in conjunction with a transdisciplinary research team to identify biopsychosocial factors that influence MSK injury and develop an updated, holistic biopsychosocial model to inform injury prevention research and practice in university sport. Ten articles were identified for inclusion in this review. Key findings were an absence of injury surveillance methodology and contextual factors that can influence the training load-fatigue-MSK injury relationship. We highlight the inclusion of academic load, social load, and mental health load as key variables contributing to a multifactorial, gendered environmental, scientific inquiry on sport injury and reinjury in university sport. An integrative biopsychosocial model for MSK injury in university sport is presented that can be used to study the biological, psychological, and social factors that modulate injury and reinjury risk in university athletes. Finally, we provide an example of how causal inference can be used to maximize the utility of longitudinally collected observational data that is characteristic of sport performance research in university sport., (Copyright © 2024 National Strength and Conditioning Association.)

Besides neuronal cells, botulinum neurotoxins (BoNTs) can also affect other cell types such as fibroblasts or keratinocytes. These cells play a key role in skin conditions. Maintaining a high-quality sebum secretion is essential to avoid premature aging. This study explored the effect of abobotulinumtoxinA (aboBoNT-A) in the rhino mouse. Briefly, anaesthetized animals were injected via the intra-dermal route (ID; four sites of injection) by either vehicle or 0.1, 0.3 and 1 Unit aboBoNT-A per mouse. A reference group was administered with adapalene gel 0.1% (daily local application) for 15 days. Adapalene is a third-generation retinoid and is used as first-line treatment of moderate acne. The body weight and the thickness of the dorsal skin were measured on days 1, 5, 10 and 15; erythema and scaling were recorded at the same time. On day 15, animals were ethically euthanized and skin samples were collected for histology, ELISA and lipidomic assays. AboBoNT-A administered ID at the doses 0.1 U and 0.3 U per mouse was well tolerated. 1 U aboBoNT-A (per mouse) induced a transient loss of muscle tone associated with a slight body weight loss after which mice recovered a good health status. AboBoNT-A did not show any significant effect on utricles surface area but induced a significant anti-inflammatory effect on dermis at the two highest doses. Moreover, aboBoNT-A showed neither side effects commonly observed with local retinoids, nor hyperplasia or dermis inflammation. No change in skin Interleukin-1alpha (IL-1α) cytokine levels was evidenced with aboBoNT-A, whereas a dose-dependent increase of substance P (SP) concentration in the skin was recorded, suggesting that aboBoNT-A induces neuropeptide accumulation in tissue by inhibiting exocytosis mechanisms. Lipidomic analysis showed that aboBoNT-A significantly increased the sebum concentration of several lipid species, presenting skin protecting properties. Overall, these data suggest that ID aboBoNT-A has skin rejuvenation, anti-inflammatory and moisture-boosting properties., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jacquie Maignel reports financial support was provided by Ipsen PharmaIpsen Pharma SAS. Jacquie Maignel reports a relationship with Ipsen Pharma SAS that includes: employment. Jacquie Maignel has patent issued to Ipsen., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody-drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker., Experimental Design: The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro . The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationships were established. SAR408701 toxicity was evaluated in cynomolgus monkey., Results: SAR408701 bound selectively to human and cynomolgus monkey CEACAM5 with similar apparent Kd values (0.017 nmol/L and 0.024 nmol/L, respectively). Both in vitro and in vivo evaluations showed that SAR408701 has cytotoxic activity, leading to in vivo efficacy in single and repeated dosing. Single doses of SAR408701 induced significant increases in the tumor expression of phosphorylated histone H3, confirming the tubulin-targeting mechanism of action. The overall toxicity profile of SAR408701 in cynomolgus monkey was similar to that observed after intravenous administration of DM4 alone., Conclusions: On the basis of these preclinical data, the ADC SAR408701 is a promising candidate for development as a potential treatment for patients with CEACAM5-positive tumors., (©2020 American Association for Cancer Research.)

Dendrimers are nanosized, arborescent macromolecules synthesized in a stepwise fashion with attractive degrees of functionality and structure definition. This is one of the reasons why they are widely used for biomedical applications. Previously, we have shown that a poly(phosphorhydrazone) (PPH) dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of acute and chronic inflammatory disorders in animal models. In these models, the active pharmaceutical ingredient was administered systematically (intravenous and oral administrations), but also loco-regionally in the vitreous tissue. Herein, we assessed the therapeutic efficacy of the ABP dendrimer in the preclinical mouse model of psoriasis induced by imiquimod. The ABP dendrimer was administered in phosphate-buffered saline solution via either systemic injection or topical application. We show that the topical application enabled the control of both the clinical and histopathological scores, and the control of the infiltration of macrophages in the skin of treated mice.

Transferrin (Tf) conjugates of monomeric artemisinin (ART) and artemisinin dimer were synthesized. The two conjugates, ART-Tf and dimer-Tf, retained the original protein structure, and formed stable aggregates in aqueous buffer. ART-Tf induced declines in proteins involved in apoptosis (survivin), cell cycling (cyclin D1), oncogenesis (c-myelocytomatosis oncogene product (c-MYC)), and dysregulated WNT signaling (beta-catenin) in both the human prostate (DU145) and breast (MCF7) cancer cell lines. Both ART-Tf and dimer-Tf induced down-regulation of survivin, c-MYC and mutated human epidermal growth factor receptor-2 (ERBB2 or HER2) in the BT474 breast cancer cell line. To our knowledge, this is the first demonstration that an ART derivative can cause a decline of ERBB2 in a human cancer cell line. Potential mechanisms for the observed effects are presented. Both transferrin conjugates strongly inhibited the growth of BT474 cells in the same concentration range that the conjugates caused declines in the levels of ERBB2, survivin, and c-MYC, while showing essentially no toxicity towards MCF10A normal breast cells.

This study quantifies benthic nutrient fluxes and sedimentation rates in the Ahe Atoll lagoon (French Polynesia), in two stations located under pearl oyster frames, and two control stations away from the pearl culture facility. Dissolved inorganic nitrogen fluxes ranged between 2 and 35 μmol N m(-2) h(-1) and Soluble Reactive Phosphorus varied between -3 and 8.2 μmol P m(-2) h(-1). Particulate sedimentation rates beneath the oysters were approximately five times higher than in the control zone and the percentage of small particles (≤63μm) were about the twice. In contrast, sediment composition was similar under and outside the direct influence of oyster frames. In this ecosystem, where primary production is dependent on the available nitrogen, our study revealed that, while highly variable, benthic fluxes could sometimes contribute up to 28% of the nitrogen demand for primary production., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

PI-2301 is an amino acid copolymer acting as an immunomodulator for the treatment of autoimmune diseases. The present study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of PI-2301 in a single ascending dose, first-in-human study involving healthy, male adult volunteers. A total of 56 subjects were given a subcutaneous injection of PI-2301 ranging from 0.035 to 60 mg. The only consistent side effect was transient injection site reactions. We describe, for the first time, a pharmacokinetic assay to monitor amino acid copolymer concentration in human serum. PI-2301 was detected in the serum of subjects in the 10-, 30-, and 60-mg cohorts. Maximum serum concentration was achieved between 10 and 30 minutes postdosing with some compound detected 4 hours after dosing. PI-2301's lasting immunological properties were evident by an ex vivo recall assay showing T-cell proliferation and IL-13 production in subjects dosed with 1, 3, or 10 mg of PI-2301, up to 6 months after dosing. A transient increase in chemokine CXCL9 and CXCL10 plasma levels was seen in subjects dosed with 30 or 60 mg of PI-2301. These results are highly consistent with our preclinical findings and suggest that PI-2301 could facilitate the expansion of a favorable immune posture in patients with autoimmune disorders.

Background: Artemisinin is a compound isolated from the wormwood Artemisia annua L. It reacts with iron and forms cytotoxic free radicals. It is selectively more toxic to cancer than normal cells because cancer cells contain significantly more intracellular free iron. Previously, we found that covalently tagging artemisinin to transferrin enhanced the selectivity and toxicity of artemisinin toward cancer cells in vitro. In the present research, artemisinin-transferrin conjugate was tested in a rat breast cancer model., Materials and Methods: Breast tumors were induced in rats by subcutaneous implantation of rat MTLn3 breast cancer cells. Once tumors were formed, daily intravenous injections of artemisinin-transferrin conjugate were administered., Results: The conjugate significantly retarded the growth rate of breast tumors in the rat. No significant side effect was observed in the rats during treatment., Conclusion: Artemisinin-transferrin conjugate could be developed into a potent therapeutic agent for cancer in humans.