The study of powder metallurgy processing methods for titanium represents a promising avenue that can respond to a growing demand. This work reports the feasibility of direct powder forging (DPF) as ...a method to process large spherical Ti-6Al-4V powder into wrought products with noteworthy properties and physical characteristics. Direct powder forging is a thermomechanical process that imparts uniaxial loading to an enclosed and uncompacted powder to produce parts of various sizes and shapes. Stainless steel canisters were filled with prealloyed Ti-6Al-4V powder and consolidated through a multi-step open-die forging and rolling process into wrought DPF bars. After DPF, annealing was performed in the upper α+β phase. The results show that full consolidation was achieved and higher mechanical properties than the Ti-6Al-4V grade F-23 requirements in annealed conditions were obtained. The results also show that direct powder forging of spherical titanium powder could produce wrought mill products and exhibit some potential for further investigation for industrial applications.
•Chemically homogenous, fully dense and highly spherical Ti-5Fe powder prepared by EIGA.•Similar PSD and oxygen pick-up as the conventional Ti-6Al-4 V.•The Omega phase is present with a minor alpha ...phase resulting from the high cooling rate.
This study demonstrated the viability of the electrode induction gas atomization process (EIGA) to produce spherical Ti-5Fe powder suitable for additive manufacturing. The resulting powder is spherical and presents no surface defects. Additionally, the iron distribution throughout the microstructure is homogenous and indicates similar particle size distribution and oxygen pick-up as the conventional Ti-6Al-4V titanium alloy, thus demonstrating that the Ti-5Fe can achieve equal atomization behavior and powder outcome. The results of the study show how EIGA-type gas atomization can be an efficient scale-up route to produce Ti-5Fe low-cost titanium alloy powder for additive manufacturing, which offers a broader perspective into biomaterial application.
This study investigates direct powder forging (DPF) as a new approach for near-net-shape processing of titanium alloys using a coarse particle size distribution (PSD) between 90 and 250 μm. This ...route was utilised to takes advantage of DPF’s enclosed nature to make near-net-shape components with conventional forging equipment, making it attractive and viable even for reactive powder such as titanium. In this study, the uncompacted Ti-6Al-4V ELI powder was sealed under vacuum in a stainless-steel canister and hot forged in air to produce a fully dense titanium femoral stem. After the final forging stage, the excess material in the flash region was cut, which efficiently released the canister, revealing the forged part with minimal surface contamination. The as-forged microstructure comprises coarse β grains with a martensitic structure. The subsequent annealing was able to generate a fine and homogenous lamellar microstructure with mechanical properties that respects the surgical implant standard, showing that DPF offers significant potential for forged titanium parts. Therefore, the DPF process provides a suitable alternative to produce titanium components using basic equipment, making it more available to the industry.
This study investigates direct powder forging (DPF) as a new approach for the consolidation and in-situ alloying of the titanium alloy Ti-5Fe from loose powder. The absence of green compaction before ...thermomechanical processing and the effect of the powder blending method have been found to significantly influence the chemical and microstructure homogeneity. Two different powder mixing techniques were compared, ball milling (BM) and blended elemental (BE). After the initial heating stage, the BM sample has a uniform α+β lamella microstructure within the particles with a homogeneous iron distribution, unlike the BE sample, which shows a heterogeneous lamella microstructure, retained β-Ti (Fe-rich) and TiFe intermetallic compounds. Even if the BM samples exhibit a slightly higher density over the BE samples after the initial heating stage, all samples achieved full density and had a α+β lamella microstructure after the thermomechanical steps. However, for the BE sample, even if the DPF process was able to eliminate the intermetallic compounds, the thermomechanical process did not homogenize the iron, resulting in a heterogeneous and coarser microstructure. Based on the results, it can be concluded that DPF using a BM technique led to a fully homogenous and fully consolidated Ti-5Fe alloy. Therefore, direct powder forging has significant potential as an alternative fabrication strategy to produce the Ti-5Fe alloy. Moreover, this work can expand the opportunities for the development of the promising Ti-5Fe alloy.
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Pancreatic ductal adenocarcinoma (PDAC) is characterised by an extensive tissue invasion and an early formation of metastasis. Alterations in the expression of cadherins have been reported in PDAC. ...Yet, how these changes contribute to tumour progression is poorly understood. Here, we investigated the relationship between cadherins expression and PDAC development.
Cadherins expression was assessed by immunostaining in both human and murine tissue specimens. We have generated pancreatic cancer cell lines expressing both cadherin-1 and cadherin-3 or only one of these cadherins. Functional implications of such genetic alterations were analysed both in vitro and in vivo.
Cadherin-3 is detected early at the plasma membrane during progression of pancreatic intraepithelial neoplasia 1 (PanIN-1) to PDAC. Despite tumoural cells turn on cadherin-3, a significant amount of cadherin-1 remains expressed at the cell surface during tumourigenesis. We found that cadherin-3 regulates tumour growth, while cadherin-1 drives type I collagen organisation in the tumour. In vitro assays showed that cadherins differentially participate to PDAC aggressiveness. Cadherin-3 regulates cell migration, whereas cadherin-1 takes part in the invadopodia activity.
Our results show differential, but complementary, roles for cadherins during PDAC carcinogenesis and illustrate how their expression conditions the PDAC aggressiveness.
Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and ...regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8
+
T-cells, and natural killer (NK)1.1
+
cells, that express granzyme B associated with Lamp-1 and IFN-γ. Efficacy of iDC-vaccination was CD8
+
T-cell-dependent but NK1.1
+
cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses.
We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC.
Alteration in intestinal permeability is the main factor underlying the pathogenesis of many diseases affecting the gut, such as inflammatory bowel disease IBD. Characterization of molecules ...targeting the restoration of intestinal barrier integrity is therefore vital for the development of alternative therapies. The yeast Saccharomyces boulardii CNCM I-745 Sb, used to prevent and treat antibiotic-associated infectious and functional diarrhea, may have a beneficial effect in the treatment of IBD.
We analyzed the impact of Sb supernatant on tissue integrity and components of adherens junctions using cultured explants of colon from both IBD and healthy patients. To evaluate the pathways by which Sb regulates the expression of E-cadherin at the cell surface, we developed in vitro assays using human colonic cell lines, including cell aggregation, a calcium switch assay, real-time measurement of transepithelial electrical resistance TEER and pulse-chase experiments.
We showed that Sb supernatant treatment of colonic explants protects the epithelial morphology and maintains E-cadherin expression at the cell surface. In vitro experiments revealed that Sb supernatant enhances E-cadherin delivery to the cell surface by re-routing endocytosed E-cadherin back to the plasma membrane. This process, involving Rab11A-dependent recycling endosome, leads to restoration of enterocyte adherens junctions, in addition to the overall restoration and strengthening of intestinal barrier function.
These findings open new possibilities of discovering novel options for prevention and therapy of diseases that affect intestinal permeability.
Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their ...important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell-cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell-cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell-cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers.
Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed ...to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC.
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