Biomechanical Analyses of Porous Designs of 3D-Printed Titanium Implant for Mandibular Segmental Osteotomy Defects

Clinically, a reconstruction plate can be used for the facial repair of patients with mandibular segmental defects, but it cannot restore their chewing function. The main purpose of this research is to design a new three-dimensionally (3D) printed porous titanium mandibular implant with both facial restoration and oral chewing function reconstruction. Its biomechanical properties were examined using both finite element analysis (FEA) and in vitro experiments. Cone beam computed tomography images of the mandible of a patient with oral cancer were selected as a reference to create 3D computational models of the bone and of the 3D-printed porous implant. The pores of the porous implant were circles or hexagons of 1 or 2 mm in size. A nonporous implant was fabricated as a control model. For the FEA, two chewing modes, namely right unilateral molar clench and right group function, were set as loading conditions. Regarding the boundary condition, the displacement of both condyles was fixed in all directions. For the in vitro experiments, an occlusal force (100 N) was applied to the abutment of the 3D-printed mandibular implants with and without porous designs as the loading condition. The porous mandibular implants withstood higher stress and strain than the nonporous mandibular implant, but all stress values were lower than the yield strength of Ti-6Al-4V (800 MPa). The strain value of the bone surrounding the mandibular implant was affected not only by the shape and size of the pores but also by the chewing mode. According to Frost’s mechanostat theory of bone, higher bone strain under the porous implants might help maintain or improve bone quality and bone strength. The findings of this study serve as a biomechanical reference for the design of 3D-printed titanium mandibular implants and require confirmation through clinical investigations.

Revisiting the Non-Coding Nature of Pospiviroids

Viroids are small, circular, highly structured pathogens that infect a broad range of plants, causing economic losses. Since their discovery in the 1970s, they have been considered as non-coding pathogens. In the last few years, the discovery of other RNA entities, similar in terms of size and structure, that were shown to be translated (e.g., cirRNAs, precursors of miRNA, RNA satellites) as well as studies showing that some viroids are located in ribosomes, have reignited the idea that viroids may be translated. In this study, we used advanced bioinformatic analysis, in vitro experiments and LC-MS/MS to search for small viroid peptides of the PSTVd. Our results suggest that in our experimental conditions, even though the circular form of PSTVd is found in ribosomes, no produced peptides were identified. This indicates that the presence of PSTVd in ribosomes is most probably not related to peptide production but rather to another unknown function that requires further study.

Hydrogel composite scaffolds achieve recruitment and chondrogenesis in cartilage tissue engineering applications

Background The regeneration and repair of articular cartilage remains a major challenge for clinicians and scientists due to the poor intrinsic healing of this tissue. Since cartilage injuries are often clinically irregular, tissue-engineered scaffolds that can be easily molded to fill cartilage defects of any shape that fit tightly into the host cartilage are needed. Method In this study, bone marrow mesenchymal stem cell (BMSC) affinity peptide sequence PFSSTKT (PFS)-modified chondrocyte extracellular matrix (ECM) particles combined with GelMA hydrogel were constructed. Results In vitro experiments showed that the pore size and porosity of the solid-supported composite scaffolds were appropriate and that the scaffolds provided a three-dimensional microenvironment supporting cell adhesion, proliferation and chondrogenic differentiation. In vitro experiments also showed that GelMA/ECM-PFS could regulate the migration of rabbit BMSCs. Two weeks after implantation in vivo, the GelMA/ECM-PFS functional scaffold system promoted the recruitment of endogenous mesenchymal stem cells from the defect site. GelMA/ECM-PFS achieved successful hyaline cartilage repair in rabbits in vivo, while the control treatment mostly resulted in fibrous tissue repair. Conclusion This combination of endogenous cell recruitment and chondrogenesis is an ideal strategy for repairing irregular cartilage defects. Graphical Abstract

High Expression of JMJD4 Is a Potential Diagnostic and Prognostic Marker of Renal Cell Carcinoma

Histone demethylase JMJD4 is a burgeoning tumor marker, which has been proven to be associated with colon cancer, but the role it plays in kidney cancer has not yet been investigated. In the present study, we evaluated whether JMJD4 can be a prognostic marker of patients with clear cell renal cell carcinoma (ccRCC) using data from public platform and in vitro experiments. Our results revealed that the expression of JMJD4 is higher in cancerous tissue than in normal tissues ( p < 0.001 ). High expression of JMJD4 is associated with a poor overall survival (OS) of ccRCC as compared with low expression of JMJD4 ( p = 0.015 ). JMJD4 showed significant relevance with M stage ( p = 0.016 ), gender ( p = 0.003 ), OS (0.018), disease-specific survival (DSS) (0.007), and percussion free interval (PFI) (0.041). Univariate and multivariate Cox analyses demonstrated that high JMJD4 expression had independent predictive value for OS in ccRCC patients ( hazard ratio HR = 1.563 , 95 % confidence interval CI = 1.055 ‐ 2.316 , and p = 0.026 ). Besides, in vitro experiments confirmed that high expression of JMJD4 can significantly promote the invasion ability ( p < 0.001 ), cloning ability ( p < 0.001 ), and proliferation ( p < 0.001 ) of renal cell carcinoma. In summary, high JMJD4 expression may be a prognostic marker in patients with kidney cancer.

Pharmacology and similia principle: indirect secondary counter-regulation. Confirmation from in vitro experiments and classical provings

Homeopathy is universally known as an opponent of allopathic Medicine, namely scientific medicine based on ponderal drugs and recognised mechanisms of receptor agonism and antagonism following the dose-response curve. Over time the difficulty to explain with arguments the action of homeopathic ultra-diluted remedies has led many homeopaths to distance themselves from any pharmacological knowledges. Nevertheless this position fortgets not only the modalities in which homeopathy was born and has grown, but a lot of modern changes of view in body-mind communication, cell communication, neuro-immune-endocrinology and bioelectromagnetism, that could give new reasons to treat as clinical homeopathic practice is teaching and to recognize the principle of similars as a modern pharmacological principle. These arguments, receptorial cell communication, bioelectromagnetism and body-mind unity are the bases of Homeopathy and of the Similia Principle and are all included in embryonic but sufficiently clear considerations in the fundamental book of Hahnemann, the Organon (parr. 11, 13, 15-18, 21, 22, 29-32, 63-70). Two kind of evidences confirm the pharmacological bases of SimiliaPriniciple, in vitro experiments and homeopathic pathogenetic trials on healthy volunteers, best known as provings. Even clinical homeopathic phenomena like initial aggravation and return of old symptoms confirm this pharmacological view of the Simila Principle.

GPER Activation Attenuates Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome Sex-Dependently and Inhibits Alveolar Macrophage Activation

Background: Acute respiratory distress syndrome (ARDS), a common and critical disease, is clinically characterized by uncontrolled inflammation and alveolar-capillary barrier disruption. Estrogen can reportedly alleviate ARDS caused by numerous insults in mice. Moreover, the estradiol receptors α, not β,participated in E2-induced attenuation of ARDS. But the role of another estradiol receptor, G protein-coupled estradiol receptor 1 (GPER1) in ARDS are not undertood. This study is aimed to investigate the effect of GPER activation on LPS-induced ARDS in mice.Methods: Female mice were randomly subjected to bilateral ovarectomy (OVX) or sham surgery two weeks before lung injury. The GPER-selective agonist G1 or vehicle were intraperitoneally injected 0.5 h before intratracheal administration of LPS or phosphate-buffered saline in male and female mice. After 24 h, mice were sacrificed to collect blood, bronchoalveolar lavage fluid (BALF), and lung tissue. Histological injury and inflammatory cell infiltration in lung tissue, as well as cytokine and protein concentrations in BALF were determined. In vitro experiments were also performed on alveolar macrophages (MH-S cells) to investigate the effect of GPER activation on LPS-induced inflammatory responses.Results: Activation of GPER by G1 administration significantly ameliorated lung pathological damage, attenuated alveolar capillary barrier destruction, inhibited recruitment of inflammatory cells into alveoli, and decreased concentrations of the pro-inflammatory factors tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in BALF of LPS-administered male and OVX female mice, but not intact female mice. In vitro experiments demonstrated that G1 pretreatment significantly inhibited LPS-mediated increases of TNF-α, IL-6, and MIP2 in a dose-dependent manner.Conclusions: These results demonstrated that GPER activation attenuated lung injury of male and OVX female mice by inhibiting the inflammatory response of alveolar macrophages.

In-vitro and In-vivo Feasibility Study for a Mobile VV-ECMO and ECCO2R System

Extracorporeal membrane oxygenation (ECMO) is an established rescue therapy for patients with chronic respiratory failure waiting for lung transplantation (LTx). The therapy inherent immobilization may result in fatigue, consecutive deteriorated prognosis and even lost eligibility for transplantation. We conducted a feasibility study on a novel system designed for the deployment of a mobile ECMO device, enabling physical exercise of awake patients prior to LTx. The system comprises a novel mobile oxygenator with a directly connected blood pump, a double lumen cannula, gas blender and supply, as well as control, and energy management. In-vitro experiments included tests regarding performance, efficiency, and blood damage. A reduced system was tested in vivo for feasibility using a novel large animal model. Six anesthetized pigs were first positioned in supine position, followed by a 45&deg; angle, simulating an upright position of the patients. We monitored performance and vital parameters. All in-vitro experiments showed good performance for the respective subsystems and the integrated system. The acute invivo trials of 8h duration confirmed the results. The novel mobile ECMO-system enables adequate oxygenation and decarboxylation sufficient for, e.g., physical exercise of designated LTx-recipients. These results are promising and suggest further preclinical studies on safety and efficacy to facilitate translation into clinical application.

A Luminescent, Water-Soluble Ir(III) Complex as a Potential Photosensitizer for Two-Photon Photodynamic Therapy

This work reports the study of two-photon induced properties of a highly luminescent cyclometalated Ir(III) complex, [Ir(ppy)2(en)] OOCCH3 (1), ppy = 2-phenylpyridine, en = ethylenediamine. Steady-state and time-resolved fluorescence measurements were performed by exciting 1 at the biologically relevant wavelength of 800 nm, whereas, the generation of singlet oxygen (1O2) was evaluated using 9,10-Anthracenediyl-bis(methylene)dimalonic acid (ABDA) as a detection probe. Preliminary in vitro experiments with U87-MG cells were performed, showing the potential of this compound as a two-photon photodynamic therapy (2P-PDT) agent at NIR wavelengths.

A Promising Cutaneous Leishmaniasis Treatment with a Nanoemulsion-Based Cream with a Generic Pentavalent Antimony (Ulamina) as the Active Ingredient

Leishmania parasites are the etiological agents of Leishmaniasis, a tropical disease that affects around 15 million people in about 90 countries. The chosen therapy for this disease is based on antimony V compounds, such as meglumine antimoniate. It can be administered as a parenteral, subcutaneous or perilesional form as successive infiltrations with pre-established doses localized in the border of the granuloma that characterizes the wound of Cutaneous Leishmaniasis (CL). Herein, a topical pharmaceutical recipe, such as an emulsion, is proposed to eliminate the trauma caused by administering the medicine in parenteral form to the face or other difficult access zones. The evaluation of this vehicle was performed by analyzing parameters such as pH, viscosity, homogeneity and droplet size distribution. Furthermore, the effectiveness of the emulsion was proved by in vitro experiments using Strat-M synthetic membranes, showing that the transdermal passage of the antimonial complex is guaranteed. Moreover, complete healing of the wound has been attained in patients with CL, as shown with two clinical cases in this article.

STAT3 inhibitor mitigates cerebral amyloid angiopathy and parenchymal amyloid plaques while improving cognitive functions and brain networks

Previous reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-β (Aβ) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer’s disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aβ peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. Further, 6 months old 5XFAD/APOE4 (5XE4) mice and age-matched negative littermates were used for in vivo experiments. These mice were treated with STAT3 specific inhibitor, LLL-12 for 2 months followed by neurobehavioral and histopathological assessment. In vitro experiments showed exposure of cerebrovascular cells to Aβ peptides upregulated activated forms of STAT3 and produced STAT3-mediated vascular oxidative stress. 5XE4 mice treated with the STAT3-specific inhibitor (LLL-12) improved cognitive functions and functional connectivity and augmented cerebral blood flow. These functional improvements were associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA.