A comparison of stress, contact pressure, and contact area on menisci in re-injury mechanisms after reconstruction of the anterior cruciate ligament with autograft and synthetic graft: a finite element study.

PURPOSE: The anterior cruciate ligament (ACL) is crucial in maintaining knee stability. Some motion mechanisms, which are common in sports, cause excessive load to be passed on the ACL. In non-contact ACL injuries, the ACL cannot sustain the high stress and becomes injured or ruptures in the valgus-external rotation mechanism (VERM) and varus-internal rotation mechanism (VIRM). The mechanical strength of the grafts used to repair the torn ligament varies. The purpose of this study is to look at the alterations in the menisci after anterior cruciate ligament repair with autografts and synthetic grafts in cases of non-contact re-injury mechanisms. METHODS: In the finite element analysis, VERM and VIRM motions of the injury were simulated with different ACL graft materials. During the simulations of these mechanism motions with polyethylene terephthalate (PET) and patellar tendon (PT), the contact pressures, contact areas, and von mises stress values created in the medial and lateral meniscus were compared. RESULTS: The peak contact pressures on the menisci during the VERM are higher than the peak contact pressures during the VIRM, except for one variation. The peak contact pressure of the medial meniscus is almost the same for both graft materials and mechanisms. Furthermore, the peak contact pressures in the menisci are higher than in the VERM. For all injury mechanisms, the peak contact stresses on the lateral meniscus are higher than on the medial meniscus. CONCLUSIONS: The findings suggest that VERM can induce further knee joint injury. It was found that the PET will lessen the pressure on the menisci even more. It is also advantageous since it does not damage the anterior extremities and transmits less pressure to the menisci. In conclusion, using a high-strength ACL is healthier for the menisci. Even though synthetic grafts are not clinically preferred, the study demonstrates that enhancing the material properties of synthetic grafts will increase the chance of their use in the future, based on the current results.

Structural and compositional segregation of the gut microbiota in HCV and liver cirrhotic patients: A clinical pilot study.

Gut microbial dysbiosis during the development of Hepatitis C virus and liver-related diseases is not well studied. Nowadays, HCV and liver cirrhosis are the major concerns that cause gut bacterial alteration, which leads to dysbiosis. For this purpose, the present study was aimed at correlating the gut bacterial community of the control group in comparison to HCV and liver cirrhotic patients. A total of 23 stool samples were collected, including control (9), liver cirrhotic (8), and HCV (6). The collected samples were subjected to 16 S rRNA Illumina gene sequencing. In comparison with control, a significant gut bacterial alteration was observed in the progression of HCV and liver cirrhosis. Overall, Firmicutes were significantly abundant in the whole study. No significant difference was observed in the alpha diversity of the control and patient studies. Additionally, the beta diversity based on non-metric multidimensional scaling (NMDS) has a significant difference (p = 0.005) (ANOSIM R2 = 0.14) in all groups. The discriminative results based on the LEfSe tool revealed that the HCV-infected patients had higher Enterobacteriaceae and Enterobacterial, as well as Lactobacillus and Bacilli in comparison than the liver-cirrhotic patients. These taxa were significantly different from the control group (p < 0.05). Regarding prospects, a detailed analysis of the function through metagenomics and transcriptomics is needed.

Review of potential risk groups for coronavirus disease 2019 (COVID-19).

The current pandemic of coronavirus disease 19 (COVID-19) is a global issue caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Studies have revealed that this virus results in poorer consequences and a higher rate of mortality in older adults and those with comorbidities such as cardiovascular disease, hypertension, diabetes and prolonged respiratory illness. In this review, we discuss in detail the potential groups at risk of COVID-19 and outline future recommendations to mitigate community transmission of COVID-19. The rate of COVID-19 was high in healthcare workers, smokers, older adults, travellers and pregnant women. Furthermore, patients with severe medical complications such as heart disease, hypertension, respiratory illness, diabetes mellitus and cancer are at higher risk of disease severity and mortality. Therefore, special effort and devotion are needed to diminish the threat of SARS-CoV-2 infection. Proper vaccination, use of sanitizers for handwashing and complete lockdown are recommended to mitigate the chain of COVID-19 transmission.

Magnetic carbon nanotube labelling for haematopoietic stem/progenitor cell tracking.

Haematopoietic stem and progenitor cell (HSPC) research has significantly contributed to the understanding and harnessing of haematopoiesis for regenerative medicine. However, the methodology for real-time tracking HSPC in vivo is still lacking, which seriously restricts the progress of research. Recently, magnetic carbon nanotubes (mCNT) have generated great excitement because they have been successfully used as vehicles to deliver a lot of biomolecules into various cells. There is, however, no report about mCNT being used for tracking HSPC. In this paper, we investigated the uptake efficiency of fluorescein-isothiocyanate-labelled mCNT (FITC-mCNT) into HSPC and their effect on the cytotoxicity and differentiation of HSPC. We found that cellular uptake of FITC-mCNT was concentration-and time-dependent. The uptake of FITC-mCNT into HSPC reached up to 100% with the highest mean fluorescence (MF). More importantly, efficient FITC-mCNT uptake has no adverse effect on the cell viability, cytotoxicity and differentiation of HSPC as confirmed by colony-forming unit assay (CFU). In conclusion, the results reported here suggest the further tailoring of mCNT for their use in HSPC labelling/tracking in vivo or gene delivery into HSPC.

Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells.

Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.

Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: Chromatin structure and thereby transcription is controlled by the level of acetylation of histones, which is determined by the balance between histone acetyl transferase (HAT) activity and histone deacetylase (HDAC) activity. HDAC inhibitors are a class of compounds able to regulate gene expression by modulating chromatin structure. There are two major classes of HDAC inhibitors: the hydroxamic acid derivatives such as trichostatin A (TSA) or SAHA, and the butyrates such as phenyl-butyrate. HDAC inhibitors interfere with differentiation, proliferation and apoptosis in tumor cells. Here, we investigated the activity of a new hydroxamic acid derivative, LAQ824, on lymphoblastic cells. DESIGN AND METHODS: Four different pre-B lymphoblastic cell lines: Sup-B15 and TMD-5, both t(9;22) positive, SEM, t(4;11) positive, and NALM-6 cells were exposed to the hydroxamic acid derivatives, LAQ824 and TSA. Histone hyperacetylation, apoptosis, cell cycle and related pathways were assessed by flow cytometry and Western blotting. RESULTS: LAQ824 significantly inhibited the proliferation of leukemic lymphoblastic cell lines. The effect of LAQ824 was due to increased apoptosis accompanied by activation of caspase-3 and caspase-9, cleavage of poly(ADP-ribose)-polymerase (PARP) as well as by down-regulation of Bcl-2 and disruption of the mitochondrial membrane potential. Surprisingly, LAQ824-induced apoptosis was at least partially independent of caspase activation as indicated by the fact that LAQ824-induced apoptosis was inhibited only partially in both t(9;22) positive Sup-B15 and TMD-5 cells, whereas no inhibition was observed in t(4;11) positive SEM cells upon exposure to the polycaspase inhibitor zVAD-fmk. INTERPRETATION AND CONCLUSIONS: Our study establishes that LAQ824 is a promising agent for the therapy of acute lymphoblastic leukemia.

Valproic acid exerts differential effects on CXCR4 expression in leukemic cells.

We recently reported that the histone deacetylase inhibitor, valproic acid (VPA), increases CXCR4 receptor expression and function in cord blood hematopoietic stem/progenitor cells (HSPC) and the immature, highly CD34-positive AML cell lines KG-1a and KG-1. In this study, we investigated whether VPA influences CXCR4 in CD34-negative AML cell lines (promyelocytic HL-60 and monocytic THP-1), as well as both CD34-positive and CD34-negative primary AML cells. We found that VPA (i) diminishes CXCR4 expression and chemotaxis in HL-60 cells and in the CD34-negative subtypes of primary AML cells and (ii) increases CXCR4 expression and function in the highly CD34-positive subtypes of primary AML cells. Hence, we suggest that VPA exerts different effects on CXCR4 depending on cell maturation status, and this novel finding may have important implications for AML therapy.

Valproic acid increases CXCR4 expression in hematopoietic stem/progenitor cells by chromatin remodeling.

A major limitation of cord blood (CB) hematopoietic stem/progenitor cell (HSPC) transplantation in adult patients is the low cell dose available, which is associated with delayed or failed engraftment. This has prompted intensive research to develop novel strategies to improve HSPC engraftment and reconstitution. The chemokine receptor CXCR4 and its ligand stromal cell-derived factor (SDF)-1alpha play a crucial role in the homing and repopulation capacity of HSPCs. We hypothesized that in HSPCs the CXCR4 receptor is regulated through chromatin remodeling by histone deacetylase inhibitors (HDIs) such as valproic acid (VPA). Using CB CD34(+) cells and the models of immature hematopoietic cells expressing CD34 antigen, namely the leukemic cell lines KG-1a and KG-1, we found that VPA increases surface and mRNA CXCR4 levels in these cells, thereby enhancing their migration toward an SDF-1alpha gradient. We also found that modulation of CXCR4 gene transcription by VPA correlates with the acetylation status of histone H4 in CB CD34(+) and KG-1 cells. Hence we suggest that in CB transplantation priming of HSPCs with VPA could improve homing and engraftment.

Gamma-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells.

Acute myeloid leukemia (AML) is characterized by the block of differentiation, deregulated apoptosis, and an increased self-renewal of hematopoietic precursors. It is unclear whether the self-renewal of leukemic blasts results from the cumulative effects of blocked differentiation and impaired apoptosis or whether there are mechanisms directly increasing self-renewal. The AML-associated translocation products (AATPs) promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha), promyelocytic leukemia zinc finger (PLZF)/RAR alpha (X-RAR alpha), and AML-1/ETO block hematopoietic differentiation. The AATPs activate the Wnt signaling by up-regulating gamma-catenin. Activation of the Wnt signaling augments self-renewal of hematopoietic stem cells (HSCs). Therefore, we investigated how AATPs influence self-renewal of HSCs and evaluated the role of gamma-catenin in the determination of the phenotype of HSCs expressing AATPs. Here we show that the AATPs directly activate the gamma-catenin promoter. The crucial role of gamma-catenin in increasing the self-renewal of HSCs upon expression of AATPs is demonstrated by (i) the abrogation of replating efficiency upon hindrance of gamma-catenin expression through RNA interference, and (ii) the augmentation of replating efficiency of HSCs upon overexpression of gamma-catenin itself. In addition, the inoculation of gamma-catenin-transduced HSCs into irradiated recipient mice establishes the clinical picture of AML. These data provide the first evidence that the aberrant activation of Wnt signaling by the AATP decisively contributes to the pathogenesis of AML.