Cell Differentiation Activity Research Articles

Decellularized umbilical cord stroma in tissue engineering and regenerative medicine: a systematic review

Despite great progress in the field of biomaterials for tissue engineering and regenerative medicine, the high requirements placed on artificial matrices (matrices, carriers, scaffolds) are the reason for the ongoing search for natural or synthetic extracellular matrix mimetics. Among such materials, decellularized umbilical cord (UC) stroma appears to be very attractive – it has a high content of hyaluronic acid, cytokines, and growth factors, and there are no ethical restrictions for its production. Decellularized UC stroma has been found to promote cartilage, liver tissue and nerve tissue repair, as well as wound healing. The review critically analyzes and summarizes published data on the ability of decellularized UC stroma to maintain the necessary conditions for adhesion, migration, differentiation and functional activity of adherent cells, thus stimulating the internal (physiological) regenerative potential of tissues. Literature was searched for in the following electronic databases: Medline/PubMed (www/ncbi. nlm.nih.gov/pubmed), Cochrane library (https://www.cochrane.org), and eLIBRARY/Russian Science Citation Index (https://www.elibrary.ru). Inclusion criteria were the presence of biomaterials obtained from decellularized human UC stroma. Exclusion criteria for papers included research objects as decellularized umbilical cord vessels (veins and arteries) and umbilical cord cell cultures. Twenty-five original articles in English and Russian were selected for analysis of the products obtained, their applications, decellularization methods and research results. The review also discusses the prospects for decellularized umbilical cord in medicine.

Vitamin D in Keloids: An alternative to steroids?

Madam, Keloids are wound healing scars with well-demarcated overgrowth of fibrotic tissue, mainly involving excessive collagen proliferation produced by fibroblasts. They extend beyond the original injury site, and are associated with pain and pruritus (1,2). Few treatments available few for Keloids include occlusive dressings, compression therapy and intralesional corticosteroid injections (1). Triamcinolone acetate, a corticosteroid injection, is considered the first line treatment as it possesses anti-inflammatory and anti-mitotic activities, which reduce scar volume and prevent a recurrence. However, approximately 50percent of keloids are considered to be steroid resistant (3, 4). Moreover, as per literature, the usage of intralesional corticosteroid injections can cause several local and systemic adverse effects such as telangiectasias, skin necrosis, skin and subcutaneous fat atrophy, and Cushing’s syndrome (5) In light of the above, researchers are keen on finding other treatment modalities for treating these lesions, and among them Vitamin D, is being investigated. Vitamin D is a steroid hormone that normally plays a role in regulating serum calcium, inhibiting cellular proliferation and promoting cell differentiation and apoptotic activities. Transforming growth factor-beta (TGF-B), an inflammatory marker, has been implicated in the pathogenesis of keloids. TGF-B is believed to be inhibited with localised Vitamin D. Furthermore, Vitamin D deficiency plays a significant role in keloidogenesis, a process mediated by dysregulation of koebnerisin, an antimicrobial polypeptide (2). A study was conducted recently, where 40 adults, aged 18 to 60 years, were administered intralesional Vitamin D, on keloids sized atleast 5 cm, with sessions carried out every week for a maximum of 3-4 sessions. This study showed a highly significant reduction in the Vancouver Scar Scale, a scarring scoring system (1). However, further trials, specially comparative studies, are needed to effectively weigh in the efficacy of Vitamin D over steroids. Advantages of Vitamin D are evident and promising so far – it’s cost-friendly, and shows mild side effects such as burning, pain, swelling and tenderness that shortly disappears on its own.

Absence of Toll-like receptor 5 confers survival in mice bearing ovarian tumors treated with anti-PD-L1

Abstract Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients bearing ovarian tumors infiltrated with high frequencies of T cells associate with a greater survival probability. However, therapies targeting T cells in ovarian cancers are ineffective. We observed in models of late-stage murine ovarian cancer that in absence of Toll-Like Receptor 5 (TLR5) signaling, anti-PD-L1 promotes significant survival and protection against tumor rechallenge. Ovarian tumors from rechallenged TLR5KO mice exhibited significantly higher frequency/number of CD8 T cells expressing functional and activation markers. Thus, in the absence of TLR5 signaling, T cells mount/maintain a stronger response to ovarian tumors after inhibitory receptor blockade. Furthermore, protection against tumor progression in TLR5KO mice corresponds with a significant increase in tumor infiltrating cross presenting and IL-12 producing Dendritic cells (DCs). Additionally, in CD11c Cre x TLR5 fl/fl mice, whose DCs lack TLR5 expression, PD-L1-blockade mediated extended survival in ovarian tumor-bearing mice. Using a mixed bone marrow chimera approach, we demonstrate that direct TLR5 signaling functionally alters DCs to become more suppressive in the tumor microenvironment, impacting T cell differentiation and anti-tumor activity, thereby reducing survival during aPD-L1 therapy. Clinically, roughly 7.5% of the general population harbor a TLR5 SNP that diminishes TLR5 signaling and is associated with increased long-term survival for ovarian cancer patients. Therefore, patients who express the TLR5 SNP may immediately benefit from anti-PDL1 therapy and those without the SNP, TLR5 antagonism. NIH/NCI 1R01CA253285 UVA Farrow Fellowship

Eosinophil-derived TGFβ1 controls the new bone formation in chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by chronic eosinophilic inflammation and new bone formation (NBF). These processes may be associated with each other in the pathogenesis and influence the severity and prognosis of the disease. However, it is still unclear how eosinophilic inflammation is involved in the NBF. Sinus bone cells were isolated from ethmoid bone tissues of patients with CRSwNP and controls. Transforming growth factor beta 1 (TGFβ1) and alkaline phosphatase (ALP) expression in sinus bone cells was determined using quantitative RT-PCR, immunoblotting, and immunohistochemistry. The co-localization of TGFβ1 with eosinophils was assessed by immunofluorescence staining. Sinus bone cells were co-cultured with eosinophils (Eol-1 cell line), which were differentiated with butyrate, to measure the osteoblast differentiation activity of sinus bone cells. TGFβ1 expression was increased in sinus bone tissues and correlated with CT scores in CRSwNP. TGFβ1 was also increased in the submucosa of CRSwNP and co-localized predominantly with eosinophils compared with neutrophils Differentiated Eol-1 cells-derived TGFβ1 increased ALP expression in sinus bone cells. Treatment with a TGFβ inhibitor attenuated TGFβ1-induced ALP expression and staining in sinus bone cells of CRSwNP, leading to loss of bone formation. Eosinophil-derived TGFβ1 was enriched in the submucosa of CRSwNP, which induced ALP expression in sinus bone cells and NBF. Therefore, eosinophil-derived TGFβ1 may mediate aberrant bone remodeling in CRSwNP.

Chromosome-Level Genome Assembly of the Rough-Toothed Dolphin (Steno bredanensis)

The rough-toothed dolphin (Steno bredanensis), the single extant species of the genus Steno, inhabits tropical and subtropical oceans. It is an attractive species for studying aquatic adaptation and evolution. The latest advances in high-throughput sequencing are transforming the study of marine mammals and contributing to understanding various phenomena at the species and population level by determining high-quality genomes. Here, to comprehensively understand the genetic features and explore the molecular basis of aquatic adaption, the chromosome-level genome assembly and comparative genomics analyses of S. bredanensis were performed. The 2.30 Gb final genome assembly of S. bredanensis (scaffold N50 length of 105.53 Mb) was obtained using single-tube long fragment read (stLFR) and Hi-C technologies. The genome assembly clearly revealed the preservation of large chromosomal fragments between S. bredanensis and the melon-headed whale (Peponocephala electra). The S. bredanensis genome contained 19,451 predicted protein-coding genes, of which about 92.33% have functional annotations. The genome assembly and gene sets showed high completeness, with a BUSCO score of 90.6% and 97.3%, respectively. We also identified several positively selected genes specific to S. bredanensis, which may be related to fat cell differentiation, tooth morphogenesis, and immunoregulatory activity. Finally, the demographic dynamics of S. bredanensis were estimated by the pairwise sequentially Markovian coalescent (PSMC) model and found that the population was affected by the climate at the time. We demonstrated that improved continuity and accuracy of the assembled sequence warranted the adoption of this chromosome-level genome as the reference genome and advanced the understanding of genetic features of the rough-toothed dolphin, which will be essential for future evolutionary studies and the protection of this species.

General Characteristics of Brain Immunohistochemical Markers

Neurons and neuroglia are an important object of medical and biological studies of the brain in normal and pathological conditions. The complexity of the cyto- and myeloarchitectonic of the central nervous system requires adequate methods for studying it. Immunohistochemical methods are among the most highly informative in establishing the morphological and functional characteristics of the nervous system, including during ontogenesis. The purpose of this review is to summarize and systematize literature data on immunohistochemical markers of neuro- and gliogenesis, proliferation, differentiation, and functional activity of nerve cells.

The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer.

Matrix metalloproteinases (MMPs) are an important class of enzymes in the body that function through the extracellular matrix (ECM). They are involved in diverse pathophysiological processes, such as tumor invasion and metastasis, cardiovascular diseases, arthritis, periodontal disease, osteogenesis imperfecta, and diseases of the central nervous system. MMPs participate in the occurrence and development of numerous cancers and are closely related to immunity. In the present study, we review the immunomodulatory role of MMPs in colitis-associated cancer (CAC) and discuss relevant clinical applications. We analyze more than 300 pharmacological studies retrieved from PubMed and the Web of Science, related to MMPs, cancer, colitis, CAC, and immunomodulation. Key MMPs that interfere with pathological processes in CAC such as MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13, as well as their corresponding mechanisms are elaborated. MMPs are involved in cell proliferation, cell differentiation, angiogenesis, ECM remodeling, and the inflammatory response in CAC. They also affect the immune system by modulating differentiation and immune activity of immune cells, recruitment of macrophages, and recruitment of neutrophils. Herein we describe the immunomodulatory role of MMPs in CAC to facilitate treatment of this special type of colon cancer, which is preceded by detectable inflammatory bowel disease in clinical populations.

344Laser bioprinting of human iPSC-derived neural stem cells and neurons: Effect on cell survival, multipotency, differentiation, and neuronal activity.

Generation of human neuronal networks by three-dimensional (3D) bioprinting is promising for drug testing and hopefully will allow for the understanding of cellular mechanisms in brain tissue. The application of neural cells derived from human induced-pluripotent stem cells (hiPSCs) is an obvious choice, since hiPSCs provide access to cells unlimited in number and cell types that could be generated by differentiation. The questions in this regard include which neuronal differentiation stage is optimal for printing of such networks, and to what extent the addition of other cell types, especially astrocytes, supports network formation. These aspects are the focus of the present study, in which we applied a laser-based bioprinting technique and compared hiPSC-derived neural stem cells (NSCs) with neuronal differentiated NSCs, with and without the inclusion of co-printed astrocytes. In this study, we investigated in detail the effects of cell types, printed droplet size, and duration of differentiation before and after printing on viability, as well as proliferation, stemness, differentiation potential, formation of dendritic extensions and synapses, and functionality of the generated neuronal networks. We found a significant dependence of cell viability after dissociation on differentiation stage, but no impact of the printing process. Moreover, we observed a dependence of the abundance of neuronal dendrites on droplet size, a marked difference between printed cells and normal cell culture in terms of further differentiation of the cells, especially differentiation into astrocytes, as well as neuronal network formation and activity. Notably, there was a clear effect of admixed astrocytes on NSCs but not on neurons.

Changes in PRC1 activity during interphase modulate lineage transition in pluripotent cells

The potential of pluripotent cells to respond to developmental cues and trigger cell differentiation is enhanced during the G1 phase of the cell cycle, but the molecular mechanisms involved are poorly understood. Variations in polycomb activity during interphase progression have been hypothesized to regulate the cell-cycle-phase-dependent transcriptional activation of differentiation genes during lineage transition in pluripotent cells. Here, we show that recruitment of Polycomb Repressive Complex 1 (PRC1) and associated molecular functions, ubiquitination of H2AK119 and three-dimensional chromatin interactions, are enhanced during S and G2 phases compared to the G1 phase. In agreement with the accumulation of PRC1 at target promoters upon G1 phase exit, cells in S and G2 phases show firmer transcriptional repression of developmental regulator genes that is drastically perturbed upon genetic ablation of the PRC1 catalytic subunit RING1B. Importantly, depletion of RING1B during retinoic acid stimulation interferes with the preference of mouse embryonic stem cells (mESCs) to induce the transcriptional activation of differentiation genes in G1 phase. We propose that incremental enrolment of polycomb repressive activity during interphase progression reduces the tendency of cells to respond to developmental cues during S and G2 phases, facilitating activation of cell differentiation in the G1 phase of the pluripotent cell cycle.

Implications of BRAF V600E mutation in gliomas: Molecular considerations, prognostic value and treatment evolution.

Gliomas are molecularly heterogeneous brain tumors responsible for the most years of life lost by any cancer. High-grade gliomas have a poor prognosis and despite multimodal treatment including surgery, radiotherapy, and chemotherapy, exhibit a high recurrence rate. There is a need for new therapeutic approaches based on precision medicine informed by biomarker assessment and BRAF, a key regulator of MAPK signaling pathway, influencing cell differentiation, proliferation, migration and pro-tumorigenic activity, is emerging as a promising molecular target. V600E, is the most frequent BRAF alteration in gliomas, especially in pediatric low-grade astrocytomas, pleomorphic xanthoastrocytoma, papillary craniopharyngioma, epithelioid glioblastoma and ganglioglioma. The possible application of BRAF-targeted therapy in gliomas is continuously growing and there is preliminary evidence of prolonged disease control obtained by BRAF inhibitors in tumors harboring BRAF V600E mutation. The possibility of introducing targeted therapies into the treatment algorithm represents a paradigm shift for patients with BRAF V600E mutant recurrent high-grade and low-grade glioma and BRAF routine testing should be considered in clinical practice. The focus of this review is to summarize the molecular landscape of BRAF across glioma subtypes and the novel therapeutic strategies for BRAF V600E mutated tumors.

Effect of radiotherapy on the differentiation and osteogenic activity of mesenchymal stem cells on dental implants

Objective: to evaluate the differentiation and gene expression of transcripts related to osteogenesis in a primaryculture of Mesenchymal Stem Cells (MSCs) derived from rat femurs submitted to radiotherapy and the installationof pure titanium implants. Material and Methods: fifty-four rats received titanium implants in both femurs andwere divided into three groups: Control: implant surgery (C); Implant + immediate irradiation (IrI), and Implant+ late irradiation (IrL). Euthanasia occurred 3, 14, and 49 days after surgery. The bone marrow MSCs from thefemurs were isolated and cultivated. The cell viability, total protein content, alkaline phosphatase (ALP) activity,and the formation of mineralization nodules and cellular genotoxicity were analyzed. The gene expression ofAlkaline Phosphatase (phoA), Collagen 1 (COL1), Runt-related transcription factor 2 (RUNX2), Osterix (OSX),Osteopontin (OPN), Integrin B1 (ITGB1), Bone Sialoprotein (BSP), Osteonectin (SPARC), Osteocalcin (Bglap),Transforming Growth Factor B-type (TGF-B), Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF),Interleukin-6 (IL-6), Apolipoprotein E (APOE) and Prostaglandin E2 synthase (PGE2) were evaluated by qRTPCR.Results: ionizing radiation suppresses the gene expression of essential transcripts for bone regeneration,as well as cellular viability, as observed in the IrI and IrL groups. Conclusion: although this can lead to the lossof osseointegration and failure of the implant, the MSCs showed more activity at 49 days than at 3 and 14 days. KEYWORDSCancer treatment protocol; Osseointegration; Osteogenesis; Bone regeneration; Dental implants.

Альфа-фетопротеин как фактор дифференцировки и функциональной активности миелоидных супрессорных клеток

Альфа-фетопротеин как фактор дифференцировки и функциональной активности миелоидных супрессорных клеток

Stages of preadipocyte differentiation: biomarkers and pathways for extracellular structural remodeling

BackgroundThis study utilized bioinformatics to analyze the underlying biological mechanisms involved in adipogenic differentiation, synthesis of the extracellular matrix (ECM), and angiogenesis during preadipocyte differentiation in human Simpson–Golabi–Behmel syndrome at different time points and identify targets that can potentially improve fat graft survival.ResultsWe analyzed two expression profiles from the Gene Expression Omnibus and identified differentially expressed genes (DEGs) at six different time points after the initiation of preadipocyte differentiation. Related pathways were identified using Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis (GSEA). We further constructed a protein–protein interaction (PPI) network and its central genes. The results showed that upregulated DEGs were involved in cell differentiation, lipid metabolism, and other cellular activities, while downregulated DEGs were associated with angiogenesis and development, ECM tissue synthesis, and intercellular and intertissue adhesion. GSEA provided a more comprehensive basis, including participation in and positive regulation of key pathways of cell metabolic differentiation, such as the “peroxisome proliferator-activated receptor signaling pathway” and the “adenylate-activated protein kinase signaling pathway,” a key pathway that negatively regulates pro-angiogenic development, ECM synthesis, and adhesion.ConclusionsWe identified the top 20 hub genes in the PPI network, including genes involved in cell differentiation, ECM synthesis, and angiogenesis development, providing potential targets to improve the long-term survival rate of fat grafts. Additionally, we identified drugs that may interact with these targets to potentially improve fat graft survival.

The role of PRDM1 gene polymorphism in the progression of hepatocellular carcinoma in Egyptian patients.

In Egypt, hepatocellular carcinoma (HCC) ranks as the second largest cause of cancer mortality. PRDM1 is a tumor suppressor gene essential for the differentiation and regulation activity of plasma cells and T cells. It plays a vital role in T cell exhaustion of chronic viral infection and HCC. We aimed to study the role of PRDM1 gene polymorphism in HCV and HCC-related to hepatitis C virus (HCV) progress in Egyptians. Thecase-control study included 300 Egyptian patients divided into100 HCC,100 cirrhosis, and 100 control. Laboratory investigations were done for some clinicopathological biomarkers, including liver function tests,complete blood picture,serum alpha-fetoprotein, and hepatitis markers (HBsAg, anti-HCV-Ab). TaqMan allelic discrimination assay technique was used to genotype PRDM1 gene polymorphism. Multivariant analysis (logistic regression) assessed the association between the polymorphisms with HCC progression and designed thesuggested model for HCC prediction.The frequencies of the G allele and GG phenotype in the controlgroup were significantly more than that of the HCC and cirrhosis group. However,GA genotypes and A allele frequencies significantly increased in the HCC patients than in cirrhosis and controls. In addition, by comparing the HCC group and the non-HCC group (controls and cirrhotic patients), the subjects carrying AA or GA have 2 times more risk to develop HCC than those carrying GG genotypes (odd ratio = 2.045% and 95%confidence intervalare (1.123-3.722) p = 0.019). Multivariate analysis results suggested a model of Aspartate transaminase (AST), Albumin, and PRDM1 polymorphism to predictthe risk of HCC in Egyptians. In addition, PRDM1 polymorphism has an association with HCC prognosis (tumor size).For PRDM1 polymorphism, the A allele and AA might be considered as HCC-related to theHCV risk factor. In addition, AST, Albumin, and PRDM1 polymorphism predictthe risk of HCC in Egyptians Therefore, the polymorphism might help in identifying the susceptible Egyptians to HCC. In addition, polymorphism might have a role in HCC prognosis.

Topographical cues of PLGA membranes modulate the behavior of hMSCs, myoblasts and neuronal cells

Biomaterial surface modification through the introduction of defined and repeated patterns of topography helps study cell behavior in response to defined geometrical cues. The lithographic molding technique is widely used for conferring biomaterial surface microscale cues and enhancing the performance of biomedical devices. In this work, different master molds made by UV mask lithography were used to prepare poly (D,L-lactide-co-glycolide) - PLGA micropatterned membranes to present different features of topography at the cellular interface: channels, circular pillars, rectangular pillars, and pits. The effects of geometrical cues were investigated on different cell sources, such as neuronal cells, myoblasts, and stem cells. Morphological evaluation revealed a peculiar cell arrangement in response to a specific topographical stimulus sensed over the membrane surface. Cells seeded on linear-grooved membranes showed that this cue promoted elongated cell morphology. Rectangular and circular pillars act instead as discontinuous cues at the cell-membrane interface, inducing cell growth in multiple directions. The array of pits over the surface also highlighted the precise spatiotemporal organization of the cell; they grew between the interconnected membrane space within the pits, avoiding the microscale hole. The overall approach allowed the evaluation of the responses of different cell types adhered to various surface patterns, build-up on the same polymeric membrane, and disclosing the effect of specific topographical features. We explored how various microtopographic signals play distinct roles in different cells, thus affecting cell adhesion, migration, differentiation, cell-cell interactions, and other metabolic activities.

Optimizing the Supportive Care of Intensive Chemotherapy in AML : Impact of Vitamin C and D Supplementation in Patients with NPM1 Mutation. a Dataml Registry Study

Background Vitamin (vit) deficiencies are frequently observed in patients (pts) with newly diagnosed AML (ND-AML). A lower level of vit D is associated with a worse prognosis in pts treated with intensive chemotherapy (IC) (Lee HJ, Cancer 2014). Similarly, a pretransplant vit D deficiency is associated with a higher risk of relapse (Radujkovic JCO, 2017). Moreover, preclinical studies demonstrated the antileukemic activity of vit D through the modulation of cell cycle, differenciation and apoptosis even though the clinical translation has not been successful (Cao H, Exp Hematol 2017 ; Paubelle E, Cell Rep 2020). More recent data have highlighted the role of vit C in AML. Vit C is a cofactor and increases the activity of TET2 enzyme, inducing DNA demethylation, stem cell differentiation and antileukemic activity (Agathocleous M, Nature 2017; Cimmino L, Cell 2017). Cases of remission following vit C supplementation have been reported (Foster M, Antioxidants, 2018 ; Das A, Blood Cancer J, 2019) and a small study showed that the addition of vit C to decitabine/AraC/aclarubicin/G-CSF improved outcome compared to DCAG (Zhao H, Leuk Res 2018). Based on these data, we modified our practice by adding vit C and D to the supportive care (SC) of IC. Methods The study population included all pts with ND-AML treated by IC and registered in Toulouse DATAML from 01/2015 to 05/2020. As of March 2018, as part of the SC for AML pts treated by IC and in the absence of contra indication (renal lithiasis, renal insufficiency, G6PD deficiency, hypercalcemia), vit C (1g x 2/d, three times a week ; IV) and vit D (100,000 IU/week ; PO) have been administered from d10 until hematologic recovery of induction and consolidation. The principal objective of this retrospective study was to assess the impact of the vit supplementation on EFS. Secondary objectives were response to induction, early death, OS, RFS, incidence of relapse, vitamin levels during treatment and safety. Results 431 pts were included, 262 without (from 01/2015 to 02/2018 ; control group) and 169 with vit C/D supplementation (03/2018-05/2020 ; vitC/D group). Data were updated on 03/03/2022. The median FU was 45.6 months. Pt characteristics were well balanced except for age, PS and creatinine (Table 1). In the vitC/D group, the median plasma level of vit C was 3.20 mg/L (range, 0.47-15.42) at diagnosis and 4.62 mg/L (range, 0.18-18.1) at time of hematologic recovery from induction (P=0.18). The level of vit D at diagnosis was 16 ng/mL (range, 4-56) and 18 ng/mL (range, 4-42) in the control and vitC/D groups, respectively. Upon recovery from induction, vit D levels significantly increased compared to diagnosis in the vitC/D group (median, 39 ng/ml, range, 5-93 ; P<0.0001). CR/CRi rate was 84.4% (control) and 84% (vitC/D) (P=0.93). Day-30 death rate was 4.2% (control) and 2.4% (vitC/D) (P=0.31). During induction, the rates of grade 3-4 bacterial infections (vitC/D, 27.2% vs control, 35.1%, P=0.086), fungal infections (10.1 vs 18.3%, P=0.019), hemorrhages (1.8 vs 5.7%, P=0.045) or macrophage activation syndrome (1.8 vs 8.8%, P=0.002) were lower in the vitC/D group. Median level of day-21 calcemia was higher in the vitC/D group (2.48 mmol/L vs 2.44, P=0.003). Grade 2 hypercalcemia was observed in only 1 patient of the control group. Allo-SCT was performed in 37 (26.1%) and 75 (33.9%) pts of the vitC/D and control groups, respectively. Median pretransplant vit D levels were significantly higher in the vitC/D group (33 vs 19 ng/mL, P<0.0001). There was no significant difference in EFS (vitC/D, median 13.9 vs 17.4 months, P=0.26), RFS (15.5 vs 23.5, P=0.24) and OS (30.8 vs 34.5, P=0.80) between both groups. However, multivariate analysis for OS showed a significant interaction between vitC/D and NPM1 mutation meaning that vitC/D supplementation was significantly and independently associated with better OS in pts with NPM1 mutations (HR, 0.52 ; 95%CI: 0.30-0.90, P=0.019) but not in NPM1 wildtype pts (HR, 1.01 ; 95%CI: 0.68-1.51, P=0.95). MV analysis for EFS, RFS and CIR did not find any significant interactions. Conclusion Vit C and D supplementation is feasible and safe in AML pts during IC. Normal Vit D levels can be restored before transplant, which may be important. The potential impact of vit C/D supplementation in AML with NPM1 mutations needs further studies and pave the way for exploratory analyses to explain how the VDR pathway and/or vit C activity may interact with the biology of NPM1 mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Host genetic factors related to innate immunity, environmental sensing and cellular functions are associated with human skin microbiota

Despite the increasing knowledge about factors shaping the human microbiome, the host genetic factors that modulate the skin-microbiome interactions are still largely understudied. This contrasts with recent efforts to characterize host genes that influence the gut microbiota. Here, we investigated the effect of genetics on skin microbiota across three different skin microenvironments through meta-analyses of genome-wide association studies (GWAS) of two population-based German cohorts. We identified 23 genome-wide significant loci harboring 30 candidate genes involved in innate immune signaling, environmental sensing, cell differentiation, proliferation and fibroblast activity. However, no locus passed the strict threshold for study-wide significance (P < 6.3 × 10−10 for 80 features included in the analysis). Mendelian randomization (MR) analysis indicated the influence of staphylococci on eczema/dermatitis and suggested modulating effects of the microbiota on other skin diseases. Finally, transcriptional profiles of keratinocytes significantly changed after in vitro co-culturing with Staphylococcus epidermidis, chosen as a representative of skin commensals. Seven candidate genes from the GWAS were found overlapping with differential expression in the co-culturing experiments, warranting further research of the skin commensal and host genetic makeup interaction.

The Role of Endoplasmic Reticulum Stress in Differentiation of Cells of Mesenchymal Origin.

Endoplasmic reticulum (ER) is a multifunctional membrane-enclosed organelle. One of the major ER functions is cotranslational transport and processing of secretory, lysosomal, and transmembrane proteins. Impaired protein processing caused by disturbances in the ER homeostasis results in the ER stress. Restoration of normal ER functioning requires activation of an adaptive mechanism involving cell response to misfolded proteins, the so-called unfolded protein response (UPR). Besides controlling protein folding, UPR plays a key role in other physiological processes, in particular, differentiation of cells of connective, muscle, epithelial, and neural tissues. Cell differentiation is induced by the physiological levels of ER stress, while excessive ER stress suppresses differentiation and can result in cell death. So far, it remains unknown whether UPR activation induces cell differentiation or if UPR is initiated by the upregulated synthesis of secretory proteins during cell differentiation. Cell differentiation is an important stage in the development of multicellular organisms and is tightly controlled. Suppression or excessive activation of this process can lead to the development of various pathologies in an organism. In particular, impairments in the differentiation of connective tissue cells can result in the development of fibrosis, obesity, and osteoporosis. Recently, special attention has been paid to fibrosis as one of the major complications of COVID-19. Therefore, studying the role of UPR in the activation of cell differentiation is of both theoretical and practical interest, as it might result in the identification of molecular targets for selective regulation of cell differentiation stages and as well as the potential to modulate the mechanisms involved in the development of various pathological states.

Triple-functional injectable liposome–hydrogel composite enhances bacteriostasis and osteo/angio-genesis for advanced maxillary sinus floor augmentation

Bone-grafting biological materials are commonly used to increase the height of the alveolar bone in the maxillary posterior region during maxillary sinus floor augmentation. However, there has been little research on the development of an injectable bone-grafting material with bacteriostatic, angiogenic, and osteogenic properties. In this work, we developed a triple-functional vancomycin/deferoxamine/dexamethasone (Van/DFO/Dex) liposome–hydrogel composite with desirable injectability. The release kinetics confirmed orderly sustained release of Van (a bacteriostat), DFO (a vascularised small molecule), and Dex (an osteogenic small molecule). In vitro findings demonstrated the favourable cytocompatibility and antibacterial ability of this composite against Staphylococcus aureus. Additionally, the angiogenic ability of human umbilical vein endothelial cells and osteogenic differentiation activity of MC3T3-E1 cells were enhanced. An in vivo bacteriostasis assay and rabbit maxillary sinus floor augmentation model corroborated the enhanced bacteriostasis and vascularised bone regeneration properties of this functionalised composite. Overall, the favourable injectability to be fit for the minimally invasive procedure, locally sustained release property, and prominent biological functions underscore the clinical potential of Van/DFO/Dex as an ideal bone-grafting material for irregular bone defect repairs, such as maxillary sinus floor augmentation.

Integrated proteomics, phosphoproteomics and metabolomics analyses reveal similarities among giant cell granulomas of the jaws with different genetic mutations.

Giant cell granuloma of the jaws are benign osteolytic lesions of the jaws. These lesions are genetically characterized by mutually exclusive somatic mutations at TRPV4, KRAS, and FGFR1, and a fourth molecular subgroup which is wild-type for the three mutations. Irrespective of the molecular background, giant cell granulomas show MAPK/ERK activation. However, it remains unclear if these mutations lead to differences in their molecular signaling in giant cell granulomas. Metabolomics, proteomics, and phosphoproteomics analyses were carried out in formalin-fixed paraffin-embedded samples of giant cell granuloma of the jaws. The study cohort consisted of five lesions harboring mutations in FGFR1, six in KRAS, five in TRPV4, and five that were wild-type for these mutations. Lesions harboring KRAS or FGFR1 mutations showed overall similar proteomics and metabolomics profiles. In all four groups, metabolic pathways showed similarity in apoptosis, cell signaling, gene expression, cell differentiation, and erythrocyte activity. Lesions harboring TRPV4 mutations showed a greater number of enriched pathways related to tissue architecture. On the other hand, the wild-type group presented increased number of enriched pathways related to protein metabolism compared to the other groups. Despite some minor differences, our results revealed an overall similar molecular profile among the groups with different mutational profile at the metabolic, proteic, and phosphopeptidic levels.