A Snapshot of Early Transcriptional Changes Accompanying the Pro-Neural Phenotype Switch by NGN2, ASCL1, SOX2, and MSI1 in Human Fibroblasts: An RNA-Seq Study.

Direct pro-neural reprogramming is a conversion of differentiated somatic cells to neural cells without an intermediate pluripotency stage. It is usually achieved via ectopic expression (EE) of certain transcription factors (TFs) or other reprogramming factors (RFs). Determining the transcriptional changes (TCs) caused by particular RFs in a given cell line enables an informed approach to reprogramming initiation.

In Search of Spinal Muscular Atrophy Disease Modifiers.

The 5q Spinal Muscular Atrophy (SMA) is a hereditary autosomal recessive disease caused by defects in the survival motor neuron () gene encoding survival motor neuron (SMN) protein. Currently, it is the leading cause of infantile mortality worldwide. SMA is a progressive neurodegenerative disease with "continuum of clinical severity", which can be modulated by genetic and epigenetic factors known as disease modifiers (DMs).

Non-Tumor Cells within the Tumor Microenvironment-The "Eminence Grise" of the Glioblastoma Pathogenesis and Potential Targets for Therapy.

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. GBM has high levels of therapy failure and its prognosis is usually dismal. The phenotypic heterogeneity of the tumor cells, dynamic complexity of non-tumor cell populations within the GBM tumor microenvironment (TME), and their bi-directional cross-talk contribute to the challenges of current therapeutic approaches.

Improving Efficiency of Direct Pro-Neural Reprogramming: Much-Needed Aid for Neuroregeneration in Spinal Cord Injury.

Spinal cord injury (SCI) is a medical condition affecting ~2.5-4 million people worldwide. The conventional therapy for SCI fails to restore the lost spinal cord functions; thus, novel therapies are needed.

COVID-19-The Shift of Homeostasis into Oncopathology or Chronic Fibrosis in Terms of Female Reproductive System Involvement.

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus remains a global public health concern due to the systemic nature of the infection and its long-term consequences, many of which remain to be elucidated. SARS-CoV-2 targets endothelial cells and blood vessels, altering the tissue microenvironment, its secretion, immune-cell subpopulations, the extracellular matrix, and the molecular composition and mechanical properties. The female reproductive system has high regenerative potential, but can accumulate damage, including due to SARS-CoV-2.

The growth hormone receptor interacts with transcriptional regulator HMGN1 upon GH-induced nuclear translocation.

Growth hormone (GH) actions are mediated through binding to its cell-surface receptor, the GH receptor (GHR), with consequent activation of downstream signalling. However, nuclear GHR localisation has also been observed and is associated with increased cancer cell proliferation. Here we investigated the functional implications of nuclear translocation of the GHR in the human endometrial cancer cell-line, RL95-2, and human mammary epithelial cell-line, MCF-10A.

The long winding road to the safer glucocorticoid receptor (GR) targeting therapies.

Glucocorticoids (Gcs) are widely used to treat inflammatory diseases and hematological malignancies, and despite the introduction of novel anti-inflammatory and anti-cancer biologics, the use of inexpensive and effective Gcs is expected to grow. Unfortunately, chronic treatment with Gcs results in multiple atrophic and metabolic side effects. Thus, the search for safer glucocorticoid receptor (GR)-targeted therapies that preserve therapeutic potential of Gcs but result in fewer adverse effects remains highly relevant.

Aerial warfare: An inducible production of volatile bioactive metabolites in a novel species of Scytinostroma sp.

Antimicrobial volatile organic compounds (VOCs) may provide fungi an advantage over other competing microorganisms. As these defensive metabolites are often produced in response to microbial competitors, they are easily overlooked in axenic cultures. We used media supplemented with spent medium from Candida albicans to induce the expression of a broad-spectrum antimicrobial response in a previously uncharacterised white-rot fungus, Scytinostroma sp.

The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors.

The tumor biomarkers already have proven clinical value and have become an integral part in cancer management and modern translational oncology. The tumor tissue microenvironment (TME), which includes extracellular matrix (ECM), signaling molecules, immune and stromal cells, and adjacent non-tumorous tissue, contributes to cancer pathogenesis. Thus, TME-derived biomarkers have many clinical applications.

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.

Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome.

A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction.

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment.

The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent.

The Russian population consists of more than 100 ethnic groups, presenting a unique opportunity for the identification of hereditary pathogenic mutations. To gain insight into the landscape of heredity pathogenic variants, we employed targeted next-generation sequencing to analyze the germline mutation load in the DNA damage response and repair genes of hereditary breast and ovary cancer syndrome (HBOCS) patients of Tatar ethnicity, which represents ~4% of the total Russian population. Several pathogenic mutations were identified in DNA double-strand break repair genes, and the spectrum of these markers in Tatar patients varied from that previously reported for patients of Slavic ancestry.

CCI-007, a novel small molecule with cytotoxic activity against infant leukemia with MLL rearrangements.

There is an urgent need for the development of less toxic, more selective and targeted therapies for infants with leukemia characterized by translocation of the mixed lineage leukemia (MLL) gene. In this study, we performed a cell-based small molecule library screen on an infant MLL-rearranged (MLL-r) cell line, PER-485, in order to identify selective inhibitors for MLL-r leukemia. After screening initial hits for a cytotoxic effect against a panel of 30 cell lines including MLL-r and MLL wild-type (MLL-wt) leukemia, solid tumours and control cells, small molecule CCI-007 was identified as a compound that selectively and significantly decreased the viability of a subset of MLL-r and related leukemia cell lines with CALM-AF10 and SET-NUP214 translocation.

Expression of embryonic stem cell markers in keloid-associated lymphoid tissue.

Aims: To identify, characterise and localise the population of primitive cells in keloid scars (KS).

Methods: 5-µm-thick formalin-fixed paraffin-embedded sections of KS samples from 10 patients underwent immunohistochemical (IHC) staining for the embryonic stem cell (ESC) markers OCT4, SOX2, pSTAT3 and NANOG, and keloid-associated lymphoid tissue (KALT) markers CD4 and CD20. NanoString gene expression analysis and in situ hybridisation (ISH) were used to determine the abundance and localisation of the mRNA for these ESC markers.

Expression of Cathepsins B, D, and G in Infantile Hemangioma.

Aims: The role of the renin-angiotensin system (RAS) in the biology of infantile hemangioma (IH) represents an emerging paradigm, particularly the involvement of renin, angiotensin converting enzyme, and angiotensin II. This study investigated the expression of cathepsins B, D, and G, enzymes that may modulate the RAS, in IH.

Materials And Methods: The expression of cathepsins B, D, and G was examined using immunohistochemistry, enzyme activity assays, mass spectrometry, and NanoString gene expression assay in IH samples at different phases of development.

Characterisation of lymphocyte subpopulations in infantile haemangioma.

Aims: Interstitial CD45+ cells and T lymphocytes have previously been demonstrated within infantile haemangioma (IH). This study investigated the expression of B and T lymphocyte markers by the CD45+ population, and the expression of Thy-1, a marker of thymocyte progenitors, which have the ability to give rise to both B and T cells.

Methods: Immunohistochemical (IHC) staining was performed on proliferating and involuted IHs for the expression of CD45, CD3, CD20, CD79a, Thy-1 and CD34.

Characterisation of subpopulations of myeloid cells in infantile haemangioma.

Aims: Cells expressing markers of mast cells, macrophages and dendritic cells have previously been demonstrated within the interstitium of infantile haemangioma (IH). This study characterised these myeloid cellular subpopulations within IH.

Methods: Immunohistochemical staining was performed on proliferating and involuted IHs for the expression of Nanog, tryptase, CD163, DC-SIGN and CD45.

Developmentally regulated ceramide synthase 6 increases mitochondrial Ca2+ loading capacity and promotes apoptosis.

Ceramides, which are membrane sphingolipids and key mediators of cell-stress responses, are generated by a family of (dihydro) ceramide synthases (Lass1-6/CerS1-6). Here, we report that brain development features significant increases in sphingomyelin, sphingosine, and most ceramide species. In contrast, C(16:0)-ceramide was gradually reduced and CerS6 was down-regulated in mitochondria, thereby implicating CerS6 as a primary ceramide synthase generating C(16:0)-ceramide.

Integrin-associated Lyn kinase promotes cell survival by suppressing acid sphingomyelinase activity.

Integrins govern cellular adhesion and transmit signals leading to activation of intracellular signaling pathways aimed to prevent apoptosis. Herein we report that attachment of oligodendrocytes (OLs) to fibronectin via alpha(v)beta(3) integrin receptors rendered the cells more resistant to apoptosis than the cells attached to laminin via alpha(6)beta(1) integrins. Investigation of molecular mechanisms involved in alpha(v)beta(3) integrin-mediated cell survival revealed that ligation of the integrin with fibronectin results in higher expression of activated Lyn kinase.

JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction.

A cardinal feature of brain tissue injury in stroke is mitochondrial dysfunction leading to cell death, yet remarkably little is known about the mechanisms underlying mitochondrial injury in cerebral ischemia/reperfusion (IR). Ceramide, a naturally occurring membrane sphingolipid, functions as an important second messenger in apoptosis signaling and is generated by de novo synthesis, sphingomyelin hydrolysis, or recycling of sphingolipids. In this study, cerebral IR-induced ceramide elevation resulted from ceramide biosynthesis rather than from hydrolysis of sphingomyelin.