Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.

The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy.

Breast-to-brain metastasis is exacerbated with chemotherapy through blood-cerebrospinal fluid barrier and induces Alzheimer's-like pathology.

Control of breast-to-brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have been shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through the formation of neurofibrillary tangles (NFT), independently. Now, in this study, we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT.

SRRM4-mediated REST to REST4 dysregulation promotes tumor growth and neural adaptation in breast cancer leading to brain metastasis.

Background: Effective control of brain metastasis remains an urgent clinical need due a limited understanding of the mechanisms driving it. Although the gain of neuro-adaptive attributes in breast-to-brain metastases (BBMs) has been described, the mechanisms that govern this neural acclimation and the resulting brain metastasis competency are poorly understood. Herein, we define the role of neural-specific splicing factor Serine/Arginine Repetitive Matrix Protein 4 (SRRM4) in regulating microenvironmental adaptation and brain metastasis colonization in breast cancer cells.

Epigenetic dysregulation in meningiomas.

Background: Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, tumors with benign histology may behave aggressively and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue.

Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis.

Background: Brain metastases (BM) are responsible for neurological decline and poor overall survival. Although the pro-metastatic roles of glial cells, and the acquisition of neuronal attributes in established BM tumors have been described, there are no studies that investigate the initial interplay between neurons and brain-seeking tumor cells. The aim of this study was to characterize early tumor-neuron interactions and the induced CNS-adaptive changes in tumor cells prior to macro-colonization.

Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination.

Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum.

Utilization of Discarded Surgical Tissue from Ultrasonic Aspirators to Establish Patient-Derived Metastatic Brain Tumor Cells: A Guide from the Operating Room to the Research Laboratory.

Patient-derived cells from surgical resections are of paramount importance to brain tumor research. It is well known that there is cellular and microenvironmental heterogeneity within a single tumor mass. Thus, current established protocols for propagating tumor cells in vitro are limiting because resections obtained from conventional singular samples limit the diversity in cell populations and do not accurately model the heterogeneous tumor.

Cortisol promotes breast-to-brain metastasis through the blood-cerebrospinal fluid barrier.

Background: Elevated basal cortisol levels are present in women with primary and metastatic breast cancer. Although cortisol's potential role in breast-to-brain metastasis has yet to be sufficiently studied, prior evidence indicates that it functions as a double-edged sword-cortisol induces breast cancer metastasis in vivo, but strengthens the blood-brain-barrier (BBB) to protect the brain from microbes and peripheral immune cells.

Aims: In this study, we provide a novel examination on whether cortisol's role in tumor invasiveness eclipses its supporting role in strengthening the CNS barriers.

Clinical Perspectives in Brain Metastasis.

Brain metastases (BMs) are responsible for decline in neurological function, reduction in overall quality of life, and mortality from recurrent or untreatable lesions. Advances in diagnostics and imaging have led to increased detection of central nervous system (CNS) metastases in patients with progressive cancers. Improved control of extracranial systemic disease, and the limited ability of current therapeutics to cross the blood-brain barrier (BBB) also contribute to the increase in incidence of brain metastases, as tumor cells seek refuge in the brain.

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain.

Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements.

Isolation of Neural Stem Cells from Whole Brain Tissues of Adult Mice.

A population of neural stem cells exists in the adult mammalian central nervous system. Purification and characterization of neurospheres provide valuable tools to study the regulation and differentiation of neural stem cells both in vitro and in vivo. Successful stimulation and production of neurospheres can ultimately be used for therapeutic purposes.

Medulloblastoma initiation and spread: Where neurodevelopment, microenvironment and cancer cross pathways.

Medulloblastomas are the most common malignant pediatric brain tumors. Over the past several decades, a wide range of tumor-centric studies have identified genes and their regulators within signaling pathways that promote medulloblastoma growth. This review aims to raise awareness that transdisciplinary research between developmental neurobiology and cancer foundations can advance our current understanding of how the nervous system contributes to medulloblastomas.

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain.

Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy.

Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction.

The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as "chemobrain," a condition that can persist long after the cessation of treatment in as many as 75% of survivors. Although cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely affects quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance-based decrements on behavioral tasks designed to interrogate hippocampal and cortical function.

Defining the optimal window for cranial transplantation of human induced pluripotent stem cell-derived cells to ameliorate radiation-induced cognitive impairment.

Past preclinical studies have demonstrated the capability of using human stem cell transplantation in the irradiated brain to ameliorate radiation-induced cognitive dysfunction. Intrahippocampal transplantation of human embryonic stem cells and human neural stem cells (hNSCs) was found to functionally restore cognition in rats 1 and 4 months after cranial irradiation. To optimize the potential therapeutic benefits of human stem cell transplantation, we have further defined optimal transplantation windows for maximizing cognitive benefits after irradiation and used induced pluripotent stem cell-derived hNSCs (iPSC-hNSCs) that may eventually help minimize graft rejection in the host brain.

Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction.

Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria.

Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation.

Long-term cognitive effects of human stem cell transplantation in the irradiated brain.

Purpose: Radiotherapy remains a primary treatment modality for the majority of central nervous system tumors, but frequently leads to debilitating cognitive dysfunction. Given the absence of satisfactory solutions to this serious problem, we have used human stem cell therapies to ameliorate radiation-induced cognitive impairment. Here, past studies have been extended to determine whether engrafted cells provide even longer-term benefits to cognition.

[Feasibility and assessment of combined anti-inflammatory, antibacterial and immunocorrective treatment in periodontal disease].

The article presents the experience of using medical dressings of combined action based on antibiotic Spiramycin and antiseptic Triclosan. Investigation and treatment of 79 patients with moderate chronic periodontitis proved the given drug formulation to be highly clinically effective for local treatment of periodontal disease.

Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy.

Purpose: A substantial proportion of breast cancer survivors report significant, long-lasting impairments in cognitive function, often referred to as "chemobrain." Advances in detection and treatment mean that many more patients are surviving long-term following diagnosis of invasive breast cancer. Thus, it is important to define the types, extent, and persistence of cognitive impairments following treatment with cytotoxic cancer drugs.

[The kinin and plasmin systems of the blood serum and cerebro- spinal fluid in patients with multiple sclerosis and schizophrenia].

The article deals with the role of activation of the kinin and plasmin systems in the blood and cerebrospinal fluid for increasing the blood-brain barrier permeability, immune conflict initiation and as a factor in prediction of further exacerbations of multiple sclerosis and schizophrenia.

[Treatment of polyps and villous tumors of the large intestine].

Polyps and villous tumors were found in 1525 of 10624 patients (14.3%) aged from 40 to 60. In 82% of the cases they were in combination with ulcer disease of the stomach and duodenum, with inflammatory diseases of the gastro-intestinal tract, diverticulitis, tumors of the colon.

[Role of neuroallergy in the pathogenesis of multiple sclerosis].

The neurotropic effects of sera were determined in patients with multiple sclerosis and in animals with experimental allergic encephalomyelitis (EAE) using some newly devised methods. When multiple sclerosis and EAE were at the stage of exacerbation, the kallikrein-kinin system was activated and immune complexes content in the blood serum increased. The authors conclude that neuroallergy plays the major role in the development of multiple sclerosis exacerbations and that the devised methods are valuable for the laboratory confirmation of multiple sclerosis diagnosis.