Trans-Differentiation of Neural Stem Cells: A Therapeutic Mechanism Against the Radiation Induced Brain Damage

Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs) would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases

Patient-Specific Orthotopic Glioblastoma Xenograft Models Recapitulate the Histopathology and Biology of Human Glioblastomas In Situ

SummaryFrequent discrepancies between preclinical and clinical results of anticancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable “patient tumor’s phenocopy” that represents molecular and functional heterogeneity of GBMs

Cutting-edge knowledge on the roles of phytobiotics and their proposed modes of action in swine

With the ban on antibiotics in the swine industry, the exploration of alternative options has highlighted phytobiotics as a promising substitute for antibiotic growth promoters, aiming to foster a more sustainable swine industry. Phytobiotics are non-nutritive natural bioactive components derived from plants that offer numerous health benefits. They exhibit antioxidative, antimicrobial, and anti-inflammatory effects. Phytobiotics can be utilized in various forms, including solid, dried, ground, or as extracts, either in crude or concentrated form. They are characterized by low residual levels, a lack of resistance development, and minimal adverse effects. These qualities make phytobiotics an attractive choice for enhancing health and productivity in swine, presenting them as a viable alternative to antibiotics. While there is a general understanding of the effects of phytobiotics, there is still a need for detailed information regarding their effectiveness and mechanisms of action in practical settings. Therefore, the purpose of this mini review was to summarize the current knowledge supporting the roles of phytobiotics and their proposed modes of action, with a specific focus on swine

Swine gut microbiome associated with non-digestible carbohydrate utilization

Non-digestible carbohydrates are an unavoidable component in a pig’s diet, as all plant-based feeds contain different kinds of non-digestible carbohydrates. The major types of non-digestible carbohydrates include non-starch polysaccharides (such as cellulose, pectin, and hemicellulose), resistant starch, and non-digestible oligosaccharides (such as fructo-oligosaccharide and xylo-oligosaccharide). Non-digestible carbohydrates play a significant role in balancing the gut microbial ecology and overall health of the swine by promoting the production of short chain fatty acids. Although non-digestible carbohydrates are rich in energy, swine cannot extract this energy on their own due to the absence of enzymes required for their degradation. Instead, they rely on gut microbes to utilize these carbohydrates for energy production. Despite the importance of non-digestible carbohydrate degradation, limited studies have been conducted on the swine gut microbes involved in this process. While next-generation high-throughput sequencing has aided in understanding the microbial compositions of the swine gut, specific information regarding the bacteria involved in non-digestible carbohydrate degradation remains limited. Therefore, it is crucial to investigate and comprehend the bacteria responsible for the breakdown of non-digestible carbohydrates in the gut. In this mini review, we have discussed the major bacteria involved in the fermentation of different types of non-digestible carbohydrates in the large intestine of swine, shedding light on their potential roles and contributions to swine nutrition and health

Albuminuria, Cerebrovascular Disease and Cortical Atrophy: among Cognitively Normal Elderly Individuals

We tested the hypothesis that decreased glomerular filtration rate and albuminuria have different roles in brain structure alterations. We enrolled 1,215 cognitively normal individuals, all of whom underwent high-resolution T1-weighted volumetric magnetic resonance imaging scans. The cerebral small vessel disease burdens were assessed with white matter hyperintensities (WMH), lacunes, and microbleeds. Subjects were considered to have an abnormally elevated urine albumin creatinine ratio if the value was ≥17 mg/g for men and ≥25 mg/g for women. Albuminuria, but not estimated glomerular filtration rate (eGFR), was associated with increased WMH burdens (p = 0.002). The data was analyzed after adjusting for age, sex, education, history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, stroke, total cholesterol level, body mass index, status of smoking and alcohol drinking, and intracranial volume. Albuminuria was also associated with cortical thinning, predominantly in the frontal and occipital regions (both p < 0.01) in multiple linear regression analysis. However, eGFR was not associated with cortical thickness. Furthermore, path analysis for cortical thickness showed that albuminuria was associated with frontal thinning partially mediated by WMH burdens. The assessment of albuminuria is needed to improve our ability to identify individuals with high risk for cognitive impairments, and further institute appropriate preventive measures

Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

Background: Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer's disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods: One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results: In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10-8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74-0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion: The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations

Sustainability of Analyst Recommendations in Multiple Lead Underwriter IPOs

Recently, a new organizational form of syndicate&mdash;multiple lead underwriter (MLU) initial public offerings (IPOs)&mdash;has emerged in IPOs. In addition to the increased deal complexity, lead underwriters in MLU IPOs face a new competition between them after underwriter selection, which is not present in single lead underwriter (SLU) IPOs. It is therefore questionable whether recommendations by analysts from lead underwriters of the MLU IPOs are as sustainable as those of the SLU IPOs. We examine IPO recommendations to capture how this new syndicate structure affects analyst behavior in terms of analyst optimism and investment value. In contrast to the popular conflict of interest perspective, our findings point to the notion that the new syndicate structure suppresses bias in recommendations and that reputation upholding incentive dominates pressure from competition. MLU-affiliated analysts are not more optimistic and provide more informative research coverage whose informativeness, however, fades away shortly after the recommendation releases. Our findings overall indicate the existence of sustainability in the MLU IPO recommendations