Mesenchymal Stem Cell-Derived Exosomes as a Neuroregeneration Treatment for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent kind of dementia and is a long-term degenerative disease. Pathologically, it is defined by the development of extracellular amyloid-ß plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein. This causes neuronal death, particularly in the hippocampus and cortex. Mesenchymal stem cell (MSC)-derived exosomes have been identified as possibly therapeutic and have promise for Alzheimer's disease due to their regenerative characteristics. METHODS: A systematic retrieval of information was performed on PubMed. A total of 60 articles were found in a search on mesenchymal stem cells, exosomes, and Alzheimer's disease. A total of 16 ongoing clinical trials were searched and added from clinicaltrials.gov. We added 23 supporting articles to help provide information for certain sections. In total, we included 99 articles in this manuscript: 50 are review articles, 13 are preclinical studies, 16 are clinical studies, 16 are ongoing clinical trials, and 4 are observational studies. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on mesenchymal stem cell exosomes for Alzheimer's disease were searched on clinicaltrials.gov. RESULTS: Several experimental investigations have shown that MSC-Exo improves cognitive impairment in rats. In this review paper, we summarized existing understanding regarding the molecular and cellular pathways behind MSC-Exo-based cognitive function restoration, with a focus on MSC-Exo's therapeutic potential in the treatment of Alzheimer's disease. CONCLUSION: AD is a significant health issue in our culture and is linked to several important neuropathological characteristics. Exosomes generated from stem cells, such as mesenchymal stem cells (MSCs) or neural stem cells (NSCs), have been examined more and more in a variety of AD models, indicating that they may be viable therapeutic agents for the treatment of diverse disorders. Exosome yields may be increased, and their therapeutic efficacy can be improved using a range of tailored techniques and culture conditions. It is necessary to provide standardized guidelines for exosome manufacture to carry out excellent preclinical and clinical research.

Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma.

According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.

Niche analyses and the potential distribution of four invasive bumblebees worldwide.

The introduction of bees for agricultural production in distinct parts of the world and poor management have led to invasion processes that affect biodiversity, significantly impacting native species. Different Bombus species with invasive potential have been recorded spreading in different regions worldwide, generating ecological and economic losses. We applied environmental niche and potential distribution analyses to four species of the genus Bombus to evaluate the similarities and differences between their native and invaded ranges. We found that B. impatiens has an extended environmental niche, going from dry environmental conditions in the native range to warmer and wetter conditions in the invaded range. Bombus ruderatus also exhibited an extended environmental niche with drier and warmer conditions in the invaded range than in its native range. Bombus subterraneus expanded its environmental niche from cooler and wetter conditions in the native range to drier and warmer conditions in the invaded range. Finally, B. terrestris showed the most significant variation in the environmental niche, extending to areas with similar and different environmental conditions from its native range. The distribution models agreed with the known distributions for the four Bombus species, presenting geographic areas known to be occupied by each species in different regions worldwide. The niche analysis indicate shifts in the niches from the native to the invaded distribution area of the bee species. Still, niche similarities were observed in the areas of greatest suitability in the potential distribution for B. ruderatus, B. subterraneus, and B. terrestris, and to a lesser degree in the same areas with B. impatiens. These species require similar environmental conditions as in their native ranges to be established in their introduced ranges. Still, they can adapt to changes in temperature and humidity, allowing them to expand their ranges into new climatic conditions.

Descompresión microvascular para el manejo de la neuralgia del trigemino: presentación de caso clínico y revisión de la literatura / Microvascular decompression for the handling of trigeminal neuralgia: clinical case report and literature review

La neuralgia del trigémino es un trastorno neuropático paroxístico que afecta a una o varias de las ramas sensoriales del nervio trigémino cuya etiología es variada, la más aceptada es por compresiones vasculares a nivel del ángulo ponto cerebeloso que generan conflicto de espacio. Dentro de las posibilidades de tratamiento, la descompresión microvascular permite la cura fisiopatológica de la neuralgia del trigémino, teniendo resultados satisfactorios a corto/largo plazo, y bastantes ventajas en comparación a otras técnicas de mínima invasión. Se presenta el caso de una paciente con tratamiento médico máximo no efectivo, a la cual se realizó descompresión microvascular evidenciando conflicto arterial y venoso con el nervio.

Trigeminal neuralgia is a paroxysmal neuropathic disorder that affects one or more of the sensory branches of the trigeminal nerve, the etiology of which is varied, the most accepted being due to vascular compressions at the level of the brainstem that generate conflict of space. Within the treatment possibilities, microvascular decompression allows the pathophysiological cure of trigeminal neuralgia, having satisfactory results in the short / long term, and many advantages compared to other minimally invasive techniques. We present the case of a patient with maximum ineffective medical treatment, who underwent microvascular decompression, showing arterial and venous conflict with the nerve.

COVID-19 Requires Innovation, Regulation and Rigor: Amaylid Arteaga-García MD MS Director, National Clinical Trials Coordinating Center (CENCEC).

The effects and implications of COVID-19 are global, comprehensive and long-term. The pandemic has exposed inequities, the fragility of economic and political systems, and in many cases, skewed priorities. Population health, not to mention planetary health, is suffering as a result. Nevertheless, the global health crisis in which we are embroiled has provided opportunities for effective collaboration, scientific innovation and real dialog around health and equity. Dr Amaylid Arteaga-García, director of Cuba's National Clinical Trials Coordinating Center (CENCEC), emphasized these opportunities when discussing Cuba's clinical trials in times of COVID-19. Founded in 1991 in response to the groundbreaking research emerging from the country's biopharmaceutical sector-including the first safe, effective vaccine against serogroup B meningococcal disease, VA-MENGOC-BC in 1989 and a recombinant vaccine against hepatitis B, Heberbiovac in 1990-CENCEC now coordinates some 100 clinical trials annually, many of them multi-site trials involving thousands of volunteers. Little did Dr Arteaga García know what problems lurked when she became CENCEC director in 2019. In February 2020, Cuba implemented its National COVID-19 Prevention & Control Plan. This included a scientific Innovation Committee tasked with evaluating promising projects, products and research that might be used in the health system to control and treat COVID-19. This approach taps into two of Cuba's strengths: biotechnology and primary health care. Given the volume and complexity of COVID-19 clinical trials, Dr Arteaga.

Monoclonal Antibodies vs COVID-19: Eduardo Ojito-Magaz MS General Director, Molecular Immunology Center.

Cuba has five COVID-19 vaccines in clinical trials and is on track to receive emergency use authorization from the country's regulatory agency to begin mass vaccination with two of those candidates: Abdala and SOBERANA 02. Results from phase 1 and 2 trials of these vaccines, the first developed and produced in Latin America, have been encouraging, both in terms of safety and immunogenicity. The ongoing phase 3 trials will continue to look at safety, together with efficacy; parallel intervention studies involving over a million people in Havana will begin generating data on effectiveness. Coordination between Cuba's biotechnology sector and its public health system-particularly throughout the different levels of primary care-to control and treat COVID-19 is a cornerstone of the Cuban strategy and one that could serve as a blueprint for future pandemics. Another Cuban product, itolizumab, is showing positive results mitigating cytokine release syndrome (CRS) in COVID-19 patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Developed in collaboration with Biocon (India), itolizumab is administered under an expanded access program to treat vulnerable populations in Cuba. Marshaling complementary capacities of dozens of institutions belonging to BioCubaFarma-the country's biotech conglomerate-and developing therapies, vaccines and medical technologies together, is another cornerstone of Cuba's strategy to combat COVID-19 and improve population health. The Molecular Immunology Center (CIM) is a key player in this strategy. Founded in 1992, CIM is a powerhouse in monoclonal antibody research and production, with 6 registered products and 22 in the pipeline. Known for several novel therapeutic cancer treatments, CIM has over two decades' experience producing complex recombinant proteins in mammalian cells on an industrial scale. Once Cuba's Innovation Committee (convened in January 2020 as part of the National COVID-19 Prevention & Control Plan) determined Cuban researchers would pursue protein subunit vaccine candidates, they turned to CIM to produce the required receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, among other responsibilities. CIM's General Director, Dr Eduardo Ojito-Magaz, is a chemical engineer and holds a master's degree in biotechnology. He spoke with MEDICC Review just days before 1.7 million Havana residents began participating in the country's largest intervention study with the COVID-19 vaccines his center helped make possible.

Pituitary germinomas: a multi-institutional study analyzing patient demographics and management patterns.

PURPOSE: Intracranial germinomas are exceedingly rare tumors found in the pineal and suprasellar regions. The extremely low incidence of pituitary germinoma has resulted in a significant gap in knowledge regarding its demographics, management, and treatment outcomes. We present the largest multicenter analysis of pituitary germinomas to date, focused on analyzing demographic and management patterns. METHODS: This study utilizes the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program (2004-2016) to study patients with a primary intracranial germinoma of the pituitary gland. We analyzed demographic information and management strategies among adult and pediatric populations and conducted a 20-year overall survival analysis using Kaplan-Meier curve for a descriptive evaluation of survival outcomes between age groups and treatment groups. RESULTS: 92 patients were included in the study, consisting of 58% pediatric patients and 42% adults, with overall 60% males. 82% patients received radiation as part of the treatment, with no significant difference between pediatric and adult groups. Chemotherapy was used significantly more in pediatrics (p = 0.0002) while surgery was significantly more common in adults (p = 0.0117). The most common treatment in pediatrics was radiation + chemotherapy (47%), while the most common treatment in adults was radiation + gross total resection + chemotherapy (23%) followed by radiation + gross total resection (19%). Younger age, radiotherapy, and chemotherapy were associated with increased 20-year survival on Kaplan-Meier curves. CONCLUSIONS: There exist significant differences in the management of pediatric and adult populations with pituitary germinomas. The low incidence of these tumors makes them challenging to study, but also highlights the importance of national cancer registries in amassing sufficient patient data from which to draw evidence-based conclusions.

Gut Bacterial Families Are Associated with Body Composition and Metabolic Risk Markers in School-Aged Children in Rural Mexico.

Background: Differences in gut microbiota composition have been associated with obesity and metabolic alterations in children. The aim of this study was to analyze the abundance of the main bacterial families of the gut among children according to their body composition and metabolic markers. Methods: A cross-sectional study was conducted with 93 school-aged children (8.4 ± 1.6 years old). Anthropometric and body composition variables were measured and a blood sample was collected to determine glucose, insulin, lipid profile, C-reactive protein, leptin, and cytokines [interleukin 6, interleukin 10 (IL-10), tumor necrosis factor α (TNFα)]. DNA was extracted from stool samples and the abundance of bacterial families (Bacteroidaceae-Porphyromonadaceae-Prevotellaceae, Lactobacillaceae, Enterococcaceae, and Lachnospiraceae-Ruminococcaceae) was determined by qPCR assays. Results: Children with obesity and high waist/height ratio had lower Bacteroidaceae-Porphyromonadaceae-Prevotellaceae and higher abundance of Lactobacillaceae when compared with normal-weight children. TNFα was negatively associated and IL-10 was positively associated with Bacteroidaceae-Porphyromonadaceae-Prevotellaceae. Triglycerides showed a positive relationship with Lachnospiraceae-Ruminococcaceae whereas high-density lipoprotein-cholesterol was negatively associated with Lactobacillaceae. Conclusion: In rural Mexican school-aged children, a low abundance of Bacteroidaceae-Porphyromonadaceae-Prevotellaceae and a high abundance of Lactobacillaceae are associated with obesity and metabolic disturbances.

Magnetic Drug Targeting: A Novel Treatment for Intramedullary Spinal Cord Tumors.

Most applications of nanotechnology in cancer have focused on systemic delivery of cytotoxic drugs. Systemic delivery relies on accumulation of nanoparticles in a target tissue through enhanced permeability of leaky vasculature and retention effect of poor lymphatic drainage to increase the therapeutic index. Systemic delivery is limited, however, by toxicity and difficulty crossing natural obstructions, like the blood spine barrier. Magnetic drug targeting (MDT) is a new technique to reach tumors of the central nervous system. Here, we describe a novel therapeutic approach for high-grade intramedullary spinal cord tumors using magnetic nanoparticles (MNP). Using biocompatible compounds to form a superparamagnetic carrier and magnetism as a physical stimulus, MNP-conjugated with doxorubicin were successfully localized to a xenografted tumor in a rat model. This study demonstrates proof-of-concept that MDT may provide a novel technique for effective, concentrated delivery of chemotherapeutic agents to intramedullary spinal cord tumors without the toxicity of systemic administration.

Magnetic kyphoplasty: A novel drug delivery system for the spinal column.

Vertebral compression fractures (VCFs) caused by metastatic malignancies or osteoporosis are devastating injuries with debilitating outcomes for patients. Minimally invasive kyphoplasty is a common procedure used for symptomatic amelioration. However, it fails in treating the underlying etiologies of VCFs. Use of systemic therapy is limited due to low perfusion to the spinal column and systemic toxicity. Localized delivery of drugs to the vertebral column can provide a promising alternative approach. A porcine kyphoplasty model was developed to study the magnetically guided drug delivery of systemically injected magnetic nanoparticles (MNPs). Jamshidi cannulated pedicle needles were placed into the thoracic vertebra and, following inflatable bone tamp expansion, magnetic bone cement was injected to the vertebral body. Histological analysis was performed after intravenous injection of MNPs. Qualitative analysis of harvested tissues revealed successful placement of magnetic cement into the vertebral body. Further quantitative analysis of histological sections of several vertebral bodies demonstrated enhanced accumulation of MNPs to regions that had magnetic cement injected during kyphoplasty compared to those that did not. By modifying the kyphoplasty bone cement to include magnets, thereby providing a guidance stimulus and a localizer, we were successfully able to guide intravenously injected magnetic nanoparticles to the thoracic vertebra. These results demonstrate an in-vivo proof of concept of a novel drug delivery strategy that has the potential to treat the underlying causes of VCFs, in addition to providing symptomatic support.

Surgical Complications in Intradural Extramedullary Spinal Cord Tumors - An ACS-NSQIP Analysis of Spinal Cord Level and Malignancy.

BACKGROUND: Intradural extramedullary (IDEM) spinal cord tumors account for two-thirds of all intraspinal neoplasms. Surgery for IDEM tumors carries risks for many different complications, which to date have been poorly described and quantified. In this study, we better characterize risk factors and complications for IDEM tumors, stratifying patients by spinal cord level and malignancy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to determine 30-day outcomes following surgery for IDEM tumors between 2005 and 2016. Patients with cervical, thoracic, and lumbar tumors were compared in terms of demographics, comorbidities, and postoperative complications. A similar analysis was performed comparing patients with benign and malignant tumors. RESULTS: A total of 991 patients with IDEM tumors were identified in the cohort. The majority of tumors were thoracic (44.3%), followed by lumbar (35.4%) and cervical (20.3%). Only 6.3% of patients were readmitted within 30 days, 4.2% returned to the operating room, and 1.0% died. Significant associations were noted between spinal cord level and patient sex, age, functional status, American Society of Anesthesiologists (ASA) classification, prevalence of diabetes and hypertension, and risk of developing pneumonia. Benign and malignant tumors differed by patient sex, baseline ASA class, risk of return to the operating room, mortality, and likelihood of transfusion. CONCLUSIONS: IDEM tumors are common and carry surgical risks, with different complication profiles for tumors at different spinal levels and degrees of malignancy. With definitive risk factors and outcomes, the ACS-NSQIP cohort provides a snapshot of national neurosurgery trends and outcomes in contemporary IDEM surgery.

Preoperative steroids do not improve outcomes for intramedullary spinal tumors: a NSQIP analysis of 30-day reoperation and readmission rates.

BACKGROUND: Intramedullary spinal cord tumors (IMSCTs) account for 8-10% of all spinal cord tumors and affect patients of all ages. Although uncommon, IMSCTs carry risk of neurological morbidity and mortality, with 5-year survival rates ranging from 50% to 80%. In this study, we utilize the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to determine the effect of steroid administration on 30-day outcomes following surgery for IMSCTs. METHODS: ACS-NSQIP data for patients undergoing surgery for intramedullary tumors from 2005 to 2015 was reviewed. Patients were selected based on current procedural terminology (CPT) codes 63285 (Laminectomy, intradural, intramedullary, cervical), 63286 (Laminectomy, intradural, intramedullary, thoracic), and 63287 (Laminectomy, intradural, intramedullary, thoracolumbar). ICD-9 and ICD-10 codes were chosen based on the diagnosis of a tumor. The 30-day clinical outcome data, including reoperations and readmission rates, were collected and compared. RESULTS: A total of 259 patients were reviewed. One hundred eighty-one patients had benign intramedullary tumors and 78 had malignant intramedullary tumors. The majority of IMSCTs were at the thoracic level (n=100), followed by the cervical (n=99), and thoracolumbar (n=39) levels. Thirty-one patients were on corticosteroid therapy prior to surgery. Patients with preoperative steroid administration had no significant difference in reoperation and readmission rates. No significant differences were noted between steroid vs. non-steroid therapy for discharge destination, length of hospital stay, or other postoperative complications. CONCLUSIONS: Contrary to previous reports, corticosteroid use prior to surgery for IMSCTs does not have a significant impact on 30-day risk of readmission, reoperation, and risk of postoperative complications.

Localized targeted antiangiogenic drug delivery for glioblastoma.

Systemic delivery of antiangiogenic agents has been ineffective in improving the overall survival of patients with both primary and recurrent glioblastoma, in part due to dose-limiting toxicities. With the development of new and efficient localized delivery methods and vehicles, an otherwise lethal dose of antiangiogenic chemotherapy can be used to treat tumors while minimizing systemic side effects. Current in-vitro and in-vivo animal studies have shown promising results that encourage the pursuit towards human clinical trials for localized antiangiogenic treatment in the near future.

Specific micronutrient concentrations are associated with inflammatory cytokines in a rural population of Mexican women with a high prevalence of obesity.

It has been recognised recently that obese individuals have lower concentrations of micronutrients and this may affect the concentrations of inflammatory cytokines. A cross-sectional study was carried out to evaluate the association of specific micronutrients' status with chronic inflammation caused by obesity in 280 women (36·1 (SD 7·5) years) from seven rural communities in Mexico. Measurements of weight, height and waist circumference were made on all women and body composition was determined by dual-energy X-ray absorptiometry. Concentrations of the cytokines IL-1, TNF-α, IL-6, IL-10 and IL-12, lipid profile, and the micronutrients Zn and vitamins A, C and E were determined in fasting blood samples. Ordered logistic regression models were used to determine associations between categorised cytokine levels and micronutrients. It was found that 80% of women were overweight or obese, and had significantly higher concentrations of C-reactive protein than normal-weight women (P= 0·05). The risk of higher levels of TNF-α, IL-6, IL-10 and IL-12 was reduced significantly among women with higher Zn concentrations (OR 0·63, 95% CI 0·42, 0·96, P= 0·03; OR 0·57, 95% CI 0·39, 0·86, P= 0·025; OR 0·63, 95% CI 0·41, 0·96, P= 0·04; OR 0·62, 95% CI 0·41, 0·95, P= 0·03, respectively). Higher concentrations of vitamin A were slightly associated with reduced risks of higher levels of IL-1 and IL-12 (OR 0·97, 95% CI 0·95, 0·99, P= 0·03; OR 0·97, 95% CI 0·94, 0·99, P= 0·03, respectively); when adjusting for BMI, this association was lost. No associations were found between vitamin C or vitamin E:lipids concentrations and inflammatory cytokines. In conclusion, higher Zn concentrations are associated with reduced risks of higher concentration of inflammation markers in a population of women with a high prevalence of obesity.