Identifying the cellular origins of gliomas has been elusive, partly due to the lack of models in which the neurodevelopmental biology of brain tumors can be investigated. Using molecular and genetic tools a transgenic mouse model that develops high grade gliomas was studied. We hypothesized that the neurogenic subventricular zone to be the brain region from which the glioma cell of origin would arise. This area was characterized and labeled with a oligonucleotide library that allows for lineage tracing of gliomas once formed. Gliomas were comprised of heterogeneous clones, with the consistent presence of a dominant overrepresented clone. In animals with gliomas, neurogenesis is altered with loss of neuronal committed progenitor markers. This process is partly mediated by map kinases, and their inhibition leads to increased neuronal differentiation in vitro of transgenic mouse neurospheres and human glioma cells

Background

While several medical outreach models have been designed and executed to alleviate the unmet need for international neurosurgical care, disparate strategies have evolved. There is a need to determine the optimal pediatric neurosurgical outreach model through which resources are efficiently utilized while imparting the largest possible impact on global health. This study evaluates the efficacy of an international pediatric neurosurgery outreach model at transferring operative skill in a sustainable and scalable manner in Lima, Peru over a 15-year duration.

Methods

Three 1-week neurosurgical missions were carried out (2004-2006) in Lima, Peru to teach neuroendoscopic techniques and to provide equipment to host neurosurgeons, equipping the hosts to provide care to indigent citizens beyond the duration of the missions. Follow-up data were obtained over a 15 year span, with collaboration maintained over email, two in-person visits, and video-conferencing services.

Results

Since the outreach missions in 2004-2006, the host neurosurgeons demonstrated sustainability of the neuroendoscopic instruction by independently performing neuroendoscopic operations on a growing caseload: at baseline, 0 cases were performed in 2003, but since 2012 and onwards, 40-45 cases have been performed annually. Scalability is illustrated by the fact that the institution established a rigorous neuroendoscopy training program to independently pass on the techniques to resident physicians.

Conclusion

The described international pediatric neurosurgical outreach model, centered around teaching operative technique as opposed to solely providing care to citizens, allowed operative skill to be sustainably transferred to surgeons in Lima, Peru. Having served the neuroendoscopic needs of hundreds of citizens, the strategic design is replicable and should be mirrored by future medical endeavors seeking to substantially impact the deficit in global surgical care.

With respect to the tremendous deficit in surgical care plaguing developing nations, it is critical that medical outreach models be organized in such a fashion that sustainable advancements can be durably imparted beyond the duration of targeted missions. Using a didactic framework focused on empowering host neurosurgeons with an enhanced surgical skillset, a mission was launched in Managua, Nicaragua, after previous success in Kiev, Ukraine, and Lima, Peru. Unfortunately, the failure to critically assess the internal and external state of affairs of the region's medical center compromised the outreach mission. Herein lies the visiting team's lessons from failure and insights on facilitating effective communication with host institutions, circumventing geopolitical instability, and utilizing digital collaboration and video-conferencing tools in the post-COVID-19 era to advance the surgical care of developing regions in a fashion that can be generationally felt.

The biology of both normal and tumor development clearly possesses overlapping and parallel features. Oncogenes and tumor suppressors are relevant not only in tumor biology, but also in physiological developmental regulators of growth and differentiation. Conversely, genes identified as regulators of developmental biology are relevant to tumor biology. This is particularly relevant in the context of brain tumors, where recent evidence is mounting that the origin of brain tumors, specifically gliomas, may represent dysfunctional developmental neurobiology. Neural stem cells are increasingly being investigated as the cell type that originally undergoes malignant transformation - the cell of origin - and the evidence for this is discussed.

A myriad of geopolitical and financial obstacles have kept modern neurosurgery from effectively reaching the citizens of the developing world. Targeted neurosurgical outreach by academic neurosurgeons to equip neurosurgical operating theaters and train local neurosurgeons is one method to efficiently and cost effectively improve sustainable care provided by international charity hospitals. The International Neurosurgical Children’s Association (INCA) effectively improved the available neurosurgical care in the Maria Auxiliadora Hospital of Lima, Peru through the advancement of local specialist education and training. Neurosurgical equipment and training were provided for the local neurosurgeons by a mission team from the University of California at San Diego. At the end of 3 years, with one intensive week trip per year, the host neurosurgeons were proficiently and independently applying microsurgical techniques to previously performed operations, and performing newly learned operations such as neuroendoscopy and minimally invasive neurosurgery. Our experiences may serve as a successful template for the execution of other small scale, sustainable neurosurgery missions worldwide.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.