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1.
Sci Rep ; 11(1): 16866, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654856

RESUMO

Prognosis of patients with HER2+ breast-to-brain-metastasis (BBM) is dismal even after current standard-of-care treatments, including surgical resection, whole-brain radiation, and systemic chemotherapy. Radiation and systemic chemotherapies can also induce cytotoxicity, leading to significant side effects. Studies indicate that donor-derived platelets can serve as immune-compatible drug carriers that interact with and deliver drugs to cancer cells with fewer side effects, making them a promising therapeutic option with enhanced antitumor activity. Moreover, human induced pluripotent stem cells (hiPSCs) provide a potentially renewable source of clinical-grade transfusable platelets that can be drug-loaded to complement the supply of donor-derived platelets. Here, we describe methods for ex vivo generation of megakaryocytes (MKs) and functional platelets from hiPSCs (hiPSC-platelets) in a scalable fashion. We then loaded hiPSC-platelets with lapatinib and infused them into BBM tumor-bearing NOD/SCID mouse models. Such treatment significantly increased intracellular lapatinib accumulation in BBMs in vivo, potentially via tumor cell-induced activation/aggregation. Lapatinib-loaded hiPSC-platelets exhibited normal morphology and function and released lapatinib pH-dependently. Importantly, lapatinib delivery to BBM cells via hiPSC-platelets inhibited tumor growth and prolonged survival of tumor-bearing mice. Overall, use of lapatinib-loaded hiPSC-platelets effectively reduced adverse effects of free lapatinib and enhanced its therapeutic efficacy, suggesting that they represent a novel means to deliver chemotherapeutic drugs as treatment for BBM.

2.
Surg Neurol Int ; 12: 425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513188

RESUMO

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.

3.
Childs Nerv Syst ; 37(10): 3083-3087, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34427745

RESUMO

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.


Assuntos
COVID-19 , Neurocirurgia , Humanos , Neurocirurgiões , Nicarágua , SARS-CoV-2
4.
Cancer Res ; 81(18): 4723-4735, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34247146

RESUMO

Leptomeningeal carcinomatosis (LC) occurs when tumor cells spread to the cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord. LC is an ominous complication of cancer with a dire prognosis. Although any malignancy can spread to the leptomeninges, breast cancer, particularly the HER2+ subtype, is its most common origin. HER2+ breast LC (HER2+ LC) remains incurable, with few treatment options, and the molecular mechanisms underlying proliferation of HER2+ breast cancer cells in the acellular, protein, and cytokine-poor leptomeningeal environment remain elusive. Therefore, we sought to characterize signaling pathways that drive HER2+ LC development as well as those that restrict its growth to leptomeninges. Primary HER2+ LC patient-derived ("Lepto") cell lines in coculture with various central nervous system (CNS) cell types revealed that oligodendrocyte progenitor cells (OPC), the largest population of dividing cells in the CNS, inhibited HER2+ LC growth in vitro and in vivo, thereby limiting the spread of HER2+ LC beyond the leptomeninges. Cytokine array-based analyses identified Lepto cell-secreted GMCSF as an oncogenic autocrine driver of HER2+ LC growth. LC/MS-MS-based analyses revealed that the OPC-derived protein TPP1 proteolytically degrades GMCSF, decreasing GMCSF signaling and leading to suppression of HER2+ LC growth and limiting its spread. Finally, intrathecal delivery of neutralizing anti-GMCSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) synergistically inhibited GMCSF and suppressed activity of GMCSF effectors, reducing HER2+ LC growth in vivo. Thus, OPC suppress GMCSF-driven growth of HER2+ LC in the leptomeningeal environment, providing a potential targetable axis. SIGNIFICANCE: This study characterizes molecular mechanisms that drive HER2+ leptomeningeal carcinomatosis and demonstrates the efficacy of anti-GMCSF antibodies and pan-Aurora kinase inhibitors against this disease.

5.
Cancer Res ; 81(12): 3200-3214, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33941612

RESUMO

HER2+ breast leptomeningeal carcinomatosis (HER2+ LC) occurs when tumor cells spread to cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2+ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2+ LC tumors might efficiently target HER2+ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2+ LC (Lepto) cell lines from nodular HER2+ LC tissues. These lines are phenotypically CD326+CD49f-, confirming that they are derived from HER2+ LC tumors, and express surface CD44+CD24-, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2+ breast cancer lines in vitro and in vivo. Interestingly, the three Lepto lines overexpressed Jumonji domain-containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion in vitro. JIB04 treatment of patient-derived xenograft mouse models in vivo reduced HER2+ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2+ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. SIGNIFICANCE: HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models.

6.
Neuroimaging Clin N Am ; 31(1): 93-102, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33220831

RESUMO

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms.


Assuntos
Mapeamento Encefálico/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Cuidados Pré-Operatórios/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Neoplasias Encefálicas/cirurgia , Humanos
7.
Clin Exp Metastasis ; 37(3): 401-412, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32279122

RESUMO

The brain is often reported as the first site of recurrence among breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Although most HER2+tumors metastasize to the subcortical region of the brain, a subset develops in the cortical region. We hypothesize that factors in cerebrospinal fluid (CSF) play a critical role in the adaptation, proliferation, and establishment of cortical metastases. We established novel cell lines using patient biopsies to model breast cancer cortical and subcortical metastases. We assessed the localization and growth of these cells in vivo and proliferation and apoptosis in vitro under various conditions. Proteomic analysis of human CSF identified astrocyte-derived factors that support the proliferation of cortical metastases, and we used neutralizing antibodies to test the effects of inhibiting these factors both in vivo and in vitro. The cortical breast cancer brain metastatic cells exhibited greater proliferation than subcortical breast cancer brain metastatic cells in CSF containing several growth factors that nourish both the CNS and tumor cells. Specifically, the astrocytic paracrine factors IGFBP2 and CHI3LI promoted the proliferation of cortical metastatic cells and the formation of metastatic lesions. Disruption of these factors suppressed astrocyte-tumor cell interactions in vitro and the growth of cortical tumors in vivo. Our findings suggest that inhibition of IGFBP2 and CHI3LI signaling, in addition to existing treatment modalities, may be an effective therapeutic strategy targeting breast cancer cortical metastasis.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Líquido Cefalorraquidiano/citologia , Proteína 1 Semelhante à Quitinase-3/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/líquido cefalorraquidiano , Proliferação de Células/efeitos dos fármacos , Córtex Cerebral/patologia , Proteína 1 Semelhante à Quitinase-3/antagonistas & inibidores , Técnicas de Cocultura , Feminino , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/antagonistas & inibidores , Camundongos , Comunicação Parácrina , Cultura Primária de Células , Proteômica , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Radiol Clin North Am ; 57(6): 1189-1198, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582044

RESUMO

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Cuidados Pré-Operatórios/métodos , Encéfalo/diagnóstico por imagem , Humanos
9.
Cell Rep ; 28(8): 2064-2079.e11, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31433983

RESUMO

Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.


Assuntos
Neoplasias Encefálicas/patologia , Diferenciação Celular , Glioblastoma/patologia , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Neurônios/patologia , Fatores de Transcrição SOX9/metabolismo , Animais , Astrocitoma/genética , Astrocitoma/patologia , Benzamidas/farmacologia , Neoplasias Encefálicas/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Progressão da Doença , Feminino , Glioblastoma/genética , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Tolerância a Radiação/efeitos dos fármacos
10.
Neurosurgery ; 85(2): E198-E199, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304543
11.
Neurosurgery ; 84(3): E150-E151, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767019
12.
Neurosurgery ; 84(1): E19-E20, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407586
13.
Neurosurgery ; 83(3): E110-E111, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30125032
14.
Neurosurgery ; 83(1): E8-E9, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917135
17.
Int J Mol Sci ; 19(2)2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29385725

RESUMO

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.


Assuntos
Neoplasias Encefálicas , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma , Lactoilglutationa Liase , Proteínas de Neoplasias , Receptor para Produtos Finais de Glicação Avançada/biossíntese , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Xenoenxertos , Humanos , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Surg Neurol Int ; 9: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29416906

RESUMO

Journey to Mars will be a large milestone for all humankind. Throughout history, we have learned lessons about the health dangers associated with exploratory voyages to expand our frontiers. Travelling through deep space, the final frontier, is planned for the 2030s by NASA. The lessons learned from the adverse health effects of space exposure have been encountered from previous, less-lengthy missions. Prolonged multiyear deep space travel to Mars could be encumbered by significant adverse health effects, which could critically affect the safety of the mission and its voyagers. In this review, we discuss the health effects of the central nervous system by space exposure. The negative effects from space radiation and microgravity have been detailed. Future aims and recommendations for the safety of the voyagers have been discussed. With proper planning and anticipation, the mission to Mars can be done safely and securely.

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