Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable preclinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2 and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four TCGA subtypes: 8 classical, 8 mesenchymal, and 4 proneural; none neural. Amplification of EGFR gene was observed in 9 out of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n=5) and low (n=15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent preclinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR

Estilo de aprendizaje, herramienta para la educación en Física

En el trabajo de los investigadores de Física Educativa se incluye la búsqueda de soluciones a las problemáticas existentes en las aulas de física, entre la que destaca de manera relevante que los estudiantes logren los aprendizajes propuestos. Cada ciencia y cada área de estudio tiene su propia didáctica, razón de la existencia de disciplinas como la física educativa y la matemática educativa, solo que esta especificidad de necesidades didácticas no es privativa de un cuerpo de conocimientos determinado, sino también de los individuos, quienes poseen cada uno, un estilo propio de aprender. Si bien en cada grupo escolar hay diversidad de estilos de aprendizaje, existen casos en los que determinadas circunstancias favorecen que tal variación se reduzca y exista un estilo de aprendizaje preponderante, situación que permite el diseño de secuencias de aprendizaje específicas acordes a la pedagogía idónea para tal estilo. Conforme a estas ideas, en el presente trabajo se presentan diseños didácticos elaborados para un estilo de aprendizaje particular, establecido de un estudio realizado entre los grupos escolares de una institución educativa en particular.Finding solutions to the existing problems in the classrooms of physics, among which highlights relevant way for students to achieve the proposed learning is included in the work of researchers in Physics Education. Each object has its own teaching studio, reason for stocks educational disciplines like physics and mathematics education, only this specificity is not unique learning needs of a given body of knowledge but also of individuals who have each one, a style of learning. While there is a diversity of learning styles in each school group, there are cases in which certain favored that such variation is reduced and there is style predominant learning circumstances, a situation that allows the design of sequence-specific learning chords to the appropriate pedagogy for such style. According to these ideas, this paper designs developed for teaching a particular style of learning, established a study among school groups in a particular school are presented

Obscure gastrointestinal bleeding due to multifocal intestinal angiosarcoma

Introduction: Intestinal angiosarcomas are an extremely rare and aggressive vascular tumors, with a few cases reported in the literature. Presentation of case: A 45 years-old male arrived to our hospital with intermittent gastrointestinal bleeding presenting melena and weight loss, he has antecedent of pelvic radiotherapy ten years before admission for an unknown pelvic tumor. Emergency surgery was required because of uncontrolled bleeding and hemodynamic instability. Histopathological findings revealed a multifocal high-grade epithelioid angiosarcoma, with cells reactive for CD31, keratins CKAE 1/AE3 and factor VIII. Discussion: Angiosarcomas are aggressive tumors with a high rate of lymph node metastasis and peripheral organs. The diagnosis is difficult because it present nonspecific clinical presentation, radiological and histopathological findings. There are few reports of angiosarcoma involving the small intestine and the most common presentation are abdominal pain and gastrointestinal bleeding. There is not enough information for intestinal angiosarcoma secondary to radiation therapy, but there have been proposed criteria for diagnosis: no microscopic or clinical evidence of antecedent malignant lesion, angiosarcoma presented in the field of irradiation, long latency period between radiation and angiosarcoma and histological confirmation. We suspect our patient course with a secondary form of angiosarcoma. Therapy for bleeding angiosarcoma consists in control of bleeding and medical management to stabilize the patient. Once accomplished surgical resection is required. Conclusion: We should keep in mind this tumors as a cause of obscure intestinal bleeding in patients with medical history of radiation therapy

SUMOylation in glioblastoma : a novel therapeutic target

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm

SUMOylation in Glioblastoma: A Novel Therapeutic Target

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm

Artificial intelligence in the management of glioma: Era of personalized medicine

Purpose: Artificial intelligence (AI) has accelerated novel discoveries across multiple disciplines including medicine. Clinical medicine suffers from a lack of AI-based applications, potentially due to lack of awareness of AI methodology. Future collaboration between computer scientists and clinicians is critical to maximize the benefits of transformative technology in this field for patients. To illustrate, we describe AI-based advances in the diagnosis and management of gliomas, the most common primary central nervous system (CNS) malignancy. Methods: Presented is a succinct description of foundational concepts of AI approaches and their relevance to clinical medicine, geared toward clinicians without computer science backgrounds. We also review novel AI approaches in the diagnosis and management of glioma. Results: Novel AI approaches in gliomas have been developed to predict the grading and genomics from imaging, automate the diagnosis from histopathology, and provide insight into prognosis. Conclusion: Novel AI approaches offer acceptable performance in gliomas. Further investigation is necessary to improve the methodology and determine the full clinical utility of these novel approaches

Black holes and neutron stars in vector Galileons

The direct detection of gravitational waves opens new perspectives for measuring properties of gravitationally bound compact objects. It is then important to investigate black holes and neutron stars in alternative theories of gravity, since they can have features that make them observationally distinguishable from their General Relativity (GR) counterparts. In this work, we examine a special case of vector Galileons, a vector-tensor theory of gravity with interesting cosmological properties, which consists of a one parameter modification of the Einstein-Maxwell action. Within this theory, we study configurations describing asymptotically flat, spherically symmetric black holes and neutron stars. The set of black hole solutions in this theory is surprisingly rich, generalising results found in GR or in related scalar-tensor theories. We investigate the properties and conserved charges of black holes, using both analytical and numerical techniques, highlighting configurations that are more compact than in GR. We then study properties of neutron stars, showing how the vector profile can influence the star internal structure. Depending on properties of matter and fields inside the star, neutron stars can be more massive than in GR, and they can be even more compact than Schwarzschild black holes, making these objects observationally interesting. We also comment on possible extensions of our configurations to magnetically charged or rotating configurations.Comment: 16 pages plus appendices, 9 figure

Treatment of pediatric high‐grade central nervous system tumors with high‐dose methotrexate in combination with multiagent chemotherapy: A single‐institution experience

BackgroundEffective treatment for pediatric embryonal brain tumors includes dose-intensive multiagent chemotherapy (DIMAC) followed by high-dose chemotherapy with stem cell rescue (HDCSCR). Use of repeated cycles of DIMAC including high-dose methotrexate (HDMTX) without HDCSCR has not been described.ProcedureWe retrospectively reviewed the responses/toxicities in 13 patients (aged 2-155 months, median 22 months) with central nervous system (CNS) tumors (atypical teratoid rhabdoid tumors, CNS embryonal tumors not otherwise specified, pineoblastoma, embryonal tumor with multilayered rosettes, and CNS sarcoma) treated over a 12-year period with repeated cycles of HDMTX followed by etoposide, cisplatin, cyclophosphamide, and vincristine.ResultsSix patients (46.2%) had disseminated disease at presentation and five (38.5%) had gross total resection. A total of 64 courses of therapy were administered with a median of five courses per patient.  Eight patients (61.5%) received radiation therapy (one at relapse). By completion of therapy, 11 patients (84.6%) achieved a response (six complete, five partial).  Six of the 13 patients (46.2%) remain alive with a median follow-up of 48 months (6-146).  Acute toxicities included fever/neutropenia (70.3%), bacteremia (15.6%), and grade 3 mucositis (18.8%).  Long-term complications included learning disability, seizure disorder, and brain necrosis, without treatment-related deaths.ConclusionsDIMAC with HDMTX without HDCSCR may be an effective treatment option for selected patients with embryonal or high-grade CNS tumors