tbuckley/cabot-search huggingface dataset:
CSIG-23. CIC PROTEIN INSTABILITY DRIVES CANCER PHENOTYPES IN GLIOBLASTOMA
Authors: Severa Bunda, Pardeep Heir, Julie Metcalf, Stefan Pusch, Gelareh Zadeh, Kenneth Aldape
Journal: Neuro-Oncology (2017)

The aggressive nature of glioblastoma (GBM) has been attributed to hyperactivation of receptor tyrosine kinases (RTK) and their downstream signaling pathways including Ras/ERK. Pharmacological agents directed against membrane bound RTKs and cytoplasmic kinases within the Ras/ERK signaling pathway have shown promise pre-clinically, but success is yet to be realized in clinical trials. Because cancer is a disease associated with aberrant gene expression patterns, transcription factors that serve as the convergence points of oncogenic signaling hold great therapeutic promise. However, this has not yet been explored in the context of Ras/ERK signaling in GBM. The HMG-box transcriptional repressor, capicua (CIC), has recently emerged as a conserved nuclear sensor of RTK signaling in Drosophila and mammals. CIC represses EGFR/Ras/ERK pathway-responsive genes, keeping them silent in the absence of signaling. Despite the clear genetic evidence and its connection to one of the most important pathways in cancer, molecular mechanisms governing CIC regulation and its involvement in cancer remain poorly characterized. In GBM, unlike in oligodendroglioma (OD), CIC is not mutated. Surprisingly, we find substantial downregulation of wild type CIC protein despite intact mRNA expression in human GBM tumor samples. Here, we identify the nuclear E3-ubiquitin ligase responsible for the degradation of CIC in response to EGFR/Ras/ERK signaling. Interestingly, common disease-causing CIC variants fail to be ubiquitylated in response to Ras/ERK activation. Creation of a degradation-resistant form of CIC, unresponsive to upstream Ras/ERK signaling, reduced tumor growth and sensitized GBM cells to the effects of Ras/ERK inhibition. Our mechanistic insights into regulation of CIC provides rationale for alternative therapeutic strategies aimed at stabilizing CIC and activating its repressor function in GBM and other Ras/ERK-driven tumors.
P3.02-063 EGFR Exon 20 Insertions in Lung Adenocarcinomas: Molecular and Clinicopathologic Characteristics Among Hispanics (Geno1.2-CLICaP)
Authors: A. Cardona, O. Arrieta, G. Oblitas, L. Rojas, Z. Zatarain-Barron, L. Corrales, C. Martin, J. Rodriguez, P. Archila, A. Ruiz-Patiño, M.A. Pérez, L. González, L. Chirinos, H. Carranza, C. Vargas, R. Rosell
Journal: Journal of Thoracic Oncology (2017)
Editorial: The Innate and Adaptive Immune Response Are Both Involved in Drug‐Induced Autoimmunity
Authors: Amr H. Sawalha
Journal: Arthritis & Rheumatology (2017)

Drug-induced autoimmunity is an intriguing phenomenon that has been described in the medical literature at least since 1945, with a report from the Medical Corps of the Army of the United States describing a case of systemic lupus erythematosus induced by sulfadiazine (1). While an autoantibody response in drug-induced autoimmunity is more universal, the spectrum of clinical autoimmunity is variable and likely influenced by host genetics including genetic variants predisposing to autoimmunity and genetic variants affecting drug metabolism. Indeed, a large proportion of patients who take procainamide or hydralazine develop autoantibodies, but a smaller fraction develops clinical drug-induced autoimmunity, usually characterized by skin involvement, arthritis, serositis, and constitutional symptoms. In some patients, however, a chronic or severe autoimmune disease can develop.

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NIMG-56. CHARACTERISTIC RESPONSE PATTERNS IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA AFTER TREATMENT WITH HIGH SINGLE DOSES OF RADIOTHERAPY
Authors: Alex Förster, Melissa Winkler, Stefanie Brehmer, Marcel Seiz-Rosenhagen, Daniel Hänggi, Frederik Wenz, Christoph Groden, Frank Anton Giordano
Journal: Neuro-Oncology (2017)

Healthy brain tissue responses to radiotherapy (pseudoprogression/radiation necrosis) may bias MRI-based tumor response evaluations. To understand these changes specifically after high doses of radiotherapy, we analyzed MRIs of patients of the INTRAGO study, a phase I/II dose-escalation trial on intraoperative radiotherapy in glioblastoma. Patients enrolled in INTRAGO (NCT02104882) received an intraoperative boost of 20-40 Gy followed by standard adjuvant radiochemotherapy and maintenance chemotherapy. In the present analyses, only patients who received per-protocol therapy and those, who underwent standardized serial MRI follow-ups including DSC-PWI, were included and assessed with special focus on perilesional enhancement pattern, volume, and mean rCBV. Mean leakage-corrected rCBV within enhancing lesions was computed for all MRI follow-ups. Overall, 12/15 (80%) patients (median age 60.5 [range 46-73] years) were included in the analysis. Distant failure was the predominant failure pattern (7/12 [58.3%]) leading to salvage therapy after a median follow-up of 372.5 days (range: 72-991 days), while local tumor recurrence was observed in one case (8.3%). On the first follow-up MRI all patients demonstrated perilesional enhancement of varying extent: in 3/12 (25%) patients thin linear, in 1 (8.3%) nodular, in 7 (58.3%) combined linear and nodular, and in 1 (8.3%) voluminous, indistinct, mesh-like. In the course, most patients developed the latter two patterns (8/11 [72.2%]). Three different patterns of enhancing lesion volume were observed: in 3/10 (30%) an early (<200 days) continuous decrease, in 2/10 (20%) a marked early increase, and in 5 (50%) a marked late (≥200 days) increase. The overall linear trend in rCBV was negative in most patients (8/11 (72.2%)). High doses to the tumor cavity result in characteristic perilesional enhancement patterns. These results will be useful for the response evaluation of patients exposed to high doses of radiotherapy in future studies, such as the multicenter randomized INTRAGO II trial (NCT02685605).
Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial
Authors: Philip Noel Newsome, Richard Fox, Andrew L King, Darren Barton, Nwe-Ni Than, Joanna Moore, Christopher Corbett, Sarah Townsend, James Thomas, Kathy Guo, Diana Hull, Heather A Beard, Jacqui Thompson, Anne Atkinson, Carol Bienek, Neil McGowan, Neil Guha, John Campbell, Dan Hollyman, Deborah Stocken, Christina Yap, Stuart John Forbes
Journal: The Lancet. Gastroenterology & hepatology (2017)

Results of small-scale studies have suggested that stem-cell therapy is safe and effective in patients with liver cirrhosis, but no adequately powered randomised controlled trials have been done. We assessed the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) and haemopoietic stem-cell infusions in patients with liver cirrhosis.
IMMU-03. THERAPEUTIC TARGETING OF TUMORIGENIC EphA2+/EphA3+ BRAIN TUMOR INITIATING CELLS WITH BISPECIFIC ANTIBODY IN HUMAN GLIOBLASTOMA
Authors: Maleeha Qazi, Parvez Vora, Chitra Venugopal, Maryna Gorelik, Mohini Singh, Amy Hu, Minomi Subapanditha, Chirayu Chokshi, Neil Savage, Nicholas Yelle, Jarrett Adams, Jason Moffat, Sachdev Sidhu, Sheila Singh
Journal: Neuro-Oncology (2017)

Human glioblastoma (hGBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many of the 14 members of the Eph receptor tyrosine kinase family are expressed in hGBM initiating cells (GICs) and constitute potential molecular targets. We hypothesize that multiple members of the EphR family play a critical role in hGBM recurrence. Using a highly specific human EphR antibody panel, we identified differential expression of EphRs in recurrent hGBM (rGBM). We further characterized EphR co-expression along with multiple GIC markers using mass cytometry (CyTOF). Here we show that EphA2 and EphA3 co-expression marks a highly tumorigenic cell population in rGBM that is enriched in GIC marker expression, and exhibits higher in vitro and in vivo self-renewal and proliferation capacity as compared to EphA2+/EphA3-, EphA2-/EphA3+ or EphA2-/EphA3- cells. Knockdown of EphA2 and EphA3 blocks this self-renewal and proliferation capacity, and is marked by increase in the expression of differentiation marker GFAP. Next, we generated and tested a bispecific antibody (BsAb) that co-targets EphA2 and EphA3. In vitro treatment of rGBM with BsAb led to phosphorylation of EphA2 and EphA3, eventually leading to receptor internalization and degradation. The cellular effect of EphA2/A3 blockade was mediated through the down regulation of Akt and MAPK. Intracranial treatment of immune-deficient mice harboring hGBM with BsAb resulted in non-invasive and significantly smaller tumors. Hence, EphA2 and EphA3 co-expression marks an even more potent GIC population in rGBM, and targeting either single EphA2+ or EphA3+ populations alone will allow the remaining GICs to drive tumor recurrence. For the first time, we show that strategic co-targeting of both EphA2 and EphA3 with a BsAb presents a novel and rational therapeutic approach to recurrent GBM, where multiple GIC populations may be driving the intra-tumoral heterogeneity underlying disease progression.
Manejo actual de los pacientes afectados por fiebres hemorrágicas víricas en el Reino Unido
Authors: N Crowcroft, D W Brown, R Gopal
Journal: Eurosurveillance (2002)

Actualmente, los casos sospechosos y confirmados de fiebre hemorragica virica en el Reino Unido se manejan segun las recomendaciones publicadas en 1996 por el Comite Asesor en Materia de Patogenos Peligrosos (Advisory Committee on Dangerous Pathogens) que describen el enfoque a adoptar para evaluar el riesgo de los casos sospechosos. Tambien ofrecen pautas para el manejo de pacientes que incluyen el traslado, las investigaciones en laboratorio, el control de infecciones y la vigilancia de contactos en funcion de la evaluacion del riesgo. Los casos confirmados se manejan en camaras de aislamiento (unidades Trexler), dos de las cuales se encuentran en unidades de enfermedades infecciosas de alta seguridad del Reino Unido. Estas pautas estan siendo analizadas y es posible que cambien. La experiencia reciente ha demostrado que la tarea de comunicar y tranquilizar a los trabajadores sanitarios y al publico, son dos de los grandes cometidos en el manejo de estos casos.
PATH-19. HISTOPATHOLOGIC RESPONSE CRITERIA FOLLOWING TREATMENT OF GLIOBLASTOMA (GBM)
Authors: Andrew Lassman, George Zanazzi, Jeffrey Bruce, Zachary Englander, Stephen Bowden, Jack Grinband, Peter Chang, Angela Lignelli, Peter Canoll
Journal: Neuro-Oncology (2017)

The Response Assessment in Neuro-Oncology (RANO) Working Group published guidelines for interpretation of brain MRI scans in patients with GBM after initial or subsequent therapy (Wen PY et al 2010, PMID 20231676). To address the potential for misclassifying pseudoprogression as true disease progression, the RANO criteria define progressive disease within 12 weeks after radiotherapy as identifiable only if there is “unequivocal evidence of viable tumor on histopathologic sampling.” However, “unequivocal” is undefined, and the nomenclature used by neuro-pathologists is not uniform. The distinction is importantly clinically because clear recurrence indicates the prior therapy is no longer controlling the disease and should be changed, and the patient should be eligible for a recurrent GBM trial; by contrast, treatment effect without evidence of residual or recurrent tumor suggests the prior therapy should be continued. Two neuropathologists (PC, GZ) reviewed 131 radiographically localized samples of clinically suspected recurrence from 48 patients with GBM. Based on histopathological criteria, each biopsy was classified into one of 4 categories; 1) all treatment effect; 2) treatment effect with residual tumor, but no evidence of proliferating tumor; 3) recurrent proliferating tumor with prominent treatment effect; or 4) recurrent tumor. Total cell density was calculated using digital pathology and an automated cell-counting algorithm. There were 12, 58, 40, 21 samples scored 1-4, respectively. Cellularity correlated with score, but overlapped across the categories except for the extremes (1 vs. 4). Correlation with survival will be presented. Clear criteria are needed to define histopathologic findings after treatment of GBM in order to guide subsequent therapy. Treatment effect may be best interpreted as a response and proliferating recurrence as progressive disease, regardless of imaging. Imaged-based computer learning may model heterogeneity of areas not analyzed histologically.
SURG-31. INCIDENTAL LOW GRADE GLIOMAS: “WAIT AND SEE” OR “SURGERY”
Authors: Jaejoon Lim, Youngjoon Park, Min Jun Kim, Juwon Ahn, Kyung gi Cho
Journal: Neuro-Oncology (2017)

Incidental low grade gliomas (ILGGs) of adults have a more variable biologicaql behavior for which the value of treatment and the timing of treatment are of less clear-cut value than for their malignant gliomas. A series of retrospective reviews provides conflicting and inconclusive results about the role of observation, stereotactic biopsy, aggressive surgery, and radiation for treating these tumors, and there exists significant variability on the therapeutic approach on the part of clinicians and in the clinical course of the disease in individual patients. Between Oct 2010 and Feb 2017, 295 patients underwent intracranial glioma surgery in Bundang CHA Medical Center. Among them, 21 ILGGs surgery was done. Clinical, radiological and treatment data of the patients were collected and ILGGs were retrieved. Twenty one ILGGs (35.6%) were identified while 38 patients had symptomatic LGGs. The reasons for patients with IDLGGs having radiological examination included headache (47.6%), health check-up (23.8%), dizziness (19%) and trauma (9%). Clinically, patients with ILGGs had higher preoperative KPS, smaller tumor volume, lower frequency of eloquent areas involvement, longer survival and higher rate of complete resection comparing to those with symptomatic LGGs. Among “wait and see” treatment policy patient, 6 patient’s tissue diagnosis were confirmed to high grade transformation. A critical reason for positive effect of resection on outcome resides in the impact it makes on reducing the risk of malignant transformation. Another reason to not wait and observe the lesion is the inability of any imaging modality to confirm without adequate tissue sampling that the glioma is low-grade, LGGs may have anaplastic components. Although a “wait and see” attitude has been advocated by some authors with respect to ILGGs, our case demonstrates that transformation to high grade glioma may occur. Therefore, we propose consideration of earlier resection in ILGGs.
OA 15.08 Thoroughness of Staging and the Outcomes of Surgical Resection Outcomes in Potentially Curable Non-Small Cell Lung Cancer (NSCLC)
Authors: M. Smeltzer, Y. Lee, N. Faris, M. Ray, C. Fehnel, C. Houston-Harris, P. Ojeabulu, O. Akinbobola, L. Deese, E. Owen, B. Wolf, H. Wiggins, C. Mutrie, V. Sachdev, P. Levy, R. Signore, E. Robbins, R. Osarogiagbon
Journal: Journal of Thoracic Oncology (2017)
PATH-33. MARKERS AND MECHANISMS OF DISEASE PROGRESSION IN IDH-MUTANT ASTROCYTOMAS
Authors: Sameer H Halani, Safoora Yousefi, Jose Enrique Velazquez Vega, Amelia Baxter-Stoltzfus, Jeffrey J Olson, Lee Cooper, Daniel Brat
Journal: Neuro-Oncology (2017)

IDH-mutant astrocytomas are a subset of diffuse gliomas with unpredictable clinical course. To explain variability and stratify risk, we leveraged genomic data from The Cancer Genome Atlas (TCGA) and utilized machine-learning approaches to model clinical outcomes. We also examined radiographic and pathologic features to uncover molecular markers of advanced disease. Cases of IDH-mutant astrocytomas were selected from TCGA (n=250). Machine-learning and Bayesian optimization were used to identify molecular features most associated with clinical outcomes. Pre-operative MRs were reviewed for unequivocal contrast-enhancement (CE+). Cell density was quantified from digital histopathological slides. MKI67 expression was used as a marker of tumor proliferation. Total somatic mutations per tumor were summed as a measure of genetic instability. Log-rank tests and Cox models assessed survival differences. Our machine-learning algorithm ranked molecular alterations associated with clinical outcomes and determined increased mortality risk was strongly associated with increased CDKN1A protein expression and copy number gain (ranked #2 and #3, respectively), as well as increased YAP1 protein expression (#8). CE- tumors (n=41) outnumbered CE+ (n=33); there was no significant survival difference (P=0.39). Increased cellular density did not predict survival (P=0.82), nor did histologic grade (P=0.13). Increased MKI67 expression was associated with poor survival (high=63.5 vs. low=87.4 months, P=0.012). Increased genetic instability (tumors with higher mutational burden) was associated with poor clinical outcomes (Median OS: high = 63.0 months vs. low = 105.2 months, P=0.006). Multivariable Cox modeling (controlling for age and WHO grade) showed more proliferative tumors (HR 1.93, 95%CI 1.04-3.55) and tumors with greater genetic instability (HR 2.20, 95%CI 1.11-4.30) had shorter survivals. This investigation demonstrates the strength of machine learning in uncovering biomarkers of progression and clinical outcome that could potentially be used to stratify risk for IDH-mutant astrocytomas. Proliferation index and mutational burden were uncovered as factors associated with poor survival.
Immunohistochemical expression of vitamin D receptor in melanocytic naevi and cutaneous melanoma: a case-control study
Authors: C. del Puerto, C. Navarrete-Dechent, M. Molgó, C.A. Camargo, A. Borzutzky, S. González
Journal: British Journal of Dermatology (2017)

Vitamin D deficiency is associated with higher risk of cancer, possibly due to its antiproliferative, antiangiogenic, proapoptotic, cell-differentiating and anti-invasive effects. The anticarcinogenic role of vitamin D in melanoma is still a matter of debate. Loss of nuclear and cytoplasmic vitamin D receptor (VDR) expression in melanoma cells has been reported.To analyse VDR immunohistochemical expression in benign dermal naevi (DN) and malignant melanoma (MM).A case-control study evaluated nuclear and cytoplasmic VDR immunohistochemical staining in 54 DN and 55 MM tissue samples.There was significantly higher cytoplasmic VDR positivity in DN compared with MM (59% vs. 16%, P < 0·001). The mean VDR cytoplasmic expression was also higher in DN vs. MM (P < 0·001). No differences in nuclear VDR positivity were observed between groups, but mean nuclear VDR expression was significantly lower in DN vs. MM (P = 0·02). The loss of cytoplasmic VDR in MM was associated with Clark level, tumour staging and American Joint Committee on Cancer pTNM staging (P=0·004, 0·009 and 0·02, respectively).Alterations in VDR expression and localization are found in MM compared with DN. Loss of cytoplasmic VDR was associated with melanoma tumour size, suggesting that loss of cytoplasmic VDR may be a prognostic factor.
Open the gates: vascular neurocrine signaling mobilizes hematopoietic stem and progenitor cells
Authors: Tomer Itkin, Jesús María Gómez-Salinero, Shahin Rafii
Journal: Journal of Clinical Investigation (2017)

Mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) into the peripheral blood is a complex process that is enhanced dramatically under stress-induced conditions. A better understanding of how the mobilization process is regulated will likely facilitate the development of improved clinical protocols for stem cell harvesting and transplantation. In this issue of the JCI, Singh et al. (1) showed that the truncated cleaved form of neurotransmitter neuropeptide Y (NPY) actively promotes a breach of BM vascular sinusoidal portals, thereby augmenting HSPC trafficking to the circulation. The authors report a previously unrecognized axis, in which expression of the enzyme dipeptidylpeptidase-4 (DPP4)/CD26 by endothelial cells activates NPY-mediated signaling by increasing the bioavailability of the truncated form of NPY. These findings underscore the importance of and urgency to develop pharmacological therapies that target the vasculature and regulate diverse aspects of hematopoiesis, such as HSPC trafficking, in steady-state and stress-induced conditions.
Role of inflammation parameters in locally advanced breast cancer: the debate is still open
Authors: F. Merloni, M. Pistelli, L. Cantini, A. Della Mora, L. Bastianelli, M. De Lisa, M. Burattini, E. Maccaroni, Z. Ballatore, A. Savini, A. Pagliacci, R. Berardi
Journal: Annals of Oncology (2017)
STEM-16. TARGETING THE SCF UBIQUITIN LIGASE IN GLIOBLASTOMA
Authors: Kelsey Pinkham, Arsalan Hashemiaghdam, Christian E Badr
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most malignant and common form of brain tumors with high mortality and resistance to therapy. The presence of glioma stem cells (GSCs) that drive tumor growth and promote recurrence exacerbates GBM prognosis. Because of its implication in cancer, and its role in regulating several proteins with oncogenic or tumor suppressor properties, we investigated the role of the SKP1–CUL1–F-Box protein (SCF) E3 ubiquitin ligase in GBM and particularly in GSCs. We demonstrate increased expression of SCF components in GBM and correlation with a worse prognosis. The downregulation of SKP1 and CUL1, two essential proteins in this complex, or blocking SKP1 binding to CUL1, resulted in GBM cell death, depletion of stem cell markers in patient-derived GSCs, and decreased tumorigenicity in mouse orthotopic GSC models. Disrupting the SCF in normal cells did not affect cell viability thereby suggesting that the role of SCF is tumor-specific and would represent an ideal therapeutic target. We show that SCF regulates c-Myc, a master regulator in GBM, implicated in tumor initiation, progression and the maintenance of self-renewal properties in GSCs. Importantly, we demonstrate that CUL1 controls the transcriptional regulation of c-Myc by increasing its promoter activity independently of the ubiquitin ligase function of this complex; CUL1 ectopic expression results in increased c-Myc transcription and protein expression, while CUL1 downregulation depleted c-Myc expression. We identified a small-molecule compound that downregulated CUL1 and consequently c-Myc and decreased GSCs proliferation in culture. This compound has been clinically used for decades and readily crosses the blood-brain-barrier. In summary, we have identified an essential role of SCF in GSCs maintenance, and a new mechanism of SCF-mediated regulation of c-Myc in GBM. We also provide a new strategy to indirectly target the “undruggable” oncoprotein c-Myc by inhibiting the expression of CUL1.