tbuckley/cabot-search huggingface dataset:
P03.18 Detection of human brain cancer in pathological slides using hyperspectral images
Authors: S. Ortega, H. Fabelo, R. Camacho, M. L. Plaza, G. M. Callico, R. Lazcano, D. Madroñal, R. Salvador, E. Juárez, R. Sarmiento
Journal: Neuro-Oncology (2017)

Introduction: Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. In this research work, a multidisciplinary team, made up of pathologists and engineers, presents a proof of concept on the use of HSI analysis in order to automatically detect human brain tumour tissue from pathological slides. The samples were acquired from four different patients diagnosed with high-grade gliomas. Based on the diagnosis provided by pathologists, a spectral library containing spectra from healthy and tumour tissues was created. Data were finally processed using three different supervised machine learning algorithms. Materials and methods: An acquisition system consisting of a HSI camera coupled to a microscope was developed to capture the hyperspectral images from pathology slides. The spectral sampling was done in the spectral range from 400 nm to 1000 nm with a spectral resolution of 2.8 nm. The biological samples consisted of biopsies of human brain tissue resected during surgery that followed a histological process, whereby tissue specimens were prepared for sectioning, staining and diagnosis. Only spectral characteristics of the data were taken into account. The inputs of the classifiers were the spectral signatures from healthy and tumour pixels. Three different supervised machine learning algorithms were employed: Support Vector Machines (SVM), Artificial Neural Networks (ANN) and Random Forests (RF). Results: The automatic diagnosis provided by the supervised classifiers shows a very high discrimination rate between healthy and tumour tissue, with high specificity and sensitivity above 90.83% and 94.55% respectively. Although all classifiers provide an accurate discrimination between healthy and tumour tissue, ANN presents the most accurate results with a specificity of 98.72% and a sensitivity of 97.71%. Conclusions: This research work presents a proof of concept in the use of HSI for automatically detecting brain tumour tissue in pathological slides. HSI can obtain an accurate diagnosis without using the morphological features of tissues, being a suitable complement to the current analysis methods, assisting pathologists to analyse the slides without having to spend a long time in the examination of each sample. FUNDING: This work has been supported by the European Commission through the FP7 FET Open programme ICT- 2011.9.2, European Project HELICoiD "HypErspectral Imaging Cancer Detection" under Grant Agreement 618080.
Skeletal muscle dysfunction in chronic obstructive pulmonary disease: A statement of the American Thoracic Society and European Respiratory Society
Authors: R. Casaburi, R. Gosselink, M. Decramer, R. P.N. Dekhuijzen, M. Fournier, M. I. Lewis, F. Maltais, D. A. Oelberg, M. B. Reid, J. Roca, A. M.W.J. Schols, G. C. Sieck, D. M. Systrom, P. D. Wagner, T. J. Williams, E. Wouters
Journal: American Journal of Respiratory and Critical Care Medicine (1999)
The Origin of the Jugular C Wave
Authors: Lloyd L. Rich, Morton E. Tavel
Journal: New England Journal of Medicine (1971)

THE origin of the jugular C wave has been disputed for over 100 years. Many workers believe that carotid arterial interference actually causes the deflection of the jugular C wave obtained on phonocardiography. It is this concept of the genesis of the jugular C wave that we investigated. Knowing that left ventricular ejection or carotid arterial upstroke is delayed in patients with left-bundle-branch block (LBBB),1 we used this as a means of comparison to investigate the origin of the jugular C wave. If the jugular C wave were caused by carotid arterial interference, as Mackenzie,2 Wood3 and many others have . . .
P01.29 Mutant (R132H) IDH1-driven cellular transformation makes cells dependent on continued wild type IDH1 expression in a model of in vitro gliomagenesis
Authors: T. Johannessen, J. Mukherjee, M. Wood, P. Viswanath, S. Ohba, S. Ronen, R. Berkvig, R. Pieper
Journal: Neuro-Oncology (2017)

Introduction: Missense R132H mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. We recently showed (Mol Cancer Res 14: 976–983, 2016) that although mutant IDH1 expression in hTERT-immortalized, p53/pRb-deficient astrocytes can drive cellular transformation and gliomagenesis, selective pharmacologic inhibition and elimination of 2-HG by the mutant IDH1 inhibitor AGI-5198 has little effect on the growth or clonagenicity of these transformed cells. To address the possible role of WT IDH1 in the growth of mutant IDH-driven tumor cells, we used a slightly different gliomagenesis model in which the transformation of TERT-deficient, p53/pRb-deficient astrocytes (pre-crisis cells) occurs only after prolonged expression of mutant IDH and passage through cellular crisis (post-crisis cells, Cancer Res 76:6680–6689, 2016). METHODS AND MATERIALS: Using this system we introduced AGI-5198, or siRNA targeting both WT and mutant forms of IDH1 into p53/pRb-deficient, mutant IDH1-expressing human astrocytes prior to or following their transformation, and compared the effects on cell growth and clonagenicity. Results: AGI-5198 exposure decreased levels of 2HG by greater than 90%, and as previously reported had no effect on the growth of either the pre-or post-crisis cell populations. A one-day exposure to a pan IDH1 siRNA resulted in a similar, prolonged (greater than 6 day), 80% inhibition of both WT and mutant IDH1 protein levels and 2HG in both cell groups. While the growth of the mutant IDH-expressing, non-transformed cells was similar to that of scramble siRNA controls, the growth of the mutant IDH-transformed cells was significantly reduced. This growth suppression was also accompanied by a four-fold increase in annexin V-positive apoptotic cells. Furthermore, the growth suppression in the cells transformed by mutant IDH1 expression could not be reversed by addition of a cell-permeable form of 2-HG. Conclusions: These results show that the in vitro transformative events driven by expression of mutant IDH1 make cells dependent not on continued mutant IDH1 expression, but rather on continued WT IDH1 expression. The data also support the development and testing of agents that can inhibit both the WT and mutant forms of IDH1.
A Cisplatin Derivative Tetra-Pt(bpy) as an Oncotherapeutic Agent for Targeting ALT Cancer
Authors: Xiao-hui Zheng, Xin Nie, Yiming Fang, Zepeng Zhang, Yingnan Xiao, Zongwan Mao, Haiying Liu, Jian Ren, Feng Wang, Lixin Xia, Junjiu Huang, Yong Zhao
Journal: JNCI Journal of the National Cancer Institute (2017)

In approximately 15% of human cancers, telomere length is maintained independently of telomerase by the homologous recombination (HR)-mediated alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for therapeutic treatment remains unknown. The purpose of this study is to develop oncotherapeutic agent to target ALT cancers.Surface plasmon resonance assay, antibody to G-quadruplex, and fluorescence in situ hybridization (FISH) were used to discover Tetra-Pt(bpy), a cisplatin derivative that specifically targets telomeric G-quadruplex. We used immunofluorescence, FISH, C-circle assay, and chromosome orientation FISH to evaluate the inhibitory effect of Tetra-Pt(bpy) on ALT activity in human ALT cancers. The shortening of telomere length induced by Tetra-Pt(bpy) was determined by telomere restriction fragment or Q-FISH. Cell destination after Tetra-Pt(bpy) treatment was determined by β-gal staining or apoptosis assay. Nude mice (n = 4 per group) were injected with U2OS cells to evaluate the effects of Tetra-Pt(bpy) on tumor growth. All statistical tests were two-sided.Tetra-Pt(bpy) inhibits the strand invasion/annealing step of telomeric homologous recombination by selectively converting telomeric ssDNA to a G-quadruplex. ALT-cells treated with Tetra-Pt(bpy) show fewer ALT-associated promyelocytic leukemia bodies (untreated: mean±SD = 5.9±0.2 vs treated: mean±SD = 3.1±0.1, P < .001), fewer extrachromosomal C-circles (untreated: mean±SD = 100.5±1.6 vs treated: mean±SD = 18.0±1.7, P < .001), and reduced telomere sister chromatin exchanges (untreated: mean±SD = 25.2%±1.5% vs treated: mean±SD = 13.1%±1.9%, P < .001). Consequently, critically short telomeres accumulate after multiple population doublings (untreated: mean±SD = 18.9%±1.7% vs treated: mean±SD = 57.4%±2.2%, P < .001), resulting in cell death by apoptosis or senescence. In vivo, Tetra-Pt(bpy) severely inhibits the growth of ALT-cell xenograft tumors in mice (untreated: mean±SD = 57.1±3.7 mm 3 vs treated: mean±SD = 19.0±3.2 mm 3 , P < .001). Importantly, Tetra-Pt(bpy) exhibits no adverse effects on proliferation, gene expression, or telomere metabolism in normal cells.These results reveal the potential of Tetra-Pt(bpy) as a novel oncotherapeutic agent for targeting ALT cancer cells.
Relationship of divergent ancestral genetic variation on chromosome 6p22 and racial disparities in survival in neuroblastoma.
Authors: Navin R. Pinto, Eric R Gamazon, Anuar Konkashbaev, Hae Kyung Im, Sharon Diskin, Wendy B. London, John M. Maris, M. Eileen Dolan, Nancy J Cox, Susan Lerner Cohn
Journal: Journal of Clinical Oncology (2012)

9516 Background: An increased prevalence of high-risk disease and worse outcome are observed in children with neuroblastoma who self-report as black versus white. We sought to determine whether genetic variation would explain this racial disparity. Methods: After quality control, we analyzed 511,836 germline genetic variants in 2,709 ethnically diverse children with neuroblastoma enrolled on Children’s Oncology Group study ANBL00B1 from 2001 to 2009. Genetic variation was summarized by conducting principal components analysis. The first principal component (PC1) separated patients with African ancestry from all others. PC1 was used as a continuous variable for ordinal regression with risk group and a Cox proportional hazard model of EFS. To identify genetic mechanisms for the observed disparities, we developed a method using genome-wide variation data applied to high-risk versus non-high risk samples. We identified a comprehensive list of loci with significant divergence between the ancestral populations. We then tested each such locus for association with high-risk phenotype using logistic regression with the proportion of African ancestry estimated by ADMIXTURE as covariate. Finally, top SNPs were added to multivariate models of both risk and event-free survival to determine if any top associations could abrogate observed disparities. Results: PC1 was associated with both risk (p = 0.007) and EFS (p = 0.037). We identified 72 population-divergent SNPs nominally associated with high-risk disease (p &lt; 0.001). The risk allele for one of the top SNPs: rs9295536 (p = 9.2x10 -8 ) was more common in the African ancestral population, was associated with high-risk phenotype and poor outcome in all patients and validated in a Caucasian-only subanalysis. In multivariate testing, this SNP abrogated the PC1 association with EFS (p = 0.18). Conclusions: A SNP with high divergence between ancestral populations on chromosome 6p22 accounts for the observed racial disparity in survival and is also a common genetic variant associated with survival in patients derived from either European or African ancestry (Bonferroni adjusted p &lt; 0.05). Studies to elucidate the function of this SNP are underway.
AEBSF sensitize APL cells to UPR-induced apoptosis
Authors: Angela Ng, Matiullah Khan
Journal: Clinical Cancer Research (2007)

B21   Acute promyelocytic leukemia (APL), which is caused by fusion protein PML-RARα, is characterized by accumulation of immature pro-myeloid cells in the blood and bone marrow. We have previously reported that PML-RARα-induced accumulation of mis-folded N-CoR in the endoplasmic reticulum (ER) triggers ER stress and unfolded protein response (UPR) in APL cells (1). Although intracellular accumulation of mis-folded protein and ER stress have been implicated in UPR-induced apoptosis of neuronal cells in various neurodegenerative diseases, APL cells escape the UPR-induced apoptosis due to proteolytic processing of mis-folded N-CoR protein by OSGEP, a glycoprotein endopeptidase selectively expressed in APL cells (2). This finding suggests that selective inhibition of OSGEP activity could restore the UPR-induced apoptosis pathway in APL cells. Based on this hypothesis, we tested several protease inhibitors on APL cells and identified AEBSF as a selective inhibitor of OSGEP activity and inducer of apoptosis of APL cells. Here, we demonstrate that AEBSF selectively inhibits the viability of APL cells and promotes UPR-induced apoptosis in a dose-dependent manner. AEBSF-induced apoptosis of APL cells is mediated by activation of Caspase 3 and 9, and cleavage of PARP. This is accompanied by a corresponding down-regulation of anti-apoptotic protein BCL2 and up-regulation of pro-apoptotic proteins BAX/ BAK, CHOP and GADD34. These results demonstrate that AEBSF could sensitize APL cells to UPR-induced apoptosis and highlights its therapeutic potential in APL.      References:  1.  Khan M.M., Nomura T., Chiba T., Tanaka K., Yoshida H., Mori K., and Ishii S. (2004) The Fusion Oncoprotein PML-RAR Induces Endoplasmic Reticulum (ER)-associated Degradation of N-CoR and ER Stress. The Journal of Biological Chemistry, 279 (12): 11814-24.  2. Ng A.P.P., Fong J.H., Nin D.S., Hirpara J.L., Asou N., Chen C.S., Pervaiz S. and Khan M. (2006) Cleavage of Misfolded Nuclear Receptor Co-repressor Confers Resistance to Unfolded Protein Response-Induced Apoptosis. Cancer Research, 60(22): 9903-12.
P04.24 Apparent diffusion coefficient histogram analysis in recurrent glioblastoma predicts overall survival after the first course of bevacizumab and lomustine
Authors: R. Gahrmann, A. Leemans, B. van der Holt, R. M. Vernhout, W. Taal, M. Vos, J. C. de Groot, M. Hanse, M. van den Bent, M. Smits
Journal: Neuro-Oncology (2017)

PURPOSE: Early prediction of response to bevacizumab based on imaging parameters is important but difficult. We investigated the value of Apparent Diffusion Coefficient (ADC) histogram analysis to predict overall survival (OS) after the first course of bevacizumab in patients with recurrent glioblastoma. METHODS: Patients were recruited from the multicenter Dutch BELOB trial (n=148), in which patients had been randomized into 3 treatment arms: bevacizumab-only, lomustine-only, or both. Volumes of interest (VOIs) of enhancing and non-enhancing tumor were drawn on resp. T1w post-contrast and T2w-FLAIR 3D images. ADC maps were derived from diffusion weighted images (DWI) scanned with b=0 and b=1000 s/mm2 (slice thickness 3mm, in-plane resolution 2mm). Registration of ADC-maps, VOIs and FLAIR images to the T1w post-contrast images was performed with custom scripts in Matlab using Elastix. Unimodal ADC-histogram parameters were extracted from the enhancing and non-enhancing VOIs. In case of multiple lesions in a single patient, VOIs were combined. VOIs <0.200 cm3 were excluded from analysis. Exploratory analysis of histogram parameters showed that change in minimum ADC from baseline to first follow-up (i.e. 6 weeks) was the most promising parameter. Patients were dichotomized using multiple cut-offs of percentage change (decrease) in minimum ADC and differences in OS were calculated from the first follow-up until death from any cause. Analyses were performed for all patients together, for both bevacizumab-treatment arms together, and for all treatment arms separately. RESULTS: Data from 118 patients was considered for analysis, consisting of 108 enhancing and 99 non-enhancing lesions. In enhancing lesions of all treatment arms together, decrease of minimum ADC using a cut-off value between 20 and 30% was associated with significantly better OS. The lowest HR was found with 27.5% (HR= .572; 95% CI .382-.858). When looking at both bevacizumab-treated arms, significantly better OS was associated with a decrease in minimum ADC using a cut-off value between 10 and 30%. The lowest HR was found with 27.5% (HR= .452; .272-.751). These findings appeared to be driven by the bevacizumab plus lomustine treatment arm, with significantly better OS in those with a decrease of minimum ADC using a cut-off value between 5 and 27.5%. The lowest HR was found with 27.5% (HR= .287; 95% CI .137-.603). The bevacizumab-only and lomustine-only treated patients did not show better OS in associated with a decrease of minimum ADC. No significant associations were found for the non-enhancing lesions. CONCLUSION: Enhancing lesions in patients with recurrent glioblastoma treated with bevacizumab and lomustine that show a decrease in minimum ADC of at least 5% have a significantly better OS than those without.
P06.05 The natural HLA ligandome of glioblastoma stem-like cells: Antigen discovery for T-cell based immunotherapy
Authors: M. C. Neidert, D. J. Kowalewski, F. Wolpert, S. Stevanovic, H. Rammensee, K. Lamszus, M. Westphal, L. Regli, M. Weller, G. Eisele
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma stem-like cells (GSC) play a major role in tumor initiation and maintenance as well as in therapy resistance and recurrence. Thus, targeting this cellular subset may be key to effective immunotherapy. Here, we present a mass spectrometry-based analysis of HLA-presented peptidomes of GSC and glioblastoma patient specimens. Materials and Methods: HLA class I and class II ligands of culture-expanded GSC lines (GS-2, GS-5, GS-9) and snap frozen freshly resected glioblastoma samples (n=9) were isolated by immunoprecipitation and characterized using liquid chromatography and tandem mass spectrometry (LC-MS/MS). HLA ligandomes of GSC and freshly resected patient samples were compared to a comprehensive HLA ligandome database of human normal tissues including human brain. Immunogenicity of top-ranking candidates was shown by T-cell priming followed by intracellular cytokine staining and HLA multimer staining. Results: We identified 15 antigens represented by 38 different HLA ligands showing natural presentation both on GSC and patient samples. Importantly, in vitro immunogenicity assays clearly suggest these peptides to be epitopes of functional CD8 T-cell responses thus rendering them prime candidates for immunotherapy. Conclusions: We present an antigen discovery approach based on the comparative analysis of the HLA class I and HLA class II peptidomes of GSC and patient samples. The characterization of the natural GSC-immunopeptidome is an important step towards the informed design of highly specific T-cell immunotherapy targeting the glioblastoma stem cell niche.
CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer
Authors: Dingzhi Wang, Haiyan Sun, Jie Wei, Bo Cen, Raymond N. DuBois
Journal: Cancer Research (2017)

Abstract Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655–65. ©2017 AACR.
The value of the immunohistochemical expression tymidilatsynthase (TS) and Ki-67 in lung adenocarcinoma (AC) for personification of adjuvant therapy.
Authors: Yury N. Lazutin, Igor A. Leyman, Sergey P. Pyltsin, Gennadiy Z. Sergostyants, Liubov Yu Vladimirova, Pavel A. Anistratov, Anna P. Charitonova
Journal: Journal of Clinical Oncology (2014)

e18530 Background: In recent years, much attention is paid to the study of morphological predictors of prognosis of lung cancer in order to personalize therapy. In this paper the comparative immunohistochemical study (IHCS) expression TS and Ki-67 depending on certain characteristics of the patients (pts). Methods: IHCS samples of tumor tissue conducted from 63 radically operated pts. AC of the lung. Aged 40-59 - 31 pts.(50,2%), 60 years and older-32 (50,8%); men-42(66,7%),women 21(33,3%); stage 1-31(49.2 %), 2-16 (25,4%), 3A-16 (25,4%). The degree of differentiation: G1-11 (17,7%), G2-40 (63,5%), G3-12 (18,8%). TS was defined by monoclonal antibodies 4H4B1 (Invitrogen CA Carlsbad), Ki-67 - MIB-1(Immunotech SA Marseille). The level of expression of the TS was estimated staining intensity of cytoplasm in points: 0-negative, 1-low, 2-high. For the Ki-67 considered cells with a distinctly coloured nucleus. The dependence of the intensity of expression index of the Ki-67 is divided into:<20%-low, 20-30%- high, >30%- very high. Results: Comparative analysis revealed significant gender differences high expression of TS that men reached 73,8%, women 61,9% (p=,042), as well as high and very high index of Ki-67 54,7% vs. 47,6% (p=,048) and 28.6% vs. 14.3% (p=,024). The study of TS and Ki-67 in the age groups has not established a reliable differences high expression of TS 83,8% vs. 58,2% (p=,07), as high and very high index of Ki-67: 58% vs. 46.8%, and 29% vs.18,7%, respectively. High level of TS registered in 38 (83%) pts., and very high index of Ki-67 in 30 (65%) pts. with the size of the primary tumor T2. Moreover, it is noted that in G2 and G3 tumors prevail high indicators of both predictors TS in 33(87.5%) and Ki-67 in 28 (70%) cases. Conclusions: Thus, proliferative potential of AC in women was significantly lower than men's in the absence of the influence of the age factor in this parameter. Consequently, older people need control of residual disease not less than younger pts. Expression of TC and Ki-67 correlated with the degree of differentiation, allowing on the basis of evaluation of these two tissue markers to determine the indications for the adjuvant therapy for localized stages.