tbuckley/cabot-search huggingface dataset:
Radiation pneumonitis in small cell lung cancer: Impact of induction chemotherapy on estimated risk.
Authors: N. P. Amin, M. Miften, B. D. Kavanagh, D. Raben, D. R. Camidge, D. Thornton, N. Rochford, L. E. Gaspar
Journal: Journal of Clinical Oncology (2010)

e17500 Background: Radiation pneumonitis (RP) is correlated with the volume of irradiated normal lung. Small cell lung cancer (SCLC) is considered highly chemosensitive. There are patients with bulky tumors for whom giving induction chemotherapy may result in less radiation to surrounding normal lung as compared to immediate concurrent chemoradiation. This study measured the change in gross tumor volume (GTV) designated as parenchymal and/or mediastinal disease, percent of lung receiving ≥ 20 Gy (V20), mean lung dose (MLD), and estimated risk of RP in SCLC patients who received chemotherapy alone, using simulated radiation therapy (RT) plans on the pre- and postchemotherapy CT scans. Methods: Between 2003 and 2009, 23 patients with extensive SCLC were treated with chemotherapy alone and had CT scans pre- and post-2 cycles of platin-based chemotherapy. Simulated RT plans were created as if to deliver 45 Gy to thoracic disease. Volumetric changes in GTV and normal lung were measured. Normal Tissue Complication Probability (NTCP) calculations were used to predict the pre- and postchemotherapy risk of pneumonitis ≥ Gr 2 based on simulated plans. Results: Nineteen of 23 patients treated with induction chemotherapy had ≥ 30% reduction in GTV, using either RECIST criteria or volumetric measurements, and therefore had pre- and postchemo RT plans created. The other 4 patients had stable disease. Among responders, the mean decrease in GTV was 66% (range -2 to 93%, p<0.01), the mean absolute decrease in V20, MLD, and NTCP was 7% (range -6.6 to 34%, p<0.01), 3.1 Gy (range -0.64 to 12.1 Gy, p<0.01), and 5.2 % (range -1.3 to 28.5%, p<0.01), respectively. The absolute risk of pneumonitis ≥ Gr 2 was decreased by ≥ 5% in 8 (35%) patients. Conclusions: Patients with limited SCLC will likely have a reduction in the risk of treatment related pneumonitis ≥ Gr 2 if treatment is planned following 2 cycles of induction chemotherapy, especially in patients who present with bulky mediastinal disease. Pre-chemo NTCP <15% Pre-chemo NTCP ≥15% p value Number of patients 9 10 Pre-chemo mean mediastinal GTV (cc) 39.5 215.7 0.03 Pre- chemo mean parenchymal GTV (cc) 182.9 211.7 0.39 Pre-chemo mean GTV (cc) 222.4 427.4 0.12 Mean absolute difference in NTCP (%) 1.8 8.2 0.03 No significant financial relationships to disclose.
Abstract 1099: Up-regulated miR-96-5p inhibits apoptosis by targeting FOXO1 in hepatocellular carcinoma
Authors: Naoto Iwai, Kohichiroh Yasui, Akira Tomie, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Itoh
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer death worldwide, especially in Asia and sub-Saharan Africa. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in HCC, we performed a genome-wide miRNA gene expression analysis using the human miRNA microarray (Agilent) in paired tumor and non-tumor tissues from patients with primary HCC. The array-based miRNA expression profiles were validated by quantitative PCR. We identified miR-96-5p as the most significantly upregulated miRNA in HCC tumors. Although miR-96-5p has been recognized as an oncogenic miRNA, its role in the pathogenesis of HCC remains unknown. Our study showed that the inhibition of miR-96-5p reduced proliferation of HCC cells and induced apoptosis. Furthermore, we found that the forkhead box O1 (FOXO1) gene was a target of miR-96-5p. FOXO1, a transcription factor, plays an essential role in cell fate decisions. FOXO1 can induce apoptosis through mitochondria-dependent and mitochondria-independent pathways. Collectively, our results suggested that miR-96-5p may function as an oncogenic miRNA through inhibiting apoptosis by targeting FOXO1 in HCC. Citation Format: Naoto Iwai, Kohichiroh Yasui, Akira Tomie, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Itoh. Up-regulated miR-96-5p inhibits apoptosis by targeting FOXO1 in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1099.
Abstract 4535: SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells
Authors: Theodore Vougiouklakis, Vassiliki Saloura, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2016)

Abstract The oncogenic protein ERK1, a member of the extracellular signal-regulated kinase (ERK) cascade, is a signaling molecule involved in various types of human cancer. Functional regulation by phosphorylation of kinases in the ERK pathway has been extensively studied, however methylation of the ERK1 protein has not been reported to date. Over the past decade, a number of protein methyltransferases have been identified and reported to methylate histone proteins as well as non-histone substrates related to various molecular functions that have pivotal roles in tumorigenesis. To identify candidate enzymes that may methylate ERK1, we performed an in vitro methyltransferase assay using various recombinant methyltransferases and found that SUV420H1 methylates ERK1. Mass spectrometry analysis validated our findings and identified ERK1 to be tri-methylated by SUV420H1 at lysines 302 and 361. Given that some protein methylation is known to affect protein phosphorylation, we then investigated the biological importance of the individual K302 and K361 methylated lysine residues on the phosphorylation status of ERK1. Substitution of methylation sites (lysine to arginine) diminished phosphorylation levels of ERK1 (Thr202 and Tyr204), supporting that methylation of these respective residues enhances ERK1 phosphorylation levels. Concordantly, siRNA-mediated SUV420H1 knockdown reduced phosphorylated ERK1 protein levels as visualized on immunoblot, while it interestingly also suppressed ERK1 at the transcript level. SUV420H1 knockdown caused a significant growth-suppressive effect in two squamous cell carcinoma head and neck (SCCHN) cell lines, and flow cytometric cell-cycle analysis showed a significant reduction in the proportion of cells at the S phase, and an increase of those at the G0/G1. Our results indicate that overexpression of SUV420H1 may result in activation of the ERK signaling pathway through enhancement of ERK phosphorylation and transcription, thereby providing new insights in the regulation of the ERK cascade in human cancer. Citation Format: Theodore Vougiouklakis, Vassiliki Saloura, Yusuke Nakamura, Ryuji Hamamoto. SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4535.
Abstract 4611: Interrogation of PI3K signaling via multiplex detection of differential phosphorylation of specific Akt isoforms
Authors: Anthony J. Saporita, Melissa Schluter, Debra MacIvor, Jehangir Mistry, Joseph Hwang
Journal: Cancer Research (2016)

Abstract The serine/threonine protein kinase Akt is a key node in the PI3K pathway, one of the primary signaling cascades hyperactivated in human cancer. Emerging evidence demonstrates that the three Akt isoforms (Akt1, Akt2, and Akt3) may have unique, isoform-specific roles in key cellular processes such as differentiation and proliferation. We have developed 2-plex assays for each of the Akt isoforms in order to measure the relative levels of phospho- and total Akt1, Akt2, and Akt3. Differential regulation of Akt isoforms was characterized in multiple human cancer cell lines, including SH-SY5Y neuroblastoma cells and MCF-7 breast cancer cells. SH-SY5Y cells were used to study Akt phosphorylation in the context of differentiation. Briefly, SH-SY5Y cells were treated with retinoic acid (RA) for 3 days to induce neuronal differentiation before cells were collected, lysed, and evaluated by Luminex assay. RA-induced differentiation of SH-SY5Y cells stimulated phosphorylation of all three Akt isoforms, with Akt2 displaying the greatest induction. Multi-pathway analysis demonstrated co-induction of phospho-JNK in the RA-treated SH-SY5Y cells, consistent with the role of JNK in RA-mediated differentiation. To study differential regulation of the Akt isoforms in response to growth-stimulatory and growth-inhibitory signals, we used MCF-7 cells. In contrast to SH-SY5Y cells which express all three isoforms, MCF-7 cells only expressed Akt1 and Akt2. Serum-starved MCF-7 cells were cultured in the presence or absence of the PI3K inhibitor LY294002 prior to stimulation with insulin growth factor (IGF). Akt1 showed a greater induction of phosphorylation in response to IGF relative to Akt2. Similarly, whereas LY294002 pre-treatment reduced phospho-Akt1 to baseline levels, it only partially inhibited the IGF-dependent induction of phospho-Akt2. This suggests that Akt1 may be more sensitive to PI3K inhibition than Akt2 in certain human breast cancer cells. Collectively, our results demonstrate that Akt1, Akt2, and Akt3 are differentially regulated in human cancer cells at both the level of phosphorylation and of total protein expression. Citation Format: Anthony J. Saporita, Melissa Schluter, Debra MacIvor, Jehangir Mistry, Joseph Hwang. Interrogation of PI3K signaling via multiplex detection of differential phosphorylation of specific Akt isoforms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4611.
Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages
Authors: Don-Hong Wang, Hyun-Sung Lee, David Yoon, Gerald Berry, Thomas M. Wheeler, David J. Sugarbaker, Farrah Kheradmand, Edgar Engleman, Bryan M. Burt
Journal: Clinical Cancer Research (2016)

Lung adenocarcinomas with mutations in the EGFR have unprecedented initial responses to targeted therapy against the EGFR. Over time, however, these tumors invariably develop resistance to these drugs. We set out to investigate alternative treatment approaches for these tumors.To investigate the immunologic underpinnings of EGFR-mutant lung adenocarcinoma, we utilized a bitransgenic mouse model in which a mutant human EGFR gene is selectively expressed in the lungs.EGFR oncogene-dependent progression and remission of lung adenocarcinoma was respectively dependent upon the expansion and contraction of alveolar macrophages, and the mechanism underlying macrophage expansion was local proliferation. In tumor-bearing mice, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. Depletion of alveolar macrophages in tumor-bearing mice resulted in reduction of tumor burden, indicating a critical role for these cells in the development of EGFR-mutant adenocarcinoma. Treatment of mice with EGFR-targeting clinical drugs (erlotinib and cetuximab) resulted in a significant decrease in alveolar macrophages in these mice. An activated alveolar macrophage mRNA signature was dominant in human EGFR-mutant lung adenocarcinomas, and the presence of this alveolar macrophage activation signature was associated with unfavorable survival among patients undergoing resection for EGFR-mutant lung adenocarcinoma.Because of the inevitability of failure of targeted therapy in EGFR-mutant non-small cell lung cancer (NSCLC), these data suggest that therapeutic strategies targeting alveolar macrophages in EGFR-mutant NSCLC have the potential to mitigate progression and survival in this disease. Clin Cancer Res; 23(3); 778-88. ©2016 AACR.
Abstract 3276: The tissue and cellular destination of therapeutic IgGs in glioblastoma
Authors: Gaelle Muller-Greven, Cathleen Carlin, Steven Toms, Manmeet Ahluwalia, Markus Bredel, Justin Lathia, Jeremy Rich, Petra Hamerlik, Candece L. Gladson
Journal: Cancer Research (2016)

Abstract Most patients with recurrent glioblastoma (GBM) are treated with bevacizumab, a humanized monoclonal antibody (mAb) that binds VEGF-A and inhibits its binding to VEGFR. Approximately 30% of GBM patients are non-responsive to bevacizumab and the underlying mechanism for the lack of response is not known. It has been assumed that bevacizumab solely targets circulating VEGF-A in blood. We hypothesized that bevacizumab and human IgGs in general gain access to the perivascular niche that contains cancer stem cells (CSCs) in GBM. We found that bevacizumab gains access to the perivascular tumor area through leaky blood vessels and was internalized by tumor cells in an orthotopic xenograft mouse model of GBM. In vitro, CSCs (CD133+) from GBM rapidly internalized either bevacizumab or human IgG into membrane protrusions that contained actin and internalization was significantly inhibited by a macropinocytosis inhibitor (EIPA), suggesting CSCs internalize bevacizumab or human IgG via macropinocytosis. Furthermore, bevacizumab or human IgG was largely detected in the Rab4+ “fast” recycling compartment at 5 min, and both were largely detected in the LAMP1+ compartment (late endosome/lysosome) at 3 hr in the CSCs. CSCs (CD133+) from GBM do not express the neonatal Fc receptor, the canonical pathway for recycling of IgG. Administration of bevacizumab to an orthotopic xenograft mouse model of established GBM showed that bevacizumab was partially co-localized with Rab4+ or with LAMP1+ in perivascular tumor cells, consistent with our in vitro findings. Taken together, our data show that in GBM, humanized IgG, including bevacizumab, gains access to the perivascular tumor space and is then macropinocytosed by CSCs and trafficked to a recycling compartment or to the late endosome/lysosome. These data suggest that alterations in endocytosis or recycling in the CSCs could impact the fate of therapeutic IgGs like bevacizumab and ultimately influence a patients’ response to GBM therapy. Citation Format: Gaelle Muller-Greven, Cathleen Carlin, Steven Toms, Manmeet Ahluwalia, Markus Bredel, Justin Lathia, Jeremy Rich, Petra Hamerlik, Candece L. Gladson. The tissue and cellular destination of therapeutic IgGs in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3276.
Factors driving the use of dermoscopy in Europe: a pan-European survey
Authors: A.M. Forsea, P. Tschandl, V. del Marmol, I. Zalaudek, H.P. Soyer, A.C. Geller, G. Argenziano, M. Arenbergerova, A. Azenha, A. Blum, J.C. Bowling, R.P. Braun, M. Bylaite-Bucinskiene, L. Čabrijan, H. Dobrev, J. Hegy, H. Helppikangas, R. Hofmann-Wellenhof, R. Karls, U. Krumkachou, N. Kukutsch, I. McCormack, L. Mekokishvili, N. Nathansohn, K. Nielsen, J. Olah, F. Özdemir, S. Puig, P. Rubegni, T. Planinsek Rucigaj, T.R. Schopf, V. Sergeev, A. Stratigos, L. Thomas, D. Tiodorovic, A. Vahlberg, Z. Zafirovik
Journal: British Journal of Dermatology (2016)

When used correctly, dermoscopy is an essential tool for helping clinicians in the diagnosis of skin diseases and the early detection of skin cancers. Despite its proven benefits, there is a lack of data about how European dermatologists use dermoscopy in everyday practice.To identify the motivations, obstacles and modifiable factors influencing the use of dermoscopy in daily dermatology practice across Europe.All registered dermatologists in 32 European countries were invited to complete an online survey of 20 questions regarding demographic and practice characteristics, dermoscopy training and self-confidence in dermoscopic skills, patterns of dermoscopy use, reasons for not using dermoscopy and attitudes relating to dermoscopy utility.We collected 7480 valid answers, of which 89% reported use of dermoscopy. The main reasons for not using dermoscopy were lack of equipment (58% of nonusers) and lack of training (42%). Dermoscopy training during residency was reported by 41% of dermoscopy users and by 12% of nonusers (P < 0·001). Dermatologists working in public hospitals were the least likely to use dermoscopy. High use of dermoscopy across the spectrum of skin diseases was reported by 62% of dermoscopy users and was associated with dermoscopy training during residency, the use of polarized light and digital dermoscopy devices, longer dermoscopy practice, younger age and female gender.Expanding access to dermoscopy equipment, especially in public healthcare facilities and establishing dermoscopy training during dermatology residency would further enhance the substantially high dermoscopy use across European countries.
Diabetes-Induced Jagged1 Overexpression in Endothelial Cells Causes Retinal Capillary Regression in a Murine Model of Diabetes Mellitus
Authors: Chang-Hwan Yoon, Young-Eun Choi, Young Ryun Cha, Seok-Jin Koh, Jae-il Choi, Tae-Won Kim, Se Joon Woo, Young-Bae Park, In-Ho Chae, Hyo-Soo Kim
Journal: Circulation (2016)

Background: Several mechanisms have been proposed to account for diabetes-induced microvasculopathy (DMV). Although Notch signaling was reported to be affected by glucose metabolism in endothelial cells during developmental angiogenesis, it has not been investigated in vascular remodeling of adult capillaries in relation to diabetes mellitus. Methods: We induced diabetes mellitus in 8-week-old adult mice by intravenously administering streptozotocin. After 6 weeks, we harvested organs, including retina, heart, and skeletal muscle, and evaluated the capillaries with immunofluorescence and confocal microscopy. We modulated endothelial Notch signaling using chemical inhibitors in wild-type mice or transgenic mice, inducing conditional knockout of Jagged1 or Mib1. Results: DMV was characterized by capillary remodeling, regression, and decreased density. Notch ligand Jagged1, but not δ-like ligand 4, was markedly increased in endothelial cells of diabetic mice. Using endothelium-specific Jagged1 knockdown mice, we found that blocking Jagged1 prevented DMV even under diabetic conditions. Furthermore, in the inducible endothelium-specific Jagged1 knockdown mice, blocking Jagged1 even at 4 weeks after the establishment of DMV could reverse it, leading to normalization of retinal vasculature. A search for downstream signals revealed that diabetes mellitus decreased the nuclear localization of Notch1 intracellular domain and reduced the expression of VE-cadherin and N-cadherin in endothelial cells. Chemical Notch inhibition phenocopied DMV in normal mice. Conclusions: Our findings indicate that diabetes mellitus induces Jagged1 overexpression and suppresses Notch signaling in endothelial cells, leading to DMV in adult mice. We conclude that dysregulated intercellular Notch signaling may be a novel mechanism of DMV.
Determinants of temporal changes in galectin-3 level in the general population : data of PREVEND
Authors: A. R. Rogier Van Der Velde, Wouter Meijers, E. R. Van Den Heuvel, Stephan Bakker, van Wiekert Gilst, van der Pim Harst, Hans Hillege, de Rudolf Boer
Journal: European Journal of Heart Failure (2016)
Effect of abundance of EGFR activating mutations and presence of T790M mutation in TKIs-naive tumor specimen on gefitinib response duration in patients with non-small cell lung cancer.
Authors: Jing Zhao, Huahua Feng, Jinyin Zhao, Licheng Liu, Yan Xu, Minjiang Chen, Wei Zhong, Longyun Li, Yi Xiao, Weijun Chen, Mengzhao Wang
Journal: Journal of Clinical Oncology (2014)

e19077 Background: T790M mutation has been suggested to be present in pre-TKIs treatment samples in some patients and associated with EGFR-TKIs response duration, but the results were conflicted. Abundance of EGFR activating mutations might be an influence factor. So we used highly sensitive methods to detect T790M mutation and quantify EGFR activating mutations in TKIs naïve specimens and investigated the clinical significance of them. Methods: A highly sensitive ACB-PCR was used to detect T790M mutation in NSCLC patients with EGFR activating mutations. The abundance of EGFR activating mutations was relatively quantified by MALDI-TOF MS. The association between T790M mutation, abundance of EGFR activating mutations and clinical benefit from TKIs treatment was analyzed. Results: In the pre-TKIs treatment samples from 27 patients, ACB-PCR identified 6 patients with T790M mutation. 18 patients had high abundance of EGFR activating mutations quatified by MALDI-TOF MS. Smoking was significantly associated with low abundance of EGFR activating mutations (P<0.05). Although not reaching significant difference, median PFS in patients with T790M in pre-TKIs samples was shorter than that without T790M mutation (3.2 v 15.9 months). Patients with high abundance of EGFR activating mutations had longer median PFS than those with low abundance (20 v 4 months, respectively; P<0.05). When the patients were subdivided into three groups (Group A, both T790M and low abundance of EGFR activating mutations; Group B, either T790M or low abundance; Group C, high abundance without T790M), the median PFS for three groups was 2, 4.2, and 20 months, respectively and had significant difference (P<0.05). In multivariate Cox regression model, abundance of EGFR activating mutations was associated with PFS (HR 14.698; 95% CI, 3.609 to 59.868; P<0.05). Conclusions: T790M mutation and abundance of EGFR activating mutations were associated with TKIs response duration. Using highly sensitive methods, the detection of de novo T790M and quantification of abundance of EGFR activating mutations should be recommended before EGFR-TKIs individualized therapy.