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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334186/natural-humic-acid-based-phototheranostic-agent
#2
Zhao-Hua Miao, Kai Li, Pei-Ying Liu, Zhenglin Li, Huanjie Yang, Qingliang Zhao, Manli Chang, Qingzhu Yang, Liang Zhen, Cheng-Yan Xu
Humic acids, a major constituent of natural organic carbon resources, are naturally formed through the microbial biodegradation of animal and plant residues. Due to numerous physiologically active groups (phenol, carboxyl, and quinone), the biomedical applications of humic acid have been already investigated across different cultures for several centuries or even longer. In this work, sodium humate, the sodium salt of humic acid, is explored as phototheranostic agent for light-induced photoacoustic imaging and photothermal therapy based on intrinsic absorption in the near-infrared region...
January 15, 2018: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/29331808/simultaneous-inhibition-of-hedgehog-signaling-and-tumor-proliferation-remodels-stroma-and-enhances-pancreatic-cancer-therapy
#3
Jun Zhao, Huamin Wang, Cheng-Hui Hsiao, Diana S-L Chow, Eugene J Koay, Yaan Kang, Xiaoxia Wen, Qian Huang, Ying Ma, James A Bankson, Stephen E Ullrich, Willem Overwijk, Anirban Maitra, David Piwnica-Worms, Jason B Fleming, Chun Li
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation...
January 9, 2018: Biomaterials
https://www.readbyqxmd.com/read/29331106/kbtbd2-inhibits-the-cytotoxic-activity-of-immortalized-nk-cells-through-down-regulating-mtor-signaling-in-a-mouse-hepatocellular-carcinoma-model
#4
Kai Dai, Yabing Huang, Zubing Chen, Xiaomei Sun, Lihua Yang, Yingan Jiang
Natural killer cell (NK cell)-based immunotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the regulation of NK cell function in the tumor sites are not completely elucidated. In this study, we identified the enhanced expression of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) in intratumoral NK cells in a mouse HCC implantation model as a negative regulator of NK cells. To investigate this interaction,, we used a Tet-on inducible expression system to control Kbtbd2 expression in an immortalized mouse NK cell line KIL C...
January 13, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29330750/immunologic-and-gene-expression-profiles-of-spontaneous-canine-oligodendrogliomas
#5
Anna Filley, Mario Henriquez, Tanmoy Bhowmik, Brij Nath Tewari, Xi Rao, Jun Wan, Margaret A Miller, Yunlong Liu, R Timothy Bentley, Mahua Dey
Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing...
January 12, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29330466/target-engagement-imaging-of-parp-inhibitors-in-small-cell-lung-cancer
#6
Brandon Carney, Susanne Kossatz, Benjamin H Lok, Valentina Schneeberger, Kishore K Gangangari, Naga Vara Kishore Pillarsetty, Wolfgang A Weber, Charles M Rudin, John T Poirier, Thomas Reiner
Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo...
January 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29329948/nkp46-receptor-mediated-interferon-%C3%AE-production-by-natural-killer-cells-increases-fibronectin-1-to-alter-tumor-architecture-and-control-metastasis
#7
Ariella Glasner, Assi Levi, Jonatan Enk, Batya Isaacson, Sergey Viukov, Shari Orlanski, Alon Scope, Tzahi Neuman, Claes D Enk, Jacob H Hanna, Veronika Sexl, Stipan Jonjic, Barbara Seliger, Laurence Zitvogel, Ofer Mandelboim
Natural killer (NK) cells are innate lymphoid cells, and their presence within human tumors correlates with better prognosis. However, the mechanisms by which NK cells control tumors in vivo are unclear. Here, we used reflectance confocal microscopy (RCM) imaging in humans and in mice to visualize tumor architecture in vivo. We demonstrated that signaling via the NK cell receptor NKp46 (human) and Ncr1 (mouse) induced interferon-γ (IFN-γ) secretion from intratumoral NK cells. NKp46- and Ncr1-mediated IFN-γ production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation...
January 4, 2018: Immunity
https://www.readbyqxmd.com/read/29327728/diverse-modes-of-clonal-evolution-in-hbv-related-hepatocellular-carcinoma-revealed-by-single-cell-genome-sequencing
#8
Meng Duan, Junfeng Hao, Sijia Cui, Daniel L Worthley, Shu Zhang, Zhichao Wang, Jieyi Shi, Longzi Liu, Xiaoying Wang, Aiwu Ke, Ya Cao, Ruibin Xi, Xiaoming Zhang, Jian Zhou, Jia Fan, Chong Li, Qiang Gao
Hepatocellular carcinoma (HCC) is a cancer of substantial morphologic, genetic and phenotypic diversity. Yet we do not understand the relationship between intratumor heterogeneity and the associated morphologic/histological characteristics of the tumor. Using single-cell whole-genome sequencing to profile 96 tumor cells (30-36 each) and 15 normal liver cells (5 each), collected from three male patients with HBV-associated HCC, we confirmed that copy number variations occur early in hepatocarcinogenesis but thereafter remain relatively stable throughout tumor progression...
January 12, 2018: Cell Research
https://www.readbyqxmd.com/read/29327160/differences-in-histological-features-and-pd-l1-expression-between-sporadic-microsatellite-instability-and-lynch-syndrome-associated-disease-in-japanese-patients-with-colorectal-cancer
#9
Rin Yamada, Tatsuro Yamaguchi, Takeru Iijima, Rika Wakaume, Misato Takao, Koichi Koizumi, Tsunekazu Hishima, Shin-Ichiro Horiguchi
BACKGROUND: The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. METHODS: Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis...
January 11, 2018: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29326364/inflammation-and-pd-l1-expression-in-pulmonary-neuroendocrine-tumors
#10
Atsuko Kasajima, Yuichi Ishikawa, Ayaka Iwata, Katja Steiger, Naomi Oka, Hirotaka Ishida, Akira Sakurada, Hiroyoshi Suzuki, Toru Kameya, Björn Konukiewitz, Gunter Kloppel, Yoshinori Okada, Hironobu Sasano, Wilko Weichert
In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas)...
January 11, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29326299/targeting-mutant-kras-with-crispr-cas9-controls-tumor-growth
#11
Hyongbum Henry Kim, Wonjoo Kim, Sangeun Lee, Han Sang Kim, Minjung Song, Yong Hoon Cha, Young-Hoon Kim, Jeonghong Shin, Eun-Seo Lee, Yeonsoo Joo, Jae J Song, Eun Ju Choi, Jae W Choi, Jinu Lee, Moonkyung Kang, Jong In Yook, Min Goo Lee, Yeon-Soo Kim, Soonmyung Paik
KRAS is the most frequently mutated oncogene in human tumors and its activating mutations represents important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA...
January 11, 2018: Genome Research
https://www.readbyqxmd.com/read/29326088/age-effects-of-distinct-immune-checkpoint-blockade-treatments-in-a-mouse-melanoma-model
#12
Álvaro Padrón, Vincent Hurez, Harshita B Gupta, Curtis A Clark, Sri Lakshmi Pandeswara, Bin Yuan, Robert S Svatek, Mary Jo Turk, Justin M Drerup, Rong Li, Tyler J Curiel
Cancer immunotherapy has shown remarkable recent progress. Immune checkpoint blocking antibodies have become the most successful anti-cancer agent class ever developed, with six distinct agents approved since 2011 for a wide variety of cancers. Although age is the biggest risk factor for cancer (aside from selected early-onset pediatric cancers), these agents were tested pre-clinically in young hosts, and there is remarkably little published on the effects of host age on treatment outcomes in pre-clinical studies or human clinical trials...
January 8, 2018: Experimental Gerontology
https://www.readbyqxmd.com/read/29325706/contrast-harmonic-eus-for-the-prediction-of-pancreatic-neuroendocrine-tumor-aggressiveness-with-videos
#13
Maxime Palazzo, Bertrand Napoléon, Rodica Gincul, Mathieu Pioche, Bertrand Pujol, Christine Lefort, Fabien Fumex, Vincent Hautefeuille, Monique Fabre, Jérome Cros, Michèle Felce, Anne Couvelard, Alain Sauvanet, Philippe Lévy, Philippe Ruszniewski, Laurent Palazzo
BACKGROUND AND AIM: Contrast-harmonic EUS (CH-EUS) has the ability to depict a tumor microvasculature. Decreased microvascular density has been identified as a factor associated with tumor aggressiveness. We aimed to study the accuracy of CH-EUS for the prediction of pancreatic neuroendocrine tumor (PNET) aggressiveness. METHODS: Between June 2009 and March 2015, all consecutive patients with histology-proven PNETs and CH-EUS examination were included. Nine endosonographers analyzed blindly all the videos...
January 8, 2018: Gastrointestinal Endoscopy
https://www.readbyqxmd.com/read/29322606/association-of-tumour-infiltrating-regulatory-t-cells-with-adverse-outcomes-in-dogs-with-malignant-tumours
#14
K Sakai, S Maeda, Y Yamada, J K Chambers, K Uchida, H Nakayama, T Yonezawa, N Matsuki
Regulatory T cells (Tregs) infiltrate into a variety of tumour tissues and associate with poor prognosis in humans. However, data on association of Treg infiltration with prognosis is limited in canine tumours. The purpose of this study was to examine the number of tumour-infiltrating Tregs and its association with overall survival (OS) in dogs with malignant tumours. The following 168 canine tumours were included: 37 oral malignant melanomas (OMMs); 14 oral squamous cell carcinomas (OSCCs); 16 pulmonary adenocarcinomas (PAs); 37 mammary carcinomas (MCs); 36 mast cell tumours (MCTs) and 28 hepatocellular carcinomas (HCCs)...
January 11, 2018: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/29320709/metabolic-reprogramming-via-targeting-cd38-nadase-augments-adoptive-t-cell-therapy
#15
Mario R Fernandez, John L Cleveland
One strategy to improve the potency of adoptive T cell therapy is to augment the function and persistence of anti-tumor T cells. In this issue of Cell Metabolism, Chatterjee et al. (2018) demonstrate that intratumoral CD4+ T cell functions and memory can be improved by targeting a CD38-NAD+-Sirt1-Foxo1 metabolic circuit.
January 9, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29317375/does-doxorubicin-survive-thermal-ablation-results-of-an-ex-vivo-bench-top-study
#16
Joseph D Morrison, Collin K Schlager, Amanda E Lee, Richard B van Breemen, Ron C Gaba
PURPOSE: We aimed to test the hypothesis that doxorubicin (DOX) survives thermal ablative heating in an ex vivo model of combined transarterial chemoembolization (TACE) and thermal ablation. METHODS: Fresh porcine psoas major muscle (3 samples, 15×10×3 cm) was submerged in aqueous DOX solution (60 µg/mL, 0.1 M) for 24 hours to passively saturate tissue. DOX-infused tissue was then dried and treated with microwave ablation (MWA) using a 2.45 GHz antenna at 65 W for 2, 5, and 10 minutes...
January 2018: Diagnostic and Interventional Radiology: Official Journal of the Turkish Society of Radiology
https://www.readbyqxmd.com/read/29317372/pancreas-ductal-adenocarcinoma-with-cystic-features-on-cross-sectional-imaging-radiologic-pathologic-correlation
#17
Seo Yeon Youn, Sung Eun Rha, Eun Sun Jung, In Seok Lee
Most pancreatic ductal adenocarcinomas (PDAs) show solid growth pattern, but ductal adenocarcinomas may demonstrate intratumoral cystic appearance or accompany peritumoral non-neoplastic cystic lesions, thus mimicking cystic pancreatic tumors on imaging studies. The histopathologic findings for PDA with cystic feature are divided into neoplastic and non-neoplastic cysts. Neoplastic cystic changes include large-duct type cysts (microcystic appearance), neoplastic mucin cysts (macrocystic appearance), colloid carcinomas (mucinous noncystic adenocarcinomas), and degenerative cystic change usually caused by hemorrhagic necrosis of tumor...
January 2018: Diagnostic and Interventional Radiology: Official Journal of the Turkish Society of Radiology
https://www.readbyqxmd.com/read/29316433/tim-3-regulates-cd103-dendritic-cell-function-and-response-to-chemotherapy-in-breast-cancer
#18
Álvaro de Mingo Pulido, Alycia Gardner, Shandi Hiebler, Hatem Soliman, Hope S Rugo, Matthew F Krummel, Lisa M Coussens, Brian Ruffell
Intratumoral CD103+ dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103+ DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no evidence of toxicity. Combined efficacy was CD8+ T cell dependent and associated with increased granzyme B expression; however, TIM-3 expression was predominantly localized to myeloid cells in both human and murine tumors...
January 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29315855/near-infrared-upconversion-mesoporous-cerium-oxide-hollow-biophotocatalyst-for-concurrent-ph-h2-o2-responsive-o2-evolving-synergetic-cancer-therapy
#19
Chi Yao, Wenxing Wang, Peiyuan Wang, Mengyao Zhao, Xiaomin Li, Fan Zhang
Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen-dependent photodynamic therapy (PDT), but also antitumor drug-based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen-dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)-mediated cytotoxicity of the drug toward normal tissues...
January 8, 2018: Advanced Materials
https://www.readbyqxmd.com/read/29315726/single-cell-analysis-reveals-cancer-stem-cell-heterogeneity-in-hepatocellular-carcinoma
#20
Hongping Zheng, Yotsawat Pomyen, Maria Olga Hernandez, Caiyi Li, Ferenc Livak, Wei Tang, Hien Dang, Tim F Greten, Jeremy L Davis, Yongmei Zhao, Monika Mehta, Yelena Levin, Jyoti Shetty, Bao Tran, Anuradha Budhu, Xin Wei Wang
Intratumor molecular heterogeneity of hepatocellular carcinoma (HCC) is partly attributed to the presence of hepatic cancer stem cells (CSCs). Different CSC populations defined by various cell surface markers may contain different oncogenic drivers, posing a challenge in defining molecular-targeted therapeutics. We combined transcriptomic and functional analyses of HCC cells at the single cell level to assess the degree of CSC heterogeneity. We provide evidence that hepatic CSCs at the single-cell level are phenotypically, functionally and transcriptionally heterogeneous...
January 9, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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