bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of inhibition of receptor tyrosine kinase AXL by a selective small molecular inhibitor R428 (BGB321) on DNA damage repair response in ovarian cancer cells.
Authors: Huang Ruby Yun-Ju , Yeo Xun Hui , Tam Wai Leong 
Published: May 2020

e15640 Background: AXL is a receptor tyrosine kinase that is often overexpressed in many cancers. It contributes to tumor progression, metastasis and drug resistance through activating downstream signaling cascades, making it an emerging therapeutic target. The first-in-class AXL inhibitor R428 (BGB321) was approved by the FDA for the treatment of relapsed or refractory acute myeloid leukemia. R428 (BGB321) was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal (Mes) molecular subtype. Recently, a novel role of AXL in the regulation of DNA damage responses has been described. In this study, we explored further the role of AXL in mediating DNA damage responses by using OC as a disease model. Methods: OC cell lines were treated with R428. Accumulation of γH2AX positive foci was assessed for DNA damage response. Western blotting for γH2AX, ATM and ATR levels were performed. Dose response curves of ATR inhibitors were generated by treating OC cells with the fixed dose of R428 (IC20 concentration of each cell line). Results: AXL inhibition by using R428 resulted in the increase of DNA damage foci in Mes OC cells SKOV3 and HeyA8. This occurred concurrently with the up-regulation of classic DNA damage response signaling molecules such as γH2AX, ATM and ATR. The IC50 of the ATR inhibitor significantly decreased for 2-3 folds in all OC cell lines tested. AXL inhibitor R428 sensitized both BRCA-mutated and non-BRCA-mutated OC cells to a potent and highly selective ATR inhibitor. Conclusions: Our results showed that AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress, paving ways to the rationale for potential combinatory use of AXL and DNA damage repair inhibitors.
Next generation proteomics in precision oncology: 1000s of proteome and phosphoproteome profiles of tumors and matching healthy tissues as meaningful layer in multi-omics database.
Authors: Escher Claudia , Vowinckel Jakob , Novy Karel , Corwin Thomas , Treiber Tobias , Bruderer Roland , Reiter Lukas , von Leitner Eike-Christin , Rinner Oliver 
Published: May 2020

e15672 Background: The rise of precision oncology therapeutics requires deep understanding of all molecular mechanisms involved in cancer biology. IndivuType offers the world’s first multi-omics database for individualized cancer therapy, analyzing the highest quality cancer biospecimens to generate the most comprehensive dataset, including genomics (WGS), transcriptomics, proteomics, and clinical outcome information. Indivumed is committed to the quality of the IndivuType ecosystem starting with stringent SOP-driven sample collection combined with thorough validation of clinical information and data integrity. The availability of multi-omics data from the same tumor can provide a comprehensive molecular picture of cancer for a given patient. Protein expression and activation are directly related to cellular function and hence provide actionable information about druggable targets. Until recently, the proteomics technology could not match the scale of next-gen sequencing and consequently precision medicine has almost exclusively been based on gene level data. Here we present the first large-scale data set for protein expression and phosphorylation. Enabled by the data independent acquisition (DIA) workflow, a mass spectrometric method provided by Biognosys that obtains peptide fragmentation data in a highly parallelized way with high sensitivity, more than 7,000 proteins in the whole proteome (WP) and 20,000 phospho-peptides in the phospho-proteome (PP) workflow were profiled. Methods: Sample processing from 5 mg of tissue per sample was performed using liquid handling robot. Phospho-peptide enrichment was carried out with a Kingfisher Flex device and MagReSyn Ti-IMAC magnetic beads. DIA LC-MS/MS was performed on multiple platforms consisting of a Thermo Scientific Q Exactive HF-X mass spectrometer coupled to a Waters M-Class LC. Chromatography was operating at 5 µL/min, and separation was achieved using 45 min (WP) and 60 min (PP) gradients. Results: Several thousands of high-quality patient samples of various cancer types have been analyzed to date. The resulting proteome and phospho-proteome data has been integrated into the IndivuType database, thereby providing a solid foundation to advance our understanding of cancer. Conclusions: With the ongoing addition of more samples and associated deep and rich data, the platform could unravel key molecular events and is expected to transform knowledge into actionable treatments and personalized therapies.
Immunohistochemical biomarker expression in gastro-entero-pancreatic neuroendocrine tumors at ENETS Centre of Excellence, University Hospital Zurich, Switzerland.
Authors: Duschek Silvia , Friemel Juliane , Curioni Fontecedro Alessandra , Siebenhuener Alexander Rheinhard 
Published: May 2020

e15673 Background: Gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) are a heterogeneous tumor entity with respect to biological behaviour and prognosis. Definition of new predictive and prognostic biomarkers as well as new therapy targets are of upmost clinical interest. Methods: At the ENETS CoE Zurich tissue microarray (TMA) blocks were constructed with 147 tissue samples of tumors diagnosed from 2000 to 2017, including primary tumors and metastasis. Tissue microarray sections were immunostained for SOX-9, SOX-10, SSTR-2 +, PDL-1, thyroid transcription factor 1 (TTF1), estrogen receptor-α (ER-α) and -β (ER-β), progesterone receptor (PR), androgen receptor (AR), BRAF and HER2. Results: In total 270 patients were screened between 2000 - 2017 and 92 patient’s material were sufficient for TMA analysis. Subgroup analysis showed 32 pancreatic, 37 ileum, 10 duodenum, 7 appendix, 3 colorectal, 3 gastric and 1 NET of gallbladder. 50% were male, the median age 63.5 years (range 19-88y). AR, ER-β, TTF1, PDL-1 and SOX10 was only present in a small number of NETs. HER2 and BRAF were negative in all samples. We found ER-α expression in 27.2%, 30% were PR positive and 67.4% showed SOX9 expression. Conclusions: We identified a frequent expression of new markers as SOX9, progesterone receptor and estrogen receptor-α in a broad amount of samples and a potential correlation with tumor grade. This finding might implicate a prognostic or predictive value of these markers, as well as it reveals new potential therapy targets for GEP-NETs. Therefore, further analyses are planned.
Expression profile and potential regulatory pathways of SFTPA1 in human tumors.
Authors: Yuan Lu , Yang Mi , Wu Xixi , Huang Wenqi , Wu Yuting , Hwang Jihong , Guan Jian , Liu Laiyu 
Published: May 2020

e15675 Background: Pulmonary surfactant protein A1(SFTPA1) plays a critical role in maintaining lung tissue homeostasis and its disruption could cause lung diseases and even lung cancer. Despite the finding that SFTPA1 is a potential biomarker for lung cancer, the expression profile and molecular mechanism of SFTPA1 in pan-cancer remain unclear. Methods: The expression of SFTPA1 in BALB/c mice, human normal tissues and human tumor tissues were explored by immunohistochemistry assay. The prognostic values were evaluated by Kaplan-Meier Plotter Database Analysis. Principal components analysis and GO and KEGG pathway enrichment analyses were exerted to identify the functional heterogeneity of SFTPA1 in various tumors. Multiple databases were used to analyze immune infiltrates and regulation networks of SFTPA1. Results: This study described the expression profile of SFTPA1 in various organs and tissues of BALB/c mice and various types of human tumor tissues. Interestingly, we found the expression level of SFTPA1 mRNA was associated with different prognosis in different cancers, even in Lung adenocarcinoma(LUAD) and Lung squamous cell carcinoma(LUSC). The further analysis confirmed a functional heterogeneity of SFTPA1 across diverse cancer types. Significantly, SFTPA1 might regulate tumor microenvironment by affecting the polarization of M2 macrophages in LUAD and LUSC. Furthermore, we found the has-miR-3200-3p-HNF1B-SFTPA1 network was a potential upstream regulatory mechanism of SFTPA1 in LUSC. Conclusions: Our study elaborated expression profile and potential regulatory pathways of SFTPA1 in human solid cancers, and might provide a potential immune infiltration biomarker for lung cancer.
Neutrophil extracellular traps blockade in combination with PD-1 inhibition in treatment of colorectal cancer metastasis.
Authors: Onuma Amblessed , He Jiayi , Xia Yujia , Zhang Hongji , Genkin Dmitry , Tetz George , Huang Hai , Tsung Allan 
Published: May 2020

e16002 Background: Immune checkpoint inhibitors (ICIs) are currently approved for microsatellite instability-high metastatic colorectal cancer (mCRC) however reported objective response rate to monotherapy range between 28-52%. Neutrophil Extracellular Traps (NETs), an extracellular network of DNA and proteins expelled by neutrophils into the tumor microenvironment, promote CRC metastasis by inducing potent immunosuppressive effects. We hypothesize that targeting this network may improve response rates to immune checkpoint therapy. The purpose of our study is to investigate the effect of combination DNase I treatment, a NET depleting agent, and PD-1 blockade in mCRC progression. Methods: Subcutaneous MC38 (MSI-H adenocarcinoma of the colon) tumors were established in 6-week-old mice. Treatment was initiated six days after tumor inoculation with daily intraperitoneal (i.p) injections of DNase I followed by i.p anti-PD-1 treatment administered every 3 days. Animals were divided into treatment groups: control, DNase alone, anti-PD-1 alone and combination of DNase I with anti-PD-1 (n = 6 mice/ group). Results: Tumors were successfully established after 6 days of inoculation. These tumors expressed high neutrophil infiltration and NETs. To determine the effects of combination therapy on tumor progression, we measured tumor volume and time to progression (TTP). We found that mice treated with combination DNase I and anti-PD-1 had significantly lower mean tumor volume compared to anti-PD-1 alone (1372.68mm3 vs 2193.20 mm3, p-value = 0.043). TTP was higher in the combination group compared to anti-PD-1 treatment alone (median time to progression 22 vs 17 days, p-value = 0.004). Next we sought to determine the mechanism behind this effect by investigating if NETs blockade modulated the tumor microenvironment. We found that treatment with DNase I decreased exhaustion of CD8+ T-cells in the tumor compared to no treatment. Conclusions: Targeting NETs in combination with immune checkpoint inhibition may be an option to improve response rate to immune checkpoint inhibitors through decreasing exhausted CD8+ T-cells.
Prognostic significance of Musashi 2 (MSI2) RNA-binding protein expression in precancerous polyps and during colorectal cancer (CRC) progression.
Authors: Kharin Leonid , Karnaukhov Nikolay S. , Voloshin Mark , Milakin Anton G. , Bychkov Igor , Deneka Alexander , Frantsiyants Elena M. , Kit Oleg Ivanovich , Golemis Erica , Boumber Yanis 
Published: May 2020

e16009 Background: The RNA-binding protein Musashi-2 (MSI2) controls the translation of proteins that support stem cell identity and lineage determination. Elevated expression of MSI2 plays an important role during progression, dissemination, and drug resistance in numerous solid and hematological malignancies. This study assessed MSI2 as potential clinical biomarker in colorectal cancer (CRC) and pre-malignant disorders of colon mucosa. Methods: This study included 125 patients, of whom 20 had tubulovillous adenomas (TAs) of the colon, and 105 had verified colorectal cancer. Of the 105 patients with CRC, 45 had locoregional invasion (stages I-III). The remaining 60 patients had liver metastases (mCRC), with 31 patients diagnosed with synchronous and 29 with metachronous metastases. We used immunohistochemical (IHC) approach to measure MSI2 expression in matching specimens of normal versus TA tissues, normal versus primary CRC tumor, and normal versus metastatic CRC, followed by correlative analysis in relation to clinical outcomes. In parallel, the biological effects of overexpressing or depleting MSI2 expression in human CRC cells were analyzed in vitro using qRT-PCR, western blot, proliferation and clonogenic assays. Results: MSI2 expression in patient samples was significantly elevated in TAs versus primary tissue (p < 0.002), and was further elevated in primary tumor, and in metastatic sites (p < 0.0001 versus normal tissue, p < 0.003 versus TAs). MSI2 expression positively correlated with decreased progression free survival (PFS) and overall survival (OS), lower tumor grade, and right-side localization (p = 0.004) of tumors. In vitro knockdown of MSI2 in CRC cells suppressed of proliferation, survival and clonogenic capacities of the cells. Conclusions: Elevated expression of MSI2 is associated with pre-cancerous polyps (TAs) in the colonic mucosa, indicating it is an early event in transformation. MSI2 is further elevated during, CRC progression, and associated with poor prognosis, and loss of MSI2 reduces multiple growth properties of CRC cell models. These data imply a causative role of MSI2 overexpression at multiple stages of CRC formation and progression.
18F-FDG PET scan and liquid biopsy as tools to assess the pace of tumor progression and to predict overall survival (OS) in refractory colorectal cancer (rCRC): The CORIOLAN trial.
Authors: Camera Silvia , Akin Telli Tugba , Woff Erwin , Kehagias Pashalina , Guiot Thomas , Critchi Gabriela , Bregni Giacomo , Trevisi Elena , Pretta Andrea , Deleruelle Amélie , Senti Chiara , Leduc Sophia , Shaza Leila , Hoerner Frédéric , Vandeputte Caroline , Sclafani Francesco , Flamen Patrick , Hendlisz Alain , Deleporte Amélie , Rothe Francoise 
Published: May 2020

e16012 Background: Decision making in rCRC patients (pts) who have exhausted all available therapies is challenging. Clinical trials, treatment re-challenge and best supportive care are possible options. There are limited data, however, to predict pt outcome and guide treatment choices. Methods: CORIOLAN was a prospective, single-centre, single-arm trial. Eligible pts had to have an ECOG PS of ≤1, a life expectancy of ≥12 weeks (wks) and had to have received prior standard chemotherapy and targeted agents. No cancer treatment was allowed within 4 wks prior to study entry. 18F-FDG PET scan and blood sample collection were carried out at baseline and after 2 wks. No treatment was given between these timepoints, while further management was left to the treating physician. The primary objective was to evaluate the association between tumour metabolic progression index as defined by changes of the whole-body metabolically active tumour volume (WB-MATV) and OS. Exploratory objectives included evaluation of the prognostic value of circulating biomarkers such as cell-free DNA (cfDNA), circulating tumour cells (CTCs, CellTracks Analyzer II, CellSearch) and CEA. Validated cut-off values, Kaplan-Meier method, Cox proportional hazards model and logrank tests were used (R version 3.5.1). Results: From 2012 to 2018, 47 eligible pts were enrolled. Median age: 65 years (38-82). ECOG PS 1: 64%. Males: 53%. Left-sided tumours: 71%. Metastases: lung (83%), liver (66%), lymph-nodes (45%), peritoneum (30%), bone (21%). Known RAS/BRAF mutations: 57%/0%. Median number of prior treatments: 5 (2-8). At the time of analysis, 45 deaths had occurred, with 26% of pts dying within 12 wks. The median relative delta between WB-MATV at baseline and after 2 wks was +21%. Changes of WB-MATV, however, failed to predict OS (p≥0.383). Similarly, no association was observed between changes of any of the circulating biomarkers investigated and prognosis. By contrast, low WB-MATV (9.4 vs 4.2 months, HR 0.65, p = 0.003), low cfDNA (7.0 vs 4.7 months, HR 0.58, p = 0.015), low CTC count (7.5 vs 3.3 months, HR 0.67, p < 0.001) and low CEA (7.0 vs 4.4 months, HR 0.58, p = 0.053) at baseline were associated with longer OS. Conclusions: This study confirms the inaccuracy of life expectancy estimation for rCRC pts based on a physician judgement largely relying on conventional criteria. Baseline assessment of WB-MATV, cfDNA, CTCs and CEA, but not early change evaluation of the same, may help to refine pt prognostication and guide management decisions. Clinical trial information: NCT01591590 .
Association between gut microbiome and T lymphocytes among different primary tumor sites of patients with metastatic colorectal cancer.
Authors: Sun Lingyun , Yan Yunzi , Chen Dongmei , Mao Jun J. , Yang Yufei 
Published: May 2020

e16013 Background: Different primary tumor sites could impact colorectal cancer (CRC)’s survival outcomes and treatment effects. Previous studies had found that gut micro-biome distributions were different between left and right colon cancer(LCC, RCC). Out study aimed to further investigate the association between micro-biome and T lymphocytes among different tumor sites of patients with metastatic CRC. Methods: Between April 2018 and Mars 2019, we enrolled 40 metastatic CRC patients in Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China. We collected patients’ stool samples for micro-biome analysis by 16s rRNA sequencing approaches, as well as patients’ blood samples to analyses T lymphocyte subsets by flow cytometry methods. The study had been proved by ethics committee of Xiyuan Hospital (2016XLA122-1). All patients consented before enrollment. Results: Among 40 patients, 28% were female, with average age of 63±15 years old. There were 10 RCC, 9 LCC and 21 rectal cancer(RC) patients. Alpha diversity analysis showed that sobs index of the micro-biome of patients with RC and RC was significantly higher than whom were RCC(254.89±99, 247±89 versus.[vs.]101.17±51, p= 0.001). PCoA analysis on OTU level detected that first principal component[PC1] (26.24%) could be separated significantly between RCC and LCC( p= 0.048), as well as between RC and RCC (PC1,14.17%, p= 0.024). Community analysis showed that the proportion of Bacteroidetes was significantly higher in patients with RCC than whom with LCC and RC( p= 0.009). Conversely, the proportion of Firmicutes, Proteobacteria and Verrucomicrobia were higher in LCC patients than others( p= 0.37, 0.047 and 0.032 respectively). Canonical Correlation Analysis (CCA) analysis proved that the CD4+ and CD8+ T cells counts were environmental factors, which were significantly associated with certain micro-biome and samples from different tumor sites( p= 0.037 and 0.01 respectively). Trends showed that CD4+ T cells were positively related with samples of RC and bacteria parabacteroides and bifidobacterium, while CD8+ T cells were positively related with samples of RCC and bacteria Lachnospira, Sutterella and Bacteroides. Conclusions: In our study, we found that patients with LCC and RC had more beneficial gut micro-biome than whom with RCC. In addition, such difference might be associated with body T cell immunity.
A multicenter, open-label, phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of JMT-101 in patients (pts) with advanced colorectal cancer (ACC).
Authors: Li Jian , Shen Lin , Gong Jifang , Peng Zhi , Liu Dan , QI Changsong , Yuan Jiajia , Hu Rong , Yang Xiugao , Li Tao , Fu Dongxue , Yang Ruirui , Feng Li , Zhang Peng , Chen Xin , Yuan Jing , Liu Yuanyuan , Wu Zhufeng , Cao Ye , Zhong Shulin 
Published: May 2020

e16025 Background: JMT101 is a fully human monoclonal IgG1 antibody targeting epidermal growth factor receptor (EGFR). This study aimed to evaluate the safety and tolerability of JMT101 alone or in combination with chemotherapy in ACC. Methods: This is an open label, dose-escalating, phase I clinical trial. The pts with ACC and naïve to systemic EGFR-targeted therapy were assigned to receive JMT101 monotherapy (JMT101 group, pts with wild-type RAS ACC and had experienced failure of at least one standard regimen) or JMT101 in combination with mFOLFOX6/FOLFIRI (combination group, pts with wild-type RAS/non-BRAF V600E mutant ACC). JMT101 was infused intravenously by accelerated titration and traditional "3+3" dose-escalation scheme. The initial dose of JMT101 monotherapy was 0.5 mg/kg (q1w), and sequentially escalated to 2.0, 4.0, 6.0, 8.0, and 10.0 mg/kg (q2w). Until the dose of JMT101 group was escalated to the higher dose and sufficient safety data were obtained, the dose of the combination group would be escalated sequentially from 6.0, 8.0, to 10.0 mg/kg (q2w). The primary endpoints were safety and tolerability. The secondary endpoints were clinical efficacy and pharmacokinetic parameters. Results: From April 2017 to December 2019, 16 enrolled pts in JMT101 group (13 males, 3 females, median age 59.5 [27-64] years) and 7 in combination group (4 males, 3 females, median age 49 [39-68] years) were evaluable. The dose of JMT101 was escalated to 10.0, 8.0, 6.0 mg/kg in JMT101 group, mFOLFOX6 group and FOLFIRI group, respectively. Dose-limiting toxicity was not observed, maximum tolerated dose was not reached, and treatment-related SAE was not reported so far. JMT101 monotherapy and combination therapy were associated with grade 1 (15 and 7 cases), grade 2 (10 and 7 cases), and grade 3 (5 and 5 cases) AEs. In all groups, the most common AEs were skin rash (81.3% [13/16] in JMT101 group, 100% [7/7] in combination group), proteinuria (62.5% [10/16] in JMT101 group, 28.6% [2/7] in combination group) and oral mucositis (86.0% [6/7] in combination group). JMT101 monotherapy and combination therapy resulted in partial response (2 and 4 pts), objective response rate (12.5% and 57.1%), disease control rate (56.2% and 100%), and disease control > 24 weeks (4 and 3 pts). Conclusions: JMT101 shows good safety, tolerability, and antitumor activity in pts with ACC. Clinical trial information: 20160904 .