bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genes CNV and expression as a factors of HT-29 cells radioresistance.
Authors: Kosheleva Natalia G , Gusareva Marina A. , Balitsky Gennady V. , Lyman Natalia A. , Gabrichidze Peter N. , Gaziev Umar Muhmadovich , Solntseva Anna A. , Karnauhova Elena A. , Krokhmal Julia N. , Vasilyeva Ekaterina O. , Vladimirova Liubov Yu , Zinkovich Mikhail S. , Kutilin Denis S. 
Published: May 2020

e15590 Background: The initial radioresistance of tumor cells associated with certain molecular genetic features has a great influence on the effectiveness of radiation therapy (RD). These features include the transcriptional activity of genes that regulate DNA repair, cell cycle and apoptosis, and their copy number variation (CNV). The aim of the study was to analyze the expression and CNV of genes that regulate DNA repair, cell cycle and apoptosis in HT-29 cells subjected to RD. Methods: HT-29 cell culture was used in the study. For the model experiment, doses of 5 and 7 Gy were used (irradiation was performed 5 times every 24 hours on a Novalis TX linear accelerator). Cell counting was carried out in Goryaev chamber (0.4% trypan blue solution). On the 5th day of irradiation, HT-29 was removed from the substrate with Trypsin / Versen solution. RNA was isolated according to the method of Chomczynski&Sacchi. For cDNA synthesis was used a "REVERTA-L". reagent. The phenol-chloroform method was used to DNA isolate. The RT-qPCR method was used to determine the CNV and expression of 32 genes: AKT, ATM, BRIP, BRCA1, BRCA2, CDK1, CDKN1B, CCND1, CCND3, EXO1, FGFR2, HIST1, H2AX, KU70, PTEN, RAD50, RAP80, RIF1, RNF8 TOPB1, TP53, XRCC4, BAX, CASP8, CASP3, CASP9, MDM2, BCL2, RBBP8, EP300, LIG4, C-FLIP. Statistical analysis was performed using ANOVA and Spearman's rank correlation coefficient (r). Results: After irradiation, only a specific pool of HT-29 cells remained viable: 32% for 5 Gy and 20% for 7 Gy of the initial number of cells. In HT-29 cells irradiated with 7 Gy, the CNV of the BRCA2, H2AX, CASP9 and RBBP8 genes was increased (p < 0.05) and the CNV of BCL2 gene was reduced (p < 0.05) relative to intact cells. In cells irradiated with 5 Gy only CASP9 and RBBP8 CNV was statistically significantly (p < 0.05) increased. In cells irradiated with 5 and 7 Gy, expression of BRCA2, H2AX, CASP9 and RBBP8 genes was statistically significantly (p < 0.05) increased and the expression of the BCL2 gene was reduced relative to intact cells. A strong positive correlation was observed between CNV and expression of the studied genes: r = 0.998 for control, r = 0.989 for cells irradiated at 5 Gy, and r = 0.993 for cells irradiated at 7 Gy. Conclusions: The study showed that 5 day RD at 5 and 7 Gy leads to selective survival of 32% and 20% of cells, respectively, with increased CNV and expression of BRCA2, H2AX, RBBP8 CASP9 genes and reduced CNV and expression of BCL2 gene.
CSNK2 in cancer: Pathophysiology and translational applications.
Authors: Strum Scott , Gyenis Laszlo , Litchfield David W 
Published: May 2020

e15594 Background: Protein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase whose expression levels are frequently elevated in solid and hematologic malignancies. CSNK2 has been discovered to hold prognostic and therapeutic significance across multiple cancers and is an excellent target for oncology research. This systematic review summarizes the current knowledge from in vitro and in vivo studies on the biology of this kinase in cancer alongside pre-clinical/clinical investigations from 24 different human cancer types. Methods: PRISMA methodology was used to generate a study protocol and building-block search strategy, from which a total of 796 publications in PubMed were retrieved across 24 human cancers. 245 of these publications met both screening and inclusion criteria. Data was then systematically extracted, including information about CSNK2 subunit mRNA/protein/activity levels, phosphorylation targets, phenotypic changes, in vivo studies, and prognostic/therapeutic data. The data was thereafter summarized and analyzed. Results: Five targets phosphorylated by CSNK2 were identified in at least 4 cancers: AKT, STAT3, RELA, PTEN, and TP53. The most heavily cited was AKT, identified in 15 cancers. Phenotypically, behaviors influenced by CSNK2 that were reported in 11 or more cancers included: evasion of apoptosis, enhancement of proliferation, enhancement of invasion/metastasis, and cell cycle control. Interestingly, these pathways correlated heavily with the most commonly cited CSNK2 targets. From a clinical perspective, CSNK2 held prognostic significance in 17 of the cancers. Additionally, xenograft experiments were found to have been performed in 13 cancers where CSNK2 inhibition resulted in a positive response to treatment. Lastly, early studies have shown promising results through the clinical application of CSNK2-specific inhibitors, with several clinical trials now underway for further assessment. Conclusions: Overall, our analysis supports CSNK2 as an attractive target for cancer therapy and points to specific areas where additional investigation is critical to advance our understanding of CSNK2 biology. The design of targeted therapies by exploiting the pathophysiology of CSNK2 has the potential to generate impactful treatment strategies across a wide range of cancers, promising exciting new discoveries scientifically and clinically.
Cytotoxic effect of unclassified group K rotaviruses on T98G and U87MG glioblastoma cells in vitro.
Authors: Sitkovskaya Anastasia O. , Kit Oleg I. , Kolpakov Sergey A. , Kolpakova Elena P. , Zlatnik Elena Yu. , Filippova Svetlana Yu. , Mezhevova Irina V. , Bondarenko Elena S. , Rostorguev Eduard E. , Ignatov Sergey N. , Kuznetsova Natalya S. , Atmachidi Dmitriy P. , Kavitskiy Sergey E. , Novikova Inna A. , Vladimirova Liubov Yu 
Published: May 2020

e15597 Background: Oncolytic virotherapy is developing intensively in modern oncology. Viruses demonstrate the ability to the direct oncolysis and to the stimulation of antitumor immune activity; this experiment was aimed at solving the question of the prevalence of one of them. Glial tumors are the most common brain tumors; oncolytic viruses show certain prospects in their treatment due to the ability to penetrate the blood-brain barrier. The aim of the study was to determine the possible oncolytic effect of new unclassified group K rotaviruses (RVK) on T98G and U87MG glioblastoma cells in vitro. Methods: T98G and U87MG cell cultures were received from Russian banks of cell lines of human and animal tissues. Standard culturing was performed with attenuated apatogenic RVK strains No. 100 and No. 228 at a concentration of 108, 107, 106 and 105 particles/mL. The cytotoxic effect was determined with MTT and Annexin V assays, cell morphology was evaluated by the light-optical method. Results: Both RVK strains demonstrated a dose-dependent cytotoxic activity; the maximal effect was observed in strain No.100 at a dose of 108 particles/mL on U87MG cells (predominantly apoptosis). Studies of cell morphology showed a pronounced effect of RVK on the cell culture: significant degenerative changes in cells, a tendency to a decrease in cluster size, a change in their shape and granularity. Cluster formation in culturing in the serum-free medium is considered in the literature as a property of cancer stem cells responsible in vivo for tumor recurrence and its chemo- and radio-resistance. T98G cells demonstrated morphological changes: nuclear segmentation, diffused cytoplasm, indistinct cell borders with signs of syncytium formation. Conclusions: The established oncolytic effect of RVK strain No. 100 in vitro on glioma cells, presumably with tumor stem cells, indicates a significant potential for the use of these rotaviruses in treatment of glial tumors.
Lipocalin 2 – Devil or Angel? A pan cancer study.
Authors: Srinivasalu Vijay Kumar , Subramaniam Narayana , Das Manjula , Dhar Sujan Kumar 
Published: May 2020

e15609 Background: Lipocalin2 (LCN2, also known as neutrophil gelatinase-associated lipocalin), is a protein that in humans is encoded by the LCN2 gene. It’s abnormal expression serves critical roles in the EMT transition process, angiogenesis, cell migration and invasion in many cancers. We aim to study the expression of LCN2 in tumours with respect to normal and its association with survival in multiple forms of cancer. Methods: On analysis of 23 TCGA datasets containing gene expression data for both tumour and adjacent normal samples, normalized RNAseq RSEM values of LCN2 were compared and differences between median expression levels were assessed using Wilcoxon rank sum test. Effect of LCN2 expression (lowest and highest tertiles) in tumour samples were estimated using Kaplan-Meier survival model. Correlation of LCN2 expression with immune cell population estimated using MCP Counter tool in Colonic Adenocarcinoma (CAC) and Head and Neck Squamous Cell Carcinoma (HNSCC) dataset were assessed. Results: LCN2 overexpression in tumour over normal was seen in 11 cancers viz. CAC, Cholangiocarcinoma, Esophageal ca, Kidney chromophobe, Kidney renal papillary cell ca, HCC, Lung adenoca, Rectum adenoca, Skin cutaneous melanoma, Thyroid ca and endometrial ca whereas LCN2 under-expression in tumour over normal was observed in 4 including HNSCC, Breast invasive ca, RCC and Prostate adenoca. For 8 cancers (Urothelial ca, Cervical and endocervical ca, Glioblastoma, Lower grade glioma, Lung squamous cell ca, Pancreatic adenoca, Phenochromocytoma and Stomach adenoca) no significant difference was observed between normal and tumour samples. LCN2 expression shows hazardous effect on OS in Renal Clear Cell ca (HR = 2.38, p = 0.00027), Glioblastoma (HR = 1.57, p = 0.036) and Pheochromocytoma (HR = 8.03, p = 0.03). On the other hand, high expression of LCN2 shows very mild protective effect on tumour progression in HNSCC (HR = 0.71, p = 0.05) and Prostate ca (HR = 0.46, p = 0.06). In CAC, the normal samples show a correlation between LCN2 expression and T-cells (Pearson r = 0.45, p = 0.0028) and with the T-cell chemo attractant CXCL10 (Pearson r = 0.5, p < 0.0001). Such correlations are broken in tumour samples. In HNSCC no correlations are visible between LCN2 expression and immune cell population estimate in either tumour or normal samples. Conclusions: Literature shows LCN2 as a potential therapeutic target. However, initial analysis of TCGA data fails to establish its role as pro- or anti-tumorigenic in multiple cancers. Further tissue-specific analysis including in vitro and invivo studies are needed to confirm its role in cancer.
Improvement of subcutaneous CDX model of lung cancer using A549 cell line.
Authors: Protasova Tatiana P. , Goncharova Anna S. , Gusareva Marina A. , Karnaukhova Elena A. , Leyman Igor A. , Sitkovskaya Anastasia O. , Volkova A. V. , Mindar M. V. , Tkachev Sergey Yu. , Zaikina Ekaterina V. , Khodakova D. V. , Lukbanova Ekaterina A. , Mezhevova Irina V. , Vladimirova Liubov Yu , Maksimov Aleksey Yu. , Kit Oleg I. 
Published: May 2020

e15618 Background: Lung cancer is a challenging cancer problem, despite significant progress in its therapy. The search of drugs for the treatment of lung cancer is an urgent task. The creation of animal models of lung cancer plays a key role in preclinical trials and in understanding the mechanisms of tumor pathogenesis. The purpose of the study was to create a subcutaneous cell line-derived xenograft (CDX) model of lung cancer using the human lung cancer cells A459 and to compare results of subcutaneous injections of a cell suspension with different numbers of cells in two groups of animals. Methods: A CDX model of lung cancer was created using the human lung cancer cells A459 and male BALB/c Nude mice divided into two groups (n = 4 and n = 6) with subcutaneous injections of a mix of a cell suspension with Matrigel (200 μl). The injection mix contained 5*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel (n = 4) and 10*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel (n = 6). Results: Animal models receiving a suspension of 10*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel were characterized by a higher tumor growth index compared to animals receiving 5*106 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel. Models created with the injections of 10*106 cells showed a larger volume of tumor nodes: 65.33±1, 39.2±1, 41.79±1, 36.64±1, 75.87±1 and 43.13±1 mm3. CDX models created with the injections of 5*106 cells were characterized by a division of the single tumor node by the 30th day of the experiment which complicated the measurement. Conclusions: The creation of a CDX model with injections of 5*106 cells is undesirable due to the nonlinear growth of the xenograft and its division into several tumor nodes. Subcutaneous CDX models of lung cancer created with injections of 10*106 cells showed the linear growth and the formation of the single tumor node.
Multi-analyte liquid biopsies based treatment in advanced refractory cancers.
Authors: Limaye Sewanti , Patil Darshana , Akolkar Dadasaheb B , Crook Timothy , Ranade Anantbhushan , Bhatt Amit , Datta Vineet , Schuster Stefan , Sims Cynthe , Srivastava Navin , Fulmali Pradip , Devhare Pradip , Patil Sanket , Apurwa Sachin , Srinivasan Ajay , Datar Rajan 
Published: May 2020

e15623 Background: Tumor tissue profiling following invasive biopsies is presently the standard approach for indication-based therapy management in solid organ cancers. However, challenges in biopsy are traditionally described due to proximity to vital organs, or patients’ co-morbidities or unwillingness for an invasive procedure. Liquid biopsies for evaluation of cancers are also largely restricted to single gene testing for selection of targeted therapy agents. We developed a comprehensive liquid biopsy based multi-analyte (molecular and functional) investigation of the cancer (eLBx: Encyclopedic Liquid Biopsy) for selection and management of individualised treatments in a cohort of advanced refractory cancers. Methods: We obtained 20 mL blood from 65 patients with solid organ cancers where the disease had progressed following failure of at least two lines of systemic therapies and where biopsy to obtain tumor tissue for molecular profiling of tumor was unviable. Cell free tumor DNA (ctDNA) was interrogated for mutations, while exosomal mRNA was profiled for gene expression. Viable circulating tumor associated cells (C-TACs) were tested in vitro for chemoresistance and used to determine expression of cell surface signalling receptors by immunocytochemistry (ICC). The findings were integrated to generate patient-specific treatment regimens. In patients who received treatment, response was determined radiologically. Results: Fifty-one patients received eLBx-guided personalized treatments with combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Forty-three patients were evaluable for treatment response per protocol among whom Partial Response (PR) was observed in 14 patients yielding an Objective Response Rate (ORR) of 32.6%. Additionally, 23 patients showed Stable Disease thus yielding an overall Disease Control rate of 86.1%. Median Progression Free Survival (PFS) was 108 days. There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: The ability to make informed treatment choices from a convenient blood draw implies a reduced dependence on invasive biopsies for disease management. We demonstrate successful management of advanced refractory solid tumor malignancies using an integrational non-invasive multi-analyte liquid biopsy approach. Clinical trial information: CTRI/2019/02/017548.
Preclinical evaluation of SC0191, a small molecule inhibitor of Wee1 kinase.
Authors: Yang Chundao , Li Zhengwei , Li Qi , Xia Yuanfeng , Chan Chi-Chung , Yuan Xusheng , Wang Yiwei , Chen Shuhui , Qian Wenyuan 
Published: May 2020

e15637 Background: TP53 mutation is common in cancer cells, especially in small cell lung cancer (SCLC) and pancreatic cancer (PC). The G1 checkpoint function is lost in these cancer cells, which more rely on G2 checkpoint to repair damaged DNA. Wee1 is a serine/threonine kinase, which phosphorylates the Tyr15 locus of CDC2, inhibits the activity of CDC2, and stays in the G2 phase. Wee1 inhibition can promote the cells with DNA damage into the M phase, thus driving the TP53 mutant cancer cells to apoptosis. The purpose of this study was to investigate the in vitro and in vivo antitumor activity of SC0191, a small molecule inhibitor of Wee1 kinase, in preclinical models of SCLC and PC with TP53 mutation. Methods: The kinase inhibiting activity of SC0191 was determined using the Wee1 kinase assays. The cellular anti-proliferative activity was evaluated with TP53 mutant NCI-H446 SCLC and BxPC-3 PC cell lines. The in vivo antitumor activity of SC0191 was evaluated in the NCI-H446 and BxPC-3 cells-derived xenograft (CDX) mouse models, respectively. Results: SC0191 displayed potent kinase inhibiting activity for Wee1 with IC50 22.3 nM. SC0191 significantly inhibited tumor cell proliferation in TP53 mutant NCI-H446 cells with IC50 231.1 nM and BxPC-3 cells with IC50 223.8 nM. Moreover, SC0191 oral administration showed significant antitumor efficacy which was better than AZD1775, in the NCI-H446 and BxPC-3 CDX mouse models, respectively. Conclusions: A novel Wee1 inhibitor, SC0191, has demonstrated excellent antitumor efficacy in TP53 mutant solid cancer preclinical studies, and represents a promising clinical candidate for treating solid tumors, such as SCLC and PC.
Preclinical evaluation of SC0245, a small molecule inhibitor of ATR kinase.
Authors: Wang Jian , Li Qi , Xia Yuanfeng , Chan Chi-Chung , Yuan Xusheng , Wang Yiwei , Chen Shuhui , Qian Wenyuan 
Published: May 2020

e15642 Background: The ataxia telangiectasia and Rad3-related (ATR) kinase is a member of the phosphoinositide 3-kinase related kinase (PIKK) family. ATR plays an important role in maintaining genome integrity during DNA replication through the activation of Chk1, and regulation of the DNA damage response (DDR). Replication stress (RS) is a major source of genomic instability in cancer, and targeting the RS-response kinase ATR has emerged as a promising antitumor approach. The purpose of this study was to investigate the antitumor activity of SC0245, a small molecule inhibitor of ATR kinase, in preclinical models of ATM pathway or ARID1A deficient solid tumors. Methods: The kinase inhibiting activity of SC0245 was determined using the ATR/ATRIP(h) complex assays. The cellular anti-proliferative activity was evaluated with tumor cells which was ATM pathway or ARID1A deficient. The in vivo antitumor activity of SC0245 was evaluated in ATM pathway or ARID1A deficient cell-derived xenograft (CDX) mouse models of gastric cancer (SNU-601) and colorectal adenocarcinoma (LoVo). Results: SC0245 displayed potent kinase inhibiting activity for ATR/ATRIP complex with IC50 14 nM, and had outstanding selectivity in the 104 onco-kinase panels. SC0245 significantly inhibited cell proliferation in ATM pathway or ARID1A deficient LoVo cells with IC50 0.163 μM, SNU-601 cells with IC50 0.218 μM. SC0245 showed excellent pharmacokinetics (PK) features with oral bioavailability ( > 80%) in mouse, rat and dog. Moreover, in the SNU601 and LoVo CDX mouse models, SC0245 oral administration significantly inhibited tumor growth, with better efficacy than AZD6738. Conclusions: SC0245, a novel potent ATR kinase inhibitor, has marked antitumor efficacy in the ATM pathway or ARID1A deficient solid tumor animal models, and has outstanding PK properties. SC0245 represents a promising clinical candidate for treating solid cancers, such as gastric and colorectal cancers.
A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors.
Authors: Wei Xiao-Li , Xu Rui-hua , Zhao Hongyun , Zhang Yang , Zou Ben-Yan , Wang Feng , Liu Jihong , Wang Zhiqiang , Qiu Miao-Zhen , Yu Qiuqiong , Liu Yun 
Published: May 2020

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.