bluuebunny/crossref_metadata_2025_split huggingface dataset:
PIK3CA-TP53 co-mutation as a biomarker of overall survival in malignant tumor.
Authors: Wang Hongyan , Zhao Xiaopeng , He Xu , Wang Miao , Zhang Haoran , Cheng Jingge , Wu Yaqing , Luo Ningning , Qi Yingxue , Duan Qianqian 
Published: June 2021

e15001 Background: Overall survival (OS) is an important endpoint, with the advantage that there is minimal ambiguity in defining an OS event; the patient is either alive or dead. Some single gene mutations, such as TP53, were identified as important predictors of shorter OS in malignant tumors. However, the relationship between gene co-mutation and OS of malignant tumors is poorly defined. Methods: Genomic and OS data were derived from The Cancer Genome Atlas (TCGA) databases. We defined the double-mutant gene pair as “hit pair” in the specific cancer type if statistically significant OS difference was observed in at least one of three comparison (double-mutant samples vs gene A-only-mutant samples; double-mutant samples vs gene B-only-mutant samples; gene A-only-mutant samples vs gene B-only-mutant samples). Results: PIK3CA-TP53 co-mutation was evaluated as “hit pair” in seven cancer types: GBM (Glioblastoma multiforme), HNSC (Head and neck squamous cell carcinoma), LUSC (Lung squamous cell carcinoma), SARC (Sarcoma), SKCM (Skin cutaneous melanoma), UCEC (Uterine corpus endometrial carcinoma), and UCS (Uterine carcinosarcoma). In SARC and SKCM, the expected hazard ratio was higher in both-mutant group than TP53-only-mutant group, and neither genes were correlated with OS. Especially in SKCM, after we took “neither” group (both genes were wild-type) into comparison, hazard ratio of both-mutant group was significantly higher than neither group. Single-gene mutation didn’t make difference on hazard ratio, which indicated that the both-mutant interaction made the leading contribution. In GBM, LUSC, and UCS, the significant difference of hazard ratio between TP53-only-mutant group and PIK3CA-only-mutant group was neutralized in the both-mutant group, to some extent equivalent to “average effect (OS curve of double-mutant group was between that of only single gene mutant groups)". For PIK3CA-TP53 in HNSC, both-mutant group and TP53-only-mutant group carried with a higher hazard ratio than PIK3CA-only-mutant group. It suggested that the increasing hazard ratio in both-mutant group might be resulted from TP53 mutation. For the circumstance in UCEC, TP53 and PIK3CA were testified to be correlated with higher and lower hazard ratio, respectively and both-mutant group and TP53-only-mutant group both with significantly higher hazard ratio than PIK3CA-only-mutant group, which further verified the greater strength of TP53 than PIK3CA in both-mutant group. Conclusions: In summary, our study identified PIK3CA-TP53 co-mutation as a predictor of OS in seven cancer types: GBM, HNSC, LUSC, SARC, SKCM, UCEC, and UCS, especially in SARC and SKCM.
Anti-PITPNM3 small molecular compounds reverse breast cancer metastasis by targeting PITPNM3.
Authors: Gong Chang , Liu Zihao , Lin Qun , Shi Yu , Luo Qing , Cen Yinghuan , Li Juanmei , Fang Xiaolin , Jiang Wenguo 
Published: June 2021

e15005 Background: Recent studies highlight the fundamental roles of PITPNM3 in breast cancer metastasis. PITPNM3 is identified as the functional receptor of CCL18 and promotes breast cancer cell invasion and metastasis by binding with CCL18. Since anti-CCL18 neutralized antibodies shows medium binding affinity which restricts their clinical application, small molecular inhibitors targeting PITPNM3 are needed to be further investigated. Therefore, we identified several first in class small molecular inhibitors potentially targeting PITPNM3 and can inhibit breast cancer metastasis conducted by PITPNM3 activation. Methods: We performed computer-assisted drug design by constructing PITPNM3 homology model, characterizing potential binding pockets and docking preselected high diversity structured small molecule compounds into the static PITPNM3 model. Top 100 small molecules in silico scores were selected and screened through basic experiments. After screening, the anti-metastasis effects of selected compounds were tested through transwell migration and invasion assay. Immunofluorescence and qPCR were applied to confirm the expression of vimentin and CDH1. Western blot were used to clarify the inhibition effects of selected compounds on PITPNM3 signaling pathways. Results: By using homology remodeling, we successfully constructed the PITPNM3(680-920aa) protein model. The PITPNM3(680-920aa) domain is responsible for interacting with PYK2 and phosphorylating PYK2. The phosphorylation of PYK2 conducted by PITPNM3 signaling pathway will lead to metastasis and epithelial-mesenchymal transition (EMT) of breast cancer cells. We then characterized the potential binding pockets of this static model and a druggable site was founded. More than 50K molecules with high diversity were docked into this druggable site and scored through their docking performance. Finally, top 100 scored small molecules were selected. In addition, through 1 rounds of toxicity screening, 1 round of transwell migration assay screening and 1 round of transwell invasion assay screening, 4 small molecules with higher bioactivity is identified and 1 compound with the highest bioactivity as well as docking performance among 50K small molecules is chose. This compound can inhibit CCL18 treatment as well as tumor associated macrophage co-culture mediated migration and invasion. Besides, it can also inhibit the phophorylation of PYK2 and Src without inhibition the expression of PITPNM3. Conclusions: Our findings identify the first-in-class anti-PITPNM3 small molecule inhibitors. These compounds can inhibit PITPNM3 signaling pathway and reverse breast cancer metastasis.
The inhibitory effect of cisplatin, paclitaxel, and pemetrexed on the growth of PC9GR cells resistant to NK cell-mediated cytotoxicity during the COVID-19 pandemic.
Authors: Mohiuddin Md , Kimura Hideharu , Watanabe Satoshi , Abo Miki , Sone Takashi , Saeki Keigo , Terada Nanao , Tanimura Kota , Kasahara Kazuo 
Published: June 2021

e15009 Background: Lung cancer patients have a significantly higher risk of contracting COVID-19, and interactions with the healthcare system during cancer therapy can put patients at risk. Preliminary studies in COVID-19 patients with severe disease found a reduction in the number and function of natural killer (NK) cells. Other studies in COVID-19 patients reported acute respiratory distress syndrome (ARDS) due to the extreme release of inflammatory cytokines. Besides, adverse effects of chemotherapy, such as chemotherapy resistance and the escalation of cellular senescence can worsen the condition of patients with COVID-19. Considering these facts, we evaluated the growth-inhibitory effects of three commonly used chemotherapy drugs, cisplatin, pemetrexed, and paclitaxel, in gefitinib-resistant non-small cell lung cancer (PC9GR) cells and investigated the underlying mechanism. Methods: In this study, flow cytometry (FCM) was used to profile the activity and function of human NK cells. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify cytokine levels. PC9GR cells were treated with cisplatin, paclitaxel, or pemetrexed as monotherapy for 72 h and then evaluated with a cell viability assay, a reactive oxygen species (ROS) assay, a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, SA-β-Gal staining, and Western blotting. Results: We demonstrated that NK cell dysfunction was linked to the reduced NK-mediated elimination of PC9GR cells. The PC9GR cells showed the marked secretion of IL-6, IL-8 and VEGF cytokines, which was connected to the activation of the inhibitory signaling pathway of NK cells. We found that paclitaxel was the most potent growth inhibitor, cisplatin had an intermediate growth inhibitory effect, and pemetrexed induced a minimal growth inhibitory effect in PC9GR cells. These growth inhibitory effects were observed to be associated with ROS-mediated DNA damage, which led to the activation of apoptotic caspases. Surprisingly, paclitaxel was the strongest remover of senescent cells; pemetrexed had an intermediate effect, and cisplatin removed the lowest number of senescent cells. Conclusions: In light of these findings, paclitaxel may have a better therapeutic effect than cisplatin or pemetrexed on PC9GR cells, suggesting that paclitaxel could offer a novel therapeutic approach for the treatment of gefitinib-resistant non-small cell lung cancer during the COVID-19 pandemic.
Antitumor efficiency of combination of bortezomib and themosolomide on subcutaneous PDX-model of human glioblastoma.
Authors: Volkova A. V. , Evgenievich Rostorguev Eduard , Goncharova Anna S. , Mindar M. V. , Zaikina Ekaterina V. , Khodakova D. V. , Lukbanova Ekaterina A. , Kurbanova L. Z. , Khatyushin Vladislav E. , Kavitskiy Sergey E. 
Published: June 2021

e15011 Background: Poor clinical effects of standard treatment for glioblastoma determine the need for the development of new therapeutic strategies. Aberrant functioning of the proteasome system, as well as activation of the HIF-1α signaling pathway, are characteristic of glial tumor cells; they can be considered as potential therapeutic targets in the treatment of malignant brain tumors. One of the possible options for improving the results of glioblastoma treatment may involve strategies for inhibiting the HIF-1α pathway. Bortezomib, a proteasome inhibitor, can block the biological effects of HIF-1α. Bortezomib showed a pronounced antitumor effect in in vitro testing on various models of solid malignant tumors, giving grounds for further studies of its effectiveness in vivo. Patient-derived xenograft (PDX) models are characterized by a variety of cell subclones and are therefore considered the most reliable tool for predicting therapeutic responses. Methods: A PDX model of glioblastoma was created in 20 Balb/c Nude mice implanted with a subcutaneously inoculated human glioblastoma. Temozolomide (0.5 mg/kg), bortezomib (0.25 mg/kg), or a combination of temozolomide and bortezomib were administered intraperitoneally daily for 21 days. The tumor histotype was confirmed by histological analysis (staining with hematoxylin and eosin). The antitumor effect was determined by the inhibition of tumor growth (ITG%), the volume of tumor nodes, and the index of tumor growth. Results: The highest value of the inhibition of tumor growth (ITG%) was registered in the group of animals receiving a combination of temozolomide and bortezomib – 85.38%. The values in the groups receiving temozolomide or bortezomib monotherapy were 57.32% and 63.11%, respectively. Conclusions: An analysis of the antitumor efficacy of bortezomib combined with temozolomide in human subcutaneous PDX-glioblastomas demonstrated their synergistic effect.
Cell-surface vimentin positive circulating tumor cells as a diagnostic and prognostic indicator in pediatric sarcoma patients.
Authors: Dao Long , Ragoonanan Dristhi , Foglesong Jessica , Batth Izhar Singh , Zaky Wafik Tharwat , Gill Jonathan Benjamin , Liu Diane D. , Albert Aisha , Gordon Nancy Beatriz , Huh Winston W. , Harrison Douglas James , Herzog Cynthia E. , Kleinerman Eugenie , Gorlick Richard Greg , Daw Najat C. , Li Shulin 
Published: June 2021

e15022 Background: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains only reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. Methods: Here, we enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients. Results: We discovered the CSV+CTC could serve as a possible biomarker of disease with sensitivity of 85.3% and specificity of 75%. Significantly, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative (773 days vs 2622 days). Addition of readily available genetic analyses improved the sensitivity in both diagnostic and prognostic tests. Conclusions: Our findings indicate that CSV+ CTCs have both diagnostic and prognostic value and can possibly serve as a measure of disease burden.
Significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China.
Authors: Song Yuntao , Liu Jie , Wang Weiran , Ma Tonghui 
Published: June 2021

e15028 Background: Ultrasound and ultrasound-guided fine needle aspiration (US-FNA) are a preferred method for judging benign and malignant thyroid nodules. For thyroid nodules that can’t be determined by FNA, molecular markers of thyroid cancer can be detected as assistant method. This study aim to verify the significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China. Methods: We carried out a prospective study of 383 FNA samples of thyroid nodules, and performed targeted multi-gene NGS on most samples with FSZ-Thyroid NGS Panel V1, the result of which would be incorporated into the reference index for clinicians to decide whether a patient should undergo surgery. And postoperative pathology were followed up. The NGS targets were divided into three categories: high risk (BRAF V600E, TP53, PIK3CA, AKT1, CTNNB1, RET, KRAS with VAF≥30%, HRAS with VAF≥30%, NRAS with VAF≥30%, RET fusion, NTRK1 fusion, NTRK3 fusion, ALK fusion, BRAF fusion), low risk (BRAF non-V600E, EIF1AX, GNAS, TSHR, TERT, KRAS with VAF < 30%, HRAS with VAF < 30%, HRAS with VAF < 30%, PPARG fusion, THADA fusion), benign like (EZH1, SPOP, ZNF148 or no mutations). Results: Among the 383 FNA samples, 333 of them were sequenced with FSZ-Thyroid NGS Panel V1, and 211 thyroid nodules were resected. Finally, postoperative pathology showed that 180 nodules was malignant and 31 was benign. Among the 180 malignant tumors, BRAF V600E (71.1%), RET fusion (7.8%), and TERT mutation (2.8%) were the top three most mutated genes; and there were also significant differences in frequency of some mutations between malignant tumors in different BSRTC class, including more BRAF V600E (83.6%) in class VI malignant tumors, more gene fusions (26.1%) in class V malignant tumors which was significantly higher than that in class VI (7%). And, the frequency of RAS mutations (8.3%) in class III and IV malignant tumors was higher than that of class V and VI. Here a test was considered as positive if a genetic alteration was annotated with High-Risk, and negative if Low-Risk or Benign-Like, the sensitivity and specificity for detecting malignant tumors in BSRTC class III-IV were 66.7% and 100%, respectively, and the total sensitivity and specificity for BSRTC class I-VI malignant tumors were 85.6% and 100%. In addition, 21 of 383 patients underwent Re-FNA. Among these 21 patients, 11 patients detected high risk mutations and 90.9% (10/11) underwent upgrade of BSRTC class on Re-FNA. As a comparation, among the remaining 10 patients who detected low risk or benign like sites, only 30% (3/10) underwent upgrade of BSRTC class on Re-FNA which suggested that the detection of high risk sites might predict the upgrade of BSRTC class on Re-FNA. Conclusions: Molecular testing can distinguish between benign and malignant thyroid nodules and predict the upgrade of BSRTC class on Re-FNA which could provide the reference for treatment decision-making of thyroid nodules in China.
Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.
Authors: Kharbanda Surender , Mohammad Anees , Tiwari Sachchidanand , Mehrotra Neha , Appajosyula Sireesh , Laumas Sandeep , Singh Harpal 
Published: June 2021

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.
Cardiovascular toxicities associated with ibrutinib in elderly patients.
Authors: Yudiono Jason , Sorooshian Hormozan 
Published: June 2021

e15061 Background: Ibrutinib is as a first line treatment option for chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström’s macroglobulinemia. It is also FDA approved as a subsequent therapy for mantle cell lymphoma, marginal zone lymphoma, and chronic graft versus host disease. Cardiovascular (CV) toxicities, such as atrial fibrillation (afib), are some of the most common reasons for modifying ibrutinib therapy and tend to occur within the first few months of initiation. There is currently no FDA approved recommendation to reduce the dose of ibrutinib in the elderly, despite the greater incidence of afib in this patient population. It is unclear if this increased incidence leads to subsequent treatment modification in the elderly. Thus, further review of CV toxicities amongst Kaiser Permanente members may provide evidence to offer a reduced starting dose of ibrutinib in the elderly. Methods: This retrospective, multi-center study evaluated patients who started ibrutinib between January 1, 2014 and January 1, 2020 at an FDA approved dose per indication. Patient charts were reviewed from the time of treatment initiation up to one year of treatment or death, whichever came first. Data such as demographic information, diagnosis, adverse events, and ibrutinib treatment modifications were collected from chart review. The primary objective of this study was to determine if elderly (70 years or older) patients starting ibrutinib experienced a greater incidence of CV toxicities resulting in treatment modification and/or death. CV toxicities were only included if they occurred within the first year after starting ibrutinib. Results: Of the 50 patients included in this study, 23 (46%) patients initiated ibrutinib at an elderly age (70 years or older). Three (11.1%) non-elderly and two (8.7%) elderly patients underwent treatment modifications due to CV toxicities (p=0.78). Three additional patients experienced CV toxicities without further treatment modifications. Two (one per patient group) patients had already suspended ibrutinib for hepatic and/or hematological toxicities when they experienced afib. One non-elderly patient was hospitalized for afib but continued ibrutinib as originally prescribed. Conclusions: This study did not detect a significant difference in CV toxicities between elderly and non-elderly patients. Cardiac arrhythmia rates appeared slightly higher than those reported in clinical trials, but this may be due to the smaller sample size of this study. At this time, further evidence is needed to support a lower starting dose for elderly patients on ibrutinib.
Oncogenic FGFR3 gene fusions in solid tumors among Chinese cancer patients.
Authors: Xu Libin , Liu Ming , Duan Jingxian , Wang Tao 
Published: June 2021

e15072 Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]