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1
Vallée-Tourangeau, Frédéric, Neville G. Austin, and Sandra Rankin. "Inducing a Rule in Wason's 2–4–6 Task: A Test of the Information-Quantity and Goal-Complementarity Hypotheses." Quarterly Journal of Experimental Psychology Section A 48, no. 4 (November 1995): 895–914. http://dx.doi.org/10.1080/14640749508401422.
Анотація:
In the standard 2–4–6 induction task, subjects are instructed to discover the rule generating sequences of three numbers by inventing number triples for which they receive immediate feedback. The rule is “ascending numbers”. Performance is greatly aided with Dual Goal (DG) instructions that ask subjects to discover two rules, one that generates “Dax” triples (equivalent to “yes” instances with Single Goal [SG] instructions) and another that generates “Med” triples (equivalent to “no” instances). The present study eliminates two explanations for this effect suggested by Wharton, Cheng, and Wickens (1993). Experiment 1 tested their Information-Quantity hypothesis that the effect results simply from the DG subjects testing more triples prior to proposing a rule. Our DG subjects were more likely to solve the problem and produced more “negative” triples than SG subjects when both groups generated exactly 15 triples. Two further groups received feedback only after generating all 15 triples, and again DG subjects were more likely to solve the problem and to generate more “negative” triples. Experiment 2 tested Wharton et al.'s Goal-Complementarity hypothesis that success under DG instructions hinges on preserving the complementary representation of the two rules. We compared SG instructions with three types of DG instructions that suggested different types of triples (Dax, Med, both Dax and Med, neither Dax nor Med). DG instructions were more effective in promoting successful rule discovery regardless of differences in rule complementarity. Our analysis of the heterogeneity of the examplars generated with DG instructions in both experiments suggest that success on the 2–4–6 task is as much a consequence of the breadth of hypotheses that subjects entertain as it is a consequence of the testing strategy.
2
Vallée-Tourangeau, Frédéric. "Utilities in the 2-4-6 Task." Experimental Psychology 59, no. 5 (May 1, 2012): 265–71. http://dx.doi.org/10.1027/1618-3169/a000152.
Анотація:
The Wason 2-4-6 task was embedded in a practical reasoning scenario where number sequences had well-defined utilities in the process of achieving a goal. Reasoners’ hypothesis-testing behavior was clearly goal-driven and was significantly influenced by whether the utilities favored positive or negative sequences. In the version of the scenario where generating positive sequences had greater benefits than generating negative ones, participants performed poorly at the task as measured by their ability to guess the correct rule and by the nature and number of triples tested before making an announcement. In contrast, the scenario that assigned a greater utility to the production of negative sequences fostered significantly more diligent and creative hypothesis-testing behavior, and participants were significantly more likely to discover the rule. These results suggest that the poor performance observed in Wason’s traditional 2-4-6 task reflects a hypothesis-testing process that by default assigns greater utility to the production of sequences that conform to the initial triple, and hence receive positive feedback. However, reasoners are not averse to producing negative sequences, and understand their implication, if their utility is made relevant in the process of achieving goals.
3
Wang, Liuquan. "Arithmetic identities and congruences for partition triples with 3-cores." International Journal of Number Theory 12, no. 04 (April 10, 2016): 995–1010. http://dx.doi.org/10.1142/s1793042116500627.
Анотація:
Let [Formula: see text] denote the number of partition triples of [Formula: see text] where each partition is 3-core. With the help of generating function manipulations, we find several infinite families of arithmetic identities and congruences for [Formula: see text]. Moreover, let [Formula: see text] denote the number of representations of a non-negative integer [Formula: see text] in the form [Formula: see text] with [Formula: see text] We find three arithmetic relations between [Formula: see text] and [Formula: see text], such as [Formula: see text].
4
Tierno, Domenico, Gabriele Grassi, Serena Scomersi, Marina Bortul, Daniele Generali, Fabrizio Zanconati, and Bruna Scaggiante. "Next-Generation Sequencing and Triple-Negative Breast Cancer: Insights and Applications." International Journal of Molecular Sciences 24, no. 11 (June 2, 2023): 9688. http://dx.doi.org/10.3390/ijms24119688.
Анотація:
The poor survival of triple-negative breast cancer (TNBC) is due to its aggressive behavior, large heterogeneity, and high risk of recurrence. A comprehensive molecular investigation of this type of breast cancer using high-throughput next-generation sequencing (NGS) methods may help to elucidate its potential progression and discover biomarkers related to patient survival. In this review, the NGS applications in TNBC research are described. Many NGS studies point to TP53 mutations, immunocheckpoint response genes, and aberrations in the PIK3CA and DNA repair pathways as recurrent pathogenic alterations in TNBC. Beyond their diagnostic and predictive/prognostic value, these findings suggest potential personalized treatments in PD -L1-positive TNBC or in TNBC with a homologous recombination deficit. Moreover, the comprehensive sequencing of large genomes with NGS has enabled the identification of novel markers with clinical value in TNBC, such as AURKA, MYC, and JARID2 mutations. In addition, NGS investigations to explore ethnicity-specific alterations have pointed to EZH2 overexpression, BRCA1 alterations, and a BRCA2-delaAAGA mutation as possible molecular signatures of African and African American TNBC. Finally, the development of long-read sequencing methods and their combination with optimized short-read techniques promise to improve the efficiency of NGS approaches for future massive clinical use.
5
Wu, Jiande, Tarun K. K. Mamidi, Lu Zhang, and Chindo Hicks. "Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer." International Journal of Genomics 2020 (July 7, 2020): 1–16. http://dx.doi.org/10.1155/2020/2641370.
Анотація:
Background. Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer. Methods. We addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations. Results. The investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC. Conclusions. The results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.
6
Lin, Po‐Han, Ming Chen, Li‐Wei Tsai, Chiao Lo, Tzu‐Chun Yen, Thomas Yoyan Huang, Chih‐Kai Chen, Sheng‐Chih Fan, Sung‐Hsin Kuo, and Chiun‐Sheng Huang. "Using next‐generation sequencing to redefine BRCAness in triple‐negative breast cancer." Cancer Science 111, no. 4 (February 19, 2020): 1375–84. http://dx.doi.org/10.1111/cas.14313.
7
Wu, Jiande, Tarun Karthik Kumar Mamidi, Lu Zhang, and Chindo Hicks. "Unraveling the Genomic-Epigenomic Interaction Landscape in Triple Negative and Non-Triple Negative Breast Cancer." Cancers 12, no. 6 (June 12, 2020): 1559. http://dx.doi.org/10.3390/cancers12061559.
Анотація:
Background: The recent surge of next generation sequencing of breast cancer genomes has enabled development of comprehensive catalogues of somatic mutations and expanded the molecular classification of subtypes of breast cancer. However, somatic mutations and gene expression data have not been leveraged and integrated with epigenomic data to unravel the genomic-epigenomic interaction landscape of triple negative breast cancer (TNBC) and non-triple negative breast cancer (non-TNBC). Methods: We performed integrative data analysis combining somatic mutation, epigenomic and gene expression data from The Cancer Genome Atlas (TCGA) to unravel the possible oncogenic interactions between genomic and epigenomic variation in TNBC and non-TNBC. We hypothesized that within breast cancers, there are differences in somatic mutation, DNA methylation and gene expression signatures between TNBC and non-TNBC. We further hypothesized that genomic and epigenomic alterations affect gene regulatory networks and signaling pathways driving the two types of breast cancer. Results: The investigation revealed somatic mutated, epigenomic and gene expression signatures unique to TNBC and non-TNBC and signatures distinguishing the two types of breast cancer. In addition, the investigation revealed molecular networks and signaling pathways enriched for somatic mutations and epigenomic changes unique to each type of breast cancer. The most significant pathways for TNBC were: retinal biosynthesis, BAG2, LXR/RXR, EIF2 and P2Y purigenic receptor signaling pathways. The most significant pathways for non-TNBC were: UVB-induced MAPK, PCP, Apelin endothelial, Endoplasmatic reticulum stress and mechanisms of viral exit from host signaling Pathways. Conclusion: The investigation revealed integrated genomic, epigenomic and gene expression signatures and signing pathways unique to TNBC and non-TNBC, and a gene signature distinguishing the two types of breast cancer. The study demonstrates that integrative analysis of multi-omics data is a powerful approach for unravelling the genomic-epigenomic interaction landscape in TNBC and non-TNBC.
8
Raftery, Martin J., Alexander Sebastian Franzén, Clarissa Radecke, Abdelhadi Boulifa, Günther Schönrich, Sebastian Stintzing, Jens-Uwe Blohmer, and Gabriele Pecher. "Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer." International Journal of Molecular Sciences 24, no. 10 (May 20, 2023): 9038. http://dx.doi.org/10.3390/ijms24109038.
Анотація:
There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.
9
Zhang, Zhenghang, Jinlu Jia, Yalin Wan, Yang Zhou, Yuting Kong, Yurong Qian, and Jun Long. "TransR*: Representation learning model by flexible translation and relation matrix projection." Journal of Intelligent & Fuzzy Systems 40, no. 5 (April 22, 2021): 10251–59. http://dx.doi.org/10.3233/jifs-202177.
Анотація:
The TransR model solves the problem that TransE and TransH models are not sufficient for modeling in public spaces, and is considered a highly potential knowledge representation model. However, TransR still adopts the translation principles based on the TransE model, and the constraints are too strict, which makes the model’s ability to distinguish between very similar entities low. Therefore, we propose a representation learning model TransR* based on flexible translation and relational matrix projection. Firstly, we separate entities and relationships in different vector spaces; secondly, we combine our flexible translation strategy to make translation strategies more flexible. During model training, the quality of generating negative triples is improved by replacing semantically similar entities, and the prior probability of the relationship is used to distinguish the relationship of similar coding. Finally, we conducted link prediction experiments on the public data sets FB15K and WN18, and conducted triple classification experiments on the WN11, FB13, and FB15K data sets to analyze and verify the effectiveness of the proposed model. The evaluation results show that our method has a better improvement effect than TransR on Mean Rank, Hits@10 and ACC indicators.
10
Ben-Baruch, Noa, Tamar Peretz-Yablonski, Georgeta Fried, Moshe J. Inbar, Yousef Samih, Victoria Neiman, Bella Nisenbaum, et al. "Next-generation sequencing (NGS) in relapsed/refractory triple-negative breast cancer (TNBC) in Israel." Journal of Clinical Oncology 32, no. 15_suppl (May 20, 2014): 1028. http://dx.doi.org/10.1200/jco.2014.32.15_suppl.1028.
11
Thouvenot, B., S. Verdun, J. Tomasina, B. Hilselberger, M. Brulliard, L. Bonnard, M. Trarbach, J. Armand, V. Ogier, and B. E. Bihain. "P272 Using next-generation sequencing to predict clinical outcome of triple negative breast cancer." Breast 24 (March 2015): S120. http://dx.doi.org/10.1016/s0960-9776(15)70304-8.
12
Elsayed, Islam, and Yoshiki Nishi. "A Feasibility Study on Power Generation from Solar Thermal Wind Tower: Inclusive Impact Assessment Concerning Environmental and Economic Costs." Energies 11, no. 11 (November 16, 2018): 3181. http://dx.doi.org/10.3390/en11113181.
Анотація:
A solar thermal wind tower (STWT) is a low-temperature power generation plant that mimics the wind cycle in nature, comprising a flat plate solar air collector and central updraft tower to produce thermal wind that drives turbines to generate electricity. The development of power generation systems toward a sustainable future needs to be made taking into account the balance between environmental impact and economic feasibility. We examine the sustainability of STWT power generation technology using the inclusive impact index light (Triple I-light), which estimates whether it is good to do the project, including both the negative environmental impact and the economic aspect. Environmental disadvantages are discussed by performing a CO2 inventory analysis for the life-cycle of the STWT power plant. Evaluation of the economic feasibility is done by calculating the levelized electricity cost (LEC), which is the cost per unit of electricity generated. From the calculations, it is found that overall system efficiency is increased by enlarging the capacity, the negative environmental impact by the STWT plant comes mainly from manufacturing stage (more than 60%), and the levelized electricity cost is dramatically decreased by enlarging the capacity of the system (about 50% reduction). A negative value of Triple I (meaning it is sustainable) can be achieved for high power generation capacity (above 100 MW). Moreover, this paper discusses the implementation and the potential of constructing offshore STWTs.
13
Caiazza, Francesco, Alyson Murray, Stephen F. Madden, Naoise C. Synnott, Elizabeth J. Ryan, Norma O’Donovan, John Crown, and Michael J. Duffy. "Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells." Endocrine-Related Cancer 23, no. 4 (April 2016): 323–34. http://dx.doi.org/10.1530/erc-16-0068.
Анотація:
AbstractThe androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC50values for the second-generation anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.
14
Lips, Esther H., Magali Michaut, Lennart Mulder, Nicolle Besselink, Marlous L. Hoogstraat, Marco J. Koudijs, Emile E. Voest, et al. "Next-generation sequencing to find predictors for chemotherapy response in triple-negative breast cancer (TNBC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1010. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1010.
Анотація:
1010 Background: In TNBC initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. Methods: To identify biomarkers of chemotherapy resistance and putative directed treatment targets, we performed next generation sequencing (NGS) of 2,000 genes implicated in oncogenesis. DNA from 31 pre-treatment biopsies and matched normal blood was sequenced. Biopsies were derived from patients scheduled to receive neoadjuvant chemotherapy with doxorubicin/cyclophosphamide. For the analysis, the tumors were divided in responders and non-responders, depending on whether or not a pathological complete remission (pCR) was achieved. Two definitions of pCR were employed: either the complete absence of infiltrating tumor cells in the breast (n=18) or a pCR of both the breast and lymph nodes (n=15). Tumors with partial or no responses were grouped in the non-responder category. Results: As a positive control, we verified that all patients with a known germline BRCA1 mutation (n=8) could be detected by the NGS analysis. In further analyses, we focused only on somatic mutations. Overall, the mutation rate was slightly higher in the non-responders (per tumor, average=12, range=[3-25]) than in the responders (average=8, range=[3-19]) (p=0.17). The analysis of individual genes did not reveal significant differences between responders and non-responders. However, pathway analysis showed that mutations in phosphatidylinositol signaling (e.g., PIK3CA, CALML5) were significantly more frequent in the non-responders, with mutations present in 10/13 non-responders and 2/18 responders (adjusted p=0.013). The chemokine and integrin signaling pathways also revealed a significantly higher mutation rate in the non-responders. Conclusions: Mutations in genes of the phosphatidylinositol pathway occur frequently in TNBCs that do not achieve a pCR on a neoadjuvant chemotherapy regimen consisting of doxorubicin and cyclophosphamide. After validation, alternative chemotherapy regimens and targeted agents should be investigated for these tumors.
15
Hu, Zhiwei, Rulong Shen, Amanda Campbell, Elizabeth McMichael, Lianbo Yu, Bhuvaneswari Ramaswamy, Cheryl A. London, Tian Xu, and William E. Carson. "Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON." Cancer Immunology Research 6, no. 6 (April 5, 2018): 671–84. http://dx.doi.org/10.1158/2326-6066.cir-17-0343.
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Wang, Wei, Hao Chen, Yang Xie, Sayantap Datta, Wei Li, and Ruiwen Zhang. "Abstract 678: Experimental therapy of triple negative breast cancer with next-generation of MDM2 inhibitors." Cancer Research 84, no. 6_Supplement (March 22, 2024): 678. http://dx.doi.org/10.1158/1538-7445.am2024-678.
Анотація:
Abstract Patients with triple-negative breast cancer (TNBC) typically experience minimal benefits from the existing hormonal or trastuzumab-based therapies, necessitating reliance on chemotherapy as the predominant treatment approach, which, unfortunately, is limited by insufficient efficacy, significant side effects, and the development of drug resistance. These issues highlight an urgent demand for the discovery and development of more effective and safer therapeutics for TNBC. Overexpression and amplification of the MDM2 oncogene frequently occur in TNBC, which is associated with invasive and high-grade/late-stage tumors, metastasis, and recurrence, and is an independent negative prognostic factor for TNBC patients. Extensive studies have indicated that MDM2 represents a novel molecular target for TNBC. Thus far, multiple strategies aiming at MDM2 inhibition have not succeeded in Phase II-III clinical trials, largely due to factors like inadequate efficacy, significant drug toxicity, and emergence of resistance. In addition, TNBC tumors commonly harbor mutant p53, and the existing MDM2 inhibitors that block p53-MDM2 binding and depend on wild-type p53 expression in the tumor to exert anticancer effects would have little or no clinical responses or even induce resistant clones by increasing MDM2 expression and its oncogenic activity. Therefore, there is a need for developing new-generation MDM2 inhibitors that are p53-independent. We recently discovered a novel class of MDM2 degraders, representing a paradigm shift in the strategy of targeting MDM2. One of these analogs, WW68, was identified as a potent and selective MDM2 inhibitor. Its in vitro and in vivo anti-breast cancer activities and underlying mechanisms of action were evaluated in breast cancer cell lines with various p53 backgrounds. Our results demonstrate that WW68 effectively induces MDM2 protein degradation. It selectively inhibits breast cancer cell growth, decreases cell proliferation, and induces G2/M phase arrest and apoptosis in breast cancer cells, regardless of p53 status. Notably, in clinically relevant TNBC PDX models, WW68 inhibited MDM2 and suppressed tumor growth without causing host toxicity. In conclusion, WW68 represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and may be developed as a novel anti-TNBC therapeutic agent. (Supported by NIH R01CA214019 and R01CA240447; and DoD W81XWH2010011) Citation Format: Wei Wang, Hao Chen, Yang Xie, Sayantap Datta, Wei Li, Ruiwen Zhang. Experimental therapy of triple negative breast cancer with next-generation of MDM2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 678.
17
Denu, Ryan A., Cissimol P. Joseph, Elizabeth S. Urquiola, Precious S. Byrd, Richard K. Yang, Ravin Ratan, Maria Alejandra Zarzour, et al. "Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors." Cancers 16, no. 9 (April 27, 2024): 1707. http://dx.doi.org/10.3390/cancers16091707.
Анотація:
Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.
18
Kareev, Yaakov, Naftali Halberstadt, and Dorit Shafir. "Improving Performance and Increasing the Use of Non-Positive Testing in a Rule-Discovery Task." Quarterly Journal of Experimental Psychology Section A 46, no. 4 (November 1993): 729–42. http://dx.doi.org/10.1080/14640749308401036.
Анотація:
A well-documented characteristic of rule discovery behaviour is subjects’ infrequent use of negative testing. Previous attempts at increasing the use of negative testing have met with little success. In an evaluation task, we found that subjects appreciate the benefits of negative testing and disconfirmation (Kareev & Halberstadt, this issue). Further, when given the choice, subjects prefer to begin their inquiry by employing a reception mode of inquiry, and only later switch to a generative strategy (Halberstadt & Kareev, 1992). In the present study we had subjects solve two rule-discovery problems. For the training problem, 180 subjects were assigned either to the traditional generation mode, in which subjects had to generate number triplets, or to a reception mode, in which subjects were presented with number triplets by the experimenter. For the subsequent test problem both groups used the traditional generation mode. Results revealed that subjects trained by the reception mode were more likely to use non-positive tests and more likely to solve the second problem. Apparently, training under the less demanding reception mode enabled subjects to realize the potential relevance of nonpositive testing.
19
Hossain, Fokhrul, Samarpan Majumder, Justin David, and Lucio Miele. "Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions." Cancers 13, no. 15 (July 26, 2021): 3739. http://dx.doi.org/10.3390/cancers13153739.
Анотація:
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and Drug Administration’ is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.
20
Alewine, Christine, Laiman Xiang, Takao Yamori, Gerhard Niederfellner, Klaus Bosslet, and Ira Pastan. "Efficacy of RG7787, a Next-Generation Mesothelin-Targeted Immunotoxin, against Triple-Negative Breast and Gastric Cancers." Molecular Cancer Therapeutics 13, no. 11 (September 19, 2014): 2653–61. http://dx.doi.org/10.1158/1535-7163.mct-14-0132.
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Zhu, X., J. Bayani, M. Dewan, H. Tovey, L. Kilburn, K. Taylor, J. Banerji, et al. "307P Identifying new biological subgroups of triple-negative breast cancer using next-generation integrative clustering pipeline." Annals of Oncology 34 (October 2023): S306—S307. http://dx.doi.org/10.1016/j.annonc.2023.09.503.
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Bhattarai, Shristi, Geetanjali Saini, Hongxiao Li, Gaurav Seth, Timothy B. Fisher, Emiel A. M. Janssen, Umay Kiraz, Jun Kong, and Ritu Aneja. "Predicting Neoadjuvant Treatment Response in Triple-Negative Breast Cancer Using Machine Learning." Diagnostics 14, no. 1 (December 28, 2023): 74. http://dx.doi.org/10.3390/diagnostics14010074.
Анотація:
Background: Neoadjuvant chemotherapy (NAC) is the standard treatment for early-stage triple negative breast cancer (TNBC). The primary endpoint of NAC is a pathological complete response (pCR). NAC results in pCR in only 30–40% of TNBC patients. Tumor-infiltrating lymphocytes (TILs), Ki67 and phosphohistone H3 (pH3) are a few known biomarkers to predict NAC response. Currently, systematic evaluation of the combined value of these biomarkers in predicting NAC response is lacking. In this study, the predictive value of markers derived from H&E and IHC stained biopsy tissue was comprehensively evaluated using a supervised machine learning (ML)-based approach. Identifying predictive biomarkers could help guide therapeutic decisions by enabling precise stratification of TNBC patients into responders and partial or non-responders. Methods: Serial sections from core needle biopsies (n = 76) were stained with H&E and immunohistochemically for the Ki67 and pH3 markers, followed by whole-slide image (WSI) generation. The serial section stains in H&E stain, Ki67 and pH3 markers formed WSI triplets for each patient. The resulting WSI triplets were co-registered with H&E WSIs serving as the reference. Separate mask region-based CNN (MRCNN) models were trained with annotated H&E, Ki67 and pH3 images for detecting tumor cells, stromal and intratumoral TILs (sTILs and tTILs), Ki67+, and pH3+ cells. Top image patches with a high density of cells of interest were identified as hotspots. Best classifiers for NAC response prediction were identified by training multiple ML models and evaluating their performance by accuracy, area under curve, and confusion matrix analyses. Results: Highest prediction accuracy was achieved when hotspot regions were identified by tTIL counts and each hotspot was represented by measures of tTILs, sTILs, tumor cells, Ki67+, and pH3+ features. Regardless of the hotspot selection metric, a complementary use of multiple histological features (tTILs, sTILs) and molecular biomarkers (Ki67 and pH3) resulted in top ranked performance at the patient level. Conclusions: Overall, our results emphasize that prediction models for NAC response should be based on biomarkers in combination rather than in isolation. Our study provides compelling evidence to support the use of ML-based models to predict NAC response in patients with TNBC.
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Khandelwal, Soni, Mallory Boylan, Gilbert Kirsch, Julian E. Spallholz, and Lauren S. Gollahon. "Investigating the Potential of Conjugated Selenium Redox Folic Acid as a Treatment for Triple Negative Breast Cancer." Antioxidants 9, no. 2 (February 5, 2020): 138. http://dx.doi.org/10.3390/antiox9020138.
Анотація:
Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•−). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2•−) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA.
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Pircher, Magdalena, Thomas Winder, and Andreas Trojan. "Response to Vemurafenib in Metastatic Triple-Negative Breast Cancer Harbouring a BRAF V600E Mutation: A Case Report and Electronically Captured Patient-Reported Outcome." Case Reports in Oncology 14, no. 1 (March 29, 2021): 616–21. http://dx.doi.org/10.1159/000513905.
Анотація:
Effective treatment options are still scarce for metastatic triple-negative breast cancers. An increasing interest in the mutational landscape of this disease will facilitate novel therapeutic strategies in a variety of cancers. Here we report the case of a 38-year-old female patient who developed multiple lung metastasis of a triple-negative breast cancer 2 years after the completion of local therapy. When she progressed after two palliative chemotherapy lines and local electroporation, a next-generation sequencing revealed a BRAF V600E mutation for which we initiated therapy with the BRAF inhibitor vemurafenib. Radiological improvement was already evident after 3 months and has been ongoing for 19 months so far with very few side effects, as is demonstrated by electronically captured patient-reported outcomes. To our knowledge, this is the first published case where a BRAF V600E-mutated advanced triple-negative breast cancer was successfully treated with vemurafenib.
25
Herrera Juarez, Mercedes, Pablo Tolosa Ortega, Ana Sanchez de Torre, and Eva Ciruelos Gil. "Biology of the Triple-Negative Breast Cancer: Immunohistochemical, RNA, and DNA Features." Breast Care 15, no. 3 (2020): 208–16. http://dx.doi.org/10.1159/000508758.
Анотація:
Background: The triple-negative breast cancer (TNBC) constitutes a heterogeneous disease with an aggressive behavior and a poor prognosis. A better understanding of its biology is required to identify new biomarkers and improve clinical outcomes. Summary: To date, the definition and classification of TNBC depends on a multiomic approach including immunohistochemistry (IHC), genomic, and transcriptomic features, and the tumor immune landscape. The development of new technologies has allowed us to sequence the whole cancer genome. The Cancer Genome Atlas (TCGA) and next-generation sequencing have led to a greater knowledge of DNA alterations such as TP53 or BRCA mutations, copy number variations, and DNA methylations. In addition, gene expression profiling has allowed to define a molecular intrinsic classification of TNBC based on mRNA. IHC and genomic profiling are also necessary to identify new immune biomarkers such as the presence of tumor-infiltrating lymphocytes and the expression of immune checkpoint molecules. Key Messages: This review aimed to provide recent knowledge of TNBC biology and classification focused on IHC, transcriptomics, genomic features, and the new immune biomarkers.
26
Desa, Danielle E., Wencheng Wu, Robert M. Brown, Edward B. Brown, Robert L. Hill, Bradley M. Turner, and Edward B. Brown. "Second-Harmonic Generation Imaging Reveals Changes in Breast Tumor Collagen Induced by Neoadjuvant Chemotherapy." Cancers 14, no. 4 (February 9, 2022): 857. http://dx.doi.org/10.3390/cancers14040857.
Анотація:
Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects, including the increased appearance of the ‘tumor microenvironment of metastasis’, image-based multicellular signatures that are prognostic of breast tumor metastasis. To assess whether NACT can induce changes in two other image-based prognostic/predictive signatures derived from tumor collagen, we quantified second-harmonic generation (SHG) directionality and fiber alignment in formalin-fixed, paraffin-embedded sections of core needle biopsies and primary tumor excisions from 22 human epidermal growth factor receptor 2-overexpressing (HER2+) and 22 triple-negative breast cancers. In both subtypes, we found that SHG directionality (i.e., the forward-to-backward scattering ratio, or F/B) is increased by NACT in the bulk of the tumor, but not the adjacent tumor-stroma interface. Overall collagen fiber alignment is increased by NACT in triple-negative but not HER2+ breast tumors. These results suggest that NACT impacts the collagenous extracellular matrix in a complex and subtype-specific manner, with some prognostic features being unchanged while others are altered in a manner suggestive of a more metastatic phenotype.
27
Yang, Biyao, Rui Sang, Yi Li, Ewa Goldys, and Wei Deng. "Abstract 5743: Liposome platform enables X-ray induced photodynamic therapy treatment against human triple negative breast cancer cells." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5743. http://dx.doi.org/10.1158/1538-7445.am2024-5743.
Анотація:
Abstract In this study, we employed X-ray induced photodynamic therapy (X-PDT) for the treatment on triple negative breast cancer (TNBC) cells. To do this, we rationally developed a liposome delivery system co-loaded with protoporphyrin IX (PPIX) and perfluorooctyl bromide (PFOB). Low-dose X-ray at 2Gy was employed to activate PPIX for reactive oxygen species (ROS) generation, and the co-loading of PFOB provided additional oxygen to augment ROS production. The highly toxic ROS triggered TNBC cell death. In vitro X-PDT effects including intracellular ROS generation, cytotoxicity, cell viability and apoptosis/necrosis assay in TNBC cells were studied. Our results indicate that the nanocarriers effectively induced X-PDT effect with very low dose radiation, which makes it possible to damage cancer cells. Our strategy may offer a paradigm-shifting treatment alternative for TNBC patients who need neoadjuvant radiotherapy but wish to avoid long term detrimental effect on functional outcome by undergoing X-PDT using only a fraction of the conventional radiotherapy. Citation Format: Biyao Yang, Rui Sang, Yi Li, Ewa Goldys, Wei Deng. Liposome platform enables X-ray induced photodynamic therapy treatment against human triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5743.
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Nagahashi, Masayuki, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Kazuhiro Yoshida, Takashi Kuwayama, Seigo Nakamura, et al. "Comprehensive genomic sequencing for triple negative breast cancer in Japan." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23122-e23122. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23122.
Анотація:
e23122 Background: Breast cancer is the leading cancer among women both in US and Japan. Triple negative breast cancer (TNBC) is the subset of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and HER2. While the selective ER modulator tamoxifen or anti-HER2 therapy for breast cancer patients with ER positive or HER2 protein overexpression are the most successful examples of targeted therapies, only limited therapies are available for patients with TNBCs, which are associated with a poor prognosis. Advance in next-generation sequencing enables us to identify actionable driver mutations that can be potentially treated by targeted therapies in each cancer patient. The aim of this study is to examine actionable driver mutations in TNBCs in Japan by comprehensive genomic sequencing (CGS) with 435 gene panel, and compare the driver events in Japan with TCGA database to validate the utility of CGS. Methods: We examined all exons of 435 known cancer genes in Japanese TNBC patients (N = 53) by CGS and evaluated for concordance among independent data obtained from The Cancer Genome Atlas-TNBC whole exome sequencing database (N = 123). Results: Oncogenic driver mutations were identified in 51 of 53 Japanese patients (96%) with TNBC and 36 of 53 patients (67%) harbored mutations in genes associated with FDA-approved targeted therapies, indicating the potential clinical utility of a large gene panel for evaluating patients with TNBC. Among 80 total genetic alterations, frequently mutated genes ( > 10% patients) were TP53, PIK3CA and PTEN. Overall, the mutation spectrum of the Japanese patients is similar to that of the TCGA population, except amplification of MYC. Conclusions: Use of a CGS panel of 435 genes can reliably identify all of the critical mutations in TNBC patients, which are similar as TCGA data. The information derived from CGS can be used to determine the optimal treatment for TNBC patients.
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Ashourpour, Maryam, Fatemeh Mostafavi Hosseini, Mohsen Amini, Ebrahim Saeedian Moghadam, Faranak Kazerouni, Seyed Yousef Arman, and Zahra Shahsavari. "Pyrazole Derivatives Induce Apoptosis via ROS Generation in the Triple Negative Breast Cancer Cells, MDA-MB-468." Asian Pacific Journal of Cancer Prevention 22, no. 7 (July 1, 2021): 2079–87. http://dx.doi.org/10.31557/apjcp.2021.22.7.2079.
30
Weisman, Paul S., Charlotte K. Y. Ng, Edi Brogi, Rachel E. Eisenberg, Helen H. Won, Salvatore Piscuoglio, Maria R. De Filippo, et al. "Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology." Modern Pathology 29, no. 5 (March 4, 2016): 476–88. http://dx.doi.org/10.1038/modpathol.2016.39.
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Sangiorgio, Valentina, Rocco Giovanni Piazza, Federica Mottadelli, Fabio Pagni, Inzoli Elena, Carlo Gambacorti-Passerini, Gianni Cazzaniga, and Elena Maria Elli. "P1056: NEXT GENERATION SEQUENCING IDENTIFIES SUBGROUPS OF PATIENTS WITH TRIPLE NEGATIVE/ PRIMARY THROMBOCYTOSIS WITH DIFFERENT CLINICAL OUTCOMES." HemaSphere 7 (August 2023): e7820571. http://dx.doi.org/10.1097/01.hs9.0000971120.78205.71.
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Berisha, Eranda, Maria del Carmen Chacon Castro, Adnin Ashrafi, Narges Salamat, Parinaz Sadat Alemi, and Li Zhang. "Abstract 4942: Heme targeting and its mechanistic role in triple-negative breast cancer suppression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4942. http://dx.doi.org/10.1158/1538-7445.am2023-4942.
Анотація:
Abstract Breast cancer is the second leading cause of cancer-related deaths and comprises of approximately 30% of all cancer cases affecting women in the United States. There are three subtypes of breast cancer based on receptor profiles, with the third subtype being triple-negative breast cancer. TNBC accounts for about 10-15% of all breast cancers. The TNBC subtype lacks estrogen, progesterone, and HER2 receptors; it is associated with BRCA1 and BRCA2 mutations. This type of cancer has poor prognosis, tends to be more aggressive, and has limited treatment options compared to the other two subtypes. Heme is an essential molecule in the oxidative phosphorylation pathway and in the generation of reactive oxygen species (ROS). ROS generation causes oxidative stress and induces DNA damage in breast cancer. Therefore, targeting its activity potentially suppresses TNBC tumors. Heme-sequestering protein 2 (HeSP2) binds and sequesters heme. It has been shown that HeSP2 treatment of MDA-MB-231 cells inhibited cell proliferation and colony formation. Moreover, HeSP2 suppresses tumor growth in subcutaneously implanted TNBC MDA-MB-231 xenografts in NOD/SCID mice. Furthermore, in vitro studies using murine TNBC cell models 4T1-fluc Neo and EMT6-fluc Puro cells have also shown that cell proliferation and colony formation were inhibited after HeSP2 treatments of increasing concentrations. Thus, these results encourage the potential use of HeSP2 for breast tumor suppression. To further explore the effects of heme targeting and sequestration, we will determine heme flux in TNBC cell models by measuring the levels of heme uptake, export, synthesis, and degradation. Moreover, we will examine mitochondrial markers for OXPHOS complexes in HeSP2 treated TNBC xenografts using immunohistochemical analysis. Further studies are still underway to understand the role of heme in breast cancer, with preliminary results indicating that heme targeting, and sequestration effectively suppress triple-negative breast cancer and its progression. Citation Format: Eranda Berisha, Maria del Carmen Chacon Castro, Adnin Ashrafi, Narges Salamat, Parinaz Sadat Alemi, Li Zhang. Heme targeting and its mechanistic role in triple-negative breast cancer suppression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4942.
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Yun, Jiwon, Jung-Ah Kim, Byungjin Hwang, Hee Sue Park, Kyongok Im, Sung-Min Kim, Dajeong Jeong, Kyu Min Lim, Duhee Bang, and Dong Soon Lee. "Triple-Negative Myeloproliferative Neoplasms Vs. Calr, JAK2 or MPL-Mutated Myeloproliferative Neoplasms: Distinct Molecular Characteristics." Blood 132, Supplement 1 (November 29, 2018): 1772. http://dx.doi.org/10.1182/blood-2018-99-118013.
Анотація:
Abstract Background: We compared the clinical, cytogenetic, molecular features, and telomere lengths of patients with triple negative MPN and MPN with any of CALR, JAK2 or MPL mutations. Methods: Target capture sequencing of 87 genes and molecular cytogenetic studies were performed in 61 Korean patients with MPN. Also, we searched the newly reported mutations and novel mutations in triple negative MPN [JAK2-G335D (germline), JAK2-F556V, JAK2-G571S (germline), JAK2-V625F (germline), MPL-T119I, MPL-S204F/P, MPL-E230G, MPL-V285E (germline), MPL-R321W (germline), MPL-Y591D, MPL-S505N and MPL-W515R]. We compared clinical and molecular characteristics between two groups. Additionally, we performed telomere quantitative FISH for 48 patients' samples and measured telomere/centromere ratios of them. Results: Among 61 patients, 13 patients showed mutations in CALR, 34 in JAK2, and 3 in MPL. All of JAK2 mutation and CALR mutation site were reported sites, but 2 among 5 mutation site of MPL were novel mutation [D128N, D261Y]. Twelve patients showed triple negative (7 of PMF 7, 2 of ET, and 3 of MPN-U) - they showed 8 different mutation sites among 6 different genes (ASXL1, DNMT3A, NPM1, POLG, SRSF2, and ZMYM3). NPM1, POLG, and ZMYM3 mutations were seen only in triple negative patients. NPM1 mutation was significantly higher in triple negative MPN (P=0.0301). In telomere length study, there was no statistical difference between triple negative group (T/C ratio mean 12.5) and CALR, JAK2 or MPL mutated group (T/C ratio mean 10.0). Although, MPN patients with telomere length shorter than normal control's lower 10% (7.04) showed poor prognosis (P=0.0045). Conclusions: Patients with triple negative MPN are characterized by high frequency of NPM1 mutation and less number of somatic mutations. Since the mutational analysis for diagnostic purposes is limited to exons 14 of JAK2, exon 10 of MPL and exon 9 of CALR at present, search for JAK2 and MPL mutations in other sites are essential in triple negative MPNs. Keywords: Myeloproliferative neoplasms, next-generation sequencing, triple negative MPN, chromosome, FISH, telomere Disclosures No relevant conflicts of interest to declare.
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Morris, Lindsay Kaye, Matthew Stein, Saradasri Karri, Srishti Sareen, Kruti Patel, Gregory A. Vidal, Lee Steven Schwartzberg, and Michael Gary Martin. "Distribution of receptor tyrosine kinase (RTK) nsSNPs in breast cancer (BC) patients (pts) using next-generation sequencing (NGS)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1080. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1080.
Анотація:
1080 Background: Non-synonymous SNPs (nsSNPs) discovered by NGS occurring in RTKs’ conserved topology in pts with BC may promote oncogenic signaling and hence may be actionable. Methods: We analyzed BC pts for nsSNPs in 29 RTKs identified by tumor profiling with NGS from Caris during 2013-2015. Mutations were classified by location including the tyrosine kinase domain (TKD), extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM) and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to determine pathogenicity. Results: 79 pts were identified with a median age of 58 years (range 32-83); 99% female; 60% white, 38% black and 2% other. 77 pts were classifiable with 8 (10%) triple-positive, 35 (46%) ER+/PR+/HER2- (ER/PR+), 10 (13%) ER-/PR-/HER2+ (HER2+) and 24 (31%) triple-negative. 78 nsSNPs and 1 Caris-reported pathogenic substitution of ERBB3 (TKD S846I) were found. 52/79 (66%) pts had ≥1 RTK nsSNP (range 0-4); 28/29 RTKs had ≥1 nsSNP with median of 2 (range 0-15). In 28 pts (35%), 40% of nsSNPs were predicted to be damaging (pnsSNP) and 3 pts had 2 pnsSNPs. 17/29 RTKs had pnsSNPs, median 1 (range 0-9). The most commonly mutated RTKs were ROS1 (9/15 variants were pnsSNPs), ALK (3/4), EPHA5 (3/3), FLT4 (2/5), cKIT (2/4) and ERBB4 (2/3). ROS1 and ALK nsSNPs were most-frequently seen in ER/PR+ (9/15 pnsSNPs), triple-positive (3/3) and HER2+ (0/2) pts; no triple-negative pts had such variants. 100% triple-positive pts (6/8 pnsSNP), 69% ER/PR+ (18/35), 60% HER2+ (2/10) and 58% triple-negative (3/24) had RTK nsSNP. nsSNP were spread in all 5 RTK regions: 58% localized to the ECD (20/45 pnsSNPs), 17% TKD (8/13), 9% CT (2/7), 9% TM (1/7) and 8% JM (1/6) lesions were found. Of 9 ROS1 pnsSNPs, 7 were ECD, 1 CT and 1 TKD. Conclusions: 35% of BC pts had pnsSNP in RTKs across various phenotypes including frequent mutations in potentially actionable genes such as ROS1 and ALK. 26% of ER/PR+ pts had pnsSNPs in ROS1 or ALK. nsSNPs in the ECD or TKD were most likely to be damaging.
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Kalyane, Dnyaneshwar, Suryanarayana Polaka, Nupur Vasdev, and Rakesh Kumar Tekade. "CD44-Receptor Targeted Gold-Doxorubicin Nanocomposite for Pulsatile Chemo-Photothermal Therapy of Triple-Negative Breast Cancer Cells." Pharmaceutics 14, no. 12 (December 6, 2022): 2734. http://dx.doi.org/10.3390/pharmaceutics14122734.
Анотація:
This study reports the CD44 receptor-targeted gold-doxorubicin nanocomposite (TGNC-DOX) for pulsatile chemo-photothermal therapy of triple-negative breast cancer (TNBC). The developed TGNC-DOX was nanometric, having a particle size of 71.34 ± 3.66 nm. The doxorubicin was loaded by electrostatic interaction with high entrapment and loading efficiency (>75%). TGNC-DOX showed potent photothermal response and reversible photothermal stability following irradiation with 808 nm NIR laser irradiation. Further, TGNC-DOX showed laser-responsive and pH-dependent drug release behavior suggesting its suitability for chemo-photothermal therapy, specifically at the tumor microenvironment site. Cellular viability, cellular uptake, ROS generation, and apoptosis assays suggested selective localization of TGNC-DOX in cancer cells that showed a significant cytotoxic effect against MDA-MB-231 breast cancer cells. Moreover, the developed TGNC-DOX showed ferroptosis in MDA-MB-231 cells. The event of TGNC-DOX-mediated thermal ablation is marked by a significant generation of reactive oxygen species (ROS) and apoptosis, as affirmed by flow cytometry. NIR-808 laser-responsive photothermal therapy of cancer cells was found to be more effective than without NIR-808 laser-treated cells, suggesting the fundamental role of photothermal ablation. The outcome concludes developed TGNC-DOX is a novel and potential tool to mediate laser-guided chemo-photothermal ablation treatment of cancer cells.
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Svidnicki, Maria Carolina Costa Melo, Paula De Melo Campos, Moisés Alves Ferreira Filho, Caio Augusto Leme Fujiura, Tetsuichi Yoshizato, Hideki Makishima, Seishi Ogawa, and Sara T. Olalla Saad. "Mutations in Triple-Negative Patients with Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 5395. http://dx.doi.org/10.1182/blood-2019-128764.
Анотація:
Background Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). JAK2, MPL, and CALR mutations are considered as "driver mutations" and are directly implicated in the disease pathogenesis by activation of JAK/STAT signaling. However, some patients do not harbor any of these mutations. Since such triple-negative MPNs are very rare, no specific molecular markers were established to use for a precise differential diagnosis yet. So far, the introduction of next generation sequencing (NGS) technologies in research of myeloid neoplasms has provided valuable contributions on the identification of new molecular biomarkers, establishing more accurate risk rating and selection of more specific therapeutic interventions. This study aimed to identify, through targeted deep sequencing, specific genetic variants in patients with triple-negative MPNs. Methods We performed NGS targeted sequencing in 18 Brazilian triple-negative patients (11 MF and 7 ET). The median age at diagnosis was 64 years for primary myelofibrosis (range 42-78), and 52 years for essential thrombocythemia (range 19-79). In 14 cases, we used the Illumina TruSight Myeloid Panel covering 54 genes and in 4 cases we used a custom Sure Select Agilent panel containing more than 300 genes previously reported to be related to myeloid neoplasm. The inclusion criteria for variant filtering was quality score>30, read count>50, minor allele frequency<0.05, frameshift, nonsense, splice site and 5`UTR variants, and missense variants described as deleterious for at least three prediction softwares. Results Possible pathogenic mutations were identified in 33 genes by Illumina and/or Agilent panels. Frameshift/nonsense or missense variants previously described as pathogenic correspond to 11 variants (Table 1). Out of these, mutations in TET2 were the most frequently identified (in 9/18 (50%) of the cases). In three MF patients with TET2 mutations no other considered pathogenic mutation was identified, indicating a possible role of TET2 as a driver gene. According to previous reports, the frequency of TET2 mutations in triple-negative MPNs patients were only 7%. Phenotypically, in our triple-negative MPNs, 6/11 (54.5%) MF and 3/7 (42.9%) ET patients harbored TET2 mutations. Clinically, the adverse prognostic impact of TET2 mutations in MPN had not been consistently shown by previous studies. In addition, mutations in SF3B1, CEBPA, and KMT2A genes were the second most frequent ones detected in 2/18 each (11%) of the patients, some of which were concomitant with TET2 mutations, suggesting additional clonal advantage due to these genetic events. Other potentially pathogenic variants were also detected is genes that have been reported to be related to other myeloid neoplasms (KMT2A, CDKN2A, TERT, DIS3, ZFPM1, PCDHA8, SAMD9, SAMD9L, DCLRE1C,ERBB3, SDHA, PCDHA6, SVEP1, MAP2K1 and EP300). Conclusions We have characterized the genomic alterations in 18 Brazilian patients with MPN triple-negative for either JAK2, CALR or MPL main mutations. Using a sensitive NGS platform, we identified significantly more frequent mutations in TET2 gene (in as many as a half of the cases) compared to JAK2, MPL, CALR mutation-positive MPN cases. We also uncovered mutations in genes not previously related with in MPN. Our novel findings call for further studies validating the frequencies, biological significance, and prognostic impacts of somatic mutations in triple-negative MPNs. Disclosures Ogawa: Qiagen Corporation: Patents & Royalties; RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; Asahi Genomics: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding.
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Dameri, Martina, Lorenzo Ferrando, Gabriella Cirmena, Claudio Vernieri, Giancarlo Pruneri, Alberto Ballestrero, and Gabriele Zoppoli. "Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer." International Journal of Molecular Sciences 22, no. 13 (July 1, 2021): 7154. http://dx.doi.org/10.3390/ijms22137154.
Анотація:
Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).
38
Bahman, Fatemah, Valeria Pittalà, Mohamed Haider, and Khaled Greish. "Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer." Journal of Personalized Medicine 11, no. 6 (June 15, 2021): 559. http://dx.doi.org/10.3390/jpm11060559.
Анотація:
Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC lacks human epidermal growth factor receptor 2 (HER2) amplification, is hormone independent estrogen (ER) and progesterone receptors (PR) negative, and is not reactive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment, but in spite of an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases, and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA–dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA–dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.
39
He, W., Y. Zhang, Y. Deng, and D. Kabelitz. "Induction of TCR-gamma delta expression on triple-negative (CD3-4-8-) human thymocytes. Comparative analysis of the effects of IL-4 and IL-7." Journal of Immunology 154, no. 8 (April 15, 1995): 3726–31. http://dx.doi.org/10.4049/jimmunol.154.8.3726.
Анотація:
Abstract It is well established that IL-4 and IL-7 control the differentiation of TCR-gamma delta-expressing cells from CD3/TCR-negative thymic precursors. In this study, we have compared the in situ expression of IL-4 and IL-7 mRNA in human postnatal thymus with the in vitro effect of IL-4 and IL-7 on the expansion of TCR-gamma delta + cells from highly purified CD3-4-8- triple-negative thymocytes. IL-4 mRNA expression was restricted to subcapsular regions of the human thymus, whereas cells expressing IL-7 mRNA were distributed throughout the thymic tissue, with some enrichment in subcapsular and cortical regions. Epithelial cells of the outer layer of Hassall's corpuscle strongly expressed IL-7 mRNA. IL-7 but not IL-4 or IL-2, stimulated strong proliferative activity and cellular expansion of triple-negative thymocytes. All three induced the appearance of TCR-gamma delta + cells within 4 days of culture. In the presence of IL-4 or IL-2, 30 to 55% of viable cells were TCR-gamma delta + after 5 to 9 days, whereas only 10 to 15% triple-negative thymocytes cultured with IL-7 expressed TCR-gamma delta. However, comparable absolute numbers of viable TCR-gamma delta + thymocytes were recovered when triple-negative thymocytes were cultured with IL-4 or IL-7, but not with IL-2. Taken together, our results suggest that IL-4 and IL-7 (both of which are produced in situ in thymic tissue) play equally important roles in the in vitro generation of TCR-gamma delta + thymocytes from triple-negative precursor cells.
40
Bian, Yanlin, Tong Lin, Tanja Jakos, Xiaodong Xiao, and Jianwei Zhu. "The Generation of Dual-Targeting Fusion Protein PD-L1/CD47 for the Inhibition of Triple-Negative Breast Cancer." Biomedicines 10, no. 8 (July 30, 2022): 1843. http://dx.doi.org/10.3390/biomedicines10081843.
Анотація:
Triple-negative breast cancer (TNBC) is a highly aggressive subset of breast cancer with limited therapeutic options. However, its immune evasion mechanisms, characterized by the over-expression of the immune checkpoint molecules PD-L1 and CD47, can be targeted in order to facilitate cancer elimination by cells of innate and adaptive immunity. In this paper, we describe the design, preparation, and evaluation of three novel dual-targeting fusion proteins that were based on the structure frame of prototype IAB (innate and adaptive dependent bispecific fusion protein) and the “Orcutt-type IgG-scFv” molecular model. Three molecules with different spatial conformations were designed to improve antigen–antibody affinity by the addition of Ag–Ab binding sites from the variable region sequences of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab and CV1, a high-affinity receptor of CD47. The results showed that the best-performing among the three proteins designed in this study was protein Pro3; its CV1 N-terminus and Fc domain C-terminus were not sterically hindered. Pro3 was better at boosting T cell proliferation and the engulfment of macrophages than the IAB prototype and, at the same time, retained a level of ADCC activity similar to that of IAB. Through improved design, the novel constructed dual-targeting immunomodulatory protein Pro3 was superior at activating the anti-tumor immune response and has thus shown potential for use in clinical applications.
41
Wang, Nan, Kun Li, Wenfa Huang, Weiyao Kong, Xiaoran Liu, Weijie Shi, Feng Xie, et al. "Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing." Chinese Journal of Cancer Research 32, no. 2 (2020): 149–62. http://dx.doi.org/10.21147/j.issn.1000-9604.2020.02.03.
42
Huang, Xin, Huanwen M. Wu, Changbin Zhu, Di Shao, Dan Guo, Yidong Zhou, Yan Lin, et al. "Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 558. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.558.
Анотація:
558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]
43
Landers, Mark, Rhonda Meredith, Jerry Lee, Yipeng Wang, Byung-In Lee, and Joseph Monforte. "Next-generation sequencing mutational analysis of triple-negative breast cancer patients from matched FFPE and fresh frozen samples." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1058. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1058.
Анотація:
1058 Background: TNBC is an aggressive subtype of breast cancer accounting for 10-15% of all cases. TNBC tumors (ER-/PR-/HER-) are more common in patients with BRCA mutations. BRCA mutations leading to homologous DNA repair deficient tumors enhance the efficacy of chemotherapy and PARP inhibitors. BRCA mutations have been identified in 20% of patients without family history. Identification of germline and somatic BRCA mutations in unselected patients could increase the number of patients who benefit from these therapies. Determining BRCA mutational status from FFPE and fresh frozen specimens may enable clinical studies in these patient populations.We describe the development of an NGS BRCA mutational assay compatible with FFPE and fresh frozen samples using tumor/adjacent normal matched tissues. Methods: Matched samples were purchased from Cureline. gDNA was isolated by lysis/column purification (Qiagen) and enriched for BRCA exons/flanking regions (Halogenomics Selector). Fragment libraries were constructed (Ion Torrent frag express) and prepared for sequencing by emPCR (Ion Torrent Template Xpress). Libraries were sequenced for 65 cycles (Ion Torrent PGM) yielding 2-4M reads/sample. Variants were called from tMAP aligned reads by GATK and VarScan. Overlapped exonic variants were filtered by p-value (<0.0001) from VarScan. Results: In the first patient set normalized average depth of BRCA exon coverage was 64X and 72X per 150K reads in FFPE and fresh frozen tissues respectively covering 95-100% of target. hg19 alignment rates varied between 97-99% across all samples. Similar numbers of variants were called in both FFPE (12) vs. fresh frozen (13) with a corresponding mean duplicate removed depth of coverage of 23.3X and 42.4X at the called positions. 10/13 calls in fresh frozen overlapped with those in FFPE. A tumor specific somatic frameshift insertion in BRCA2 was detected in both FFPE and fresh frozen tissues. Conclusions: Results indicate that NGS mediated BRCA mutational analysis demonstrates equivalent utility in both FFPE and fresh frozen tumor samples although more sequencing reads are required to produce equivalent depth of coverage starting from FFPE samples.
44
Anders, Carey K., Vandana Abramson, Tira Tan, and Rebecca Dent. "The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics." American Society of Clinical Oncology Educational Book, no. 36 (May 2016): 34–42. http://dx.doi.org/10.1200/edbk_159135.
Анотація:
Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as “immune-activated,” consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.
45
Khadela, Avinash, Vivek P. Chavda, Shruti Soni, Kaivalya Megha, Aanshi J. Pandya, and Lalitkumar Vora. "Anti-Androgenic Therapies Targeting the Luminal Androgen Receptor of a Typical Triple-Negative Breast Cancer." Cancers 15, no. 1 (December 30, 2022): 233. http://dx.doi.org/10.3390/cancers15010233.
Анотація:
Triple-negative tumors are progressively delineating their existence over the extended spectrum of breast cancers, marked by intricate molecular heterogeneity, a low overall survival rate, and an unexplored therapeutic approach. Although the basal subtype transcends the group and contributes approximately 80% to triple-negative breast cancer (TNBC) cases, the exceptionally appearing mesenchymal and luminal androgen receptor (LAR) subtypes portray an unfathomable clinical course. LAR with a distinct generic profile frequently metastasizes to regional lymph nodes and bones. This subtype is minimally affected by chemotherapy and shows the lowest pathologic complete response. The androgen receptor is the only sex steroid receptor that plays a cardinal role in the progression of breast cancers and is typically overexpressed in LAR. The partial AR antagonist bicalutamide and the next-generation AR inhibitor enzalutamide are being assessed in standard protocols for the mitigation of TNBC. There arises an inevitable need to probe into the strategies that could neutralize these androgen receptors and alleviate the trajectory of concerning cancer. This paper thus focuses on reviewing literature that provides insights into the anti-androgenic elements against LAR typical TNBC that could pave the way for clinical advancements in this dynamic sphere of oncology.
46
Andreidesz, Kitti, Balazs Koszegi, Dominika Kovacs, Viola Bagone Vantus, Ferenc Gallyas, and Krisztina Kovacs. "Effect of Oxaliplatin, Olaparib and LY294002 in Combination on Triple-Negative Breast Cancer Cells." International Journal of Molecular Sciences 22, no. 4 (February 19, 2021): 2056. http://dx.doi.org/10.3390/ijms22042056.
Анотація:
Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.
47
Shiau, Jun-Ping, Cheng-Che Wu, Shu-Jyuan Chang, Mei-Ren Pan, Wangta Liu, Fu Ou-Yang, Fang-Ming Chen, Ming-Feng Hou, Shen-Liang Shih, and Chi-Wen Luo. "FAK Regulates VEGFR2 Expression and Promotes Angiogenesis in Triple-Negative Breast Cancer." Biomedicines 9, no. 12 (November 29, 2021): 1789. http://dx.doi.org/10.3390/biomedicines9121789.
Анотація:
Triple-negative breast cancer (TNBC) remains a significant clinical challenge because of its high vascularity and metastatic and recurrent rates. Tumor angiogenesis is considered an important mediator in the regulation of tumor cell survival and metastasis in TNBC. Angiogenesis is induced by the binding of vascular endothelial growth factor to vascular endothelial growth factor receptor 2 (VEGFR2). Focal adhesion kinase (FAK) plays an important role in regulating various cell functions in normal and cancer cells. Previous studies have focused on investigating the function of endothelial FAK in tumor cell angiogenesis. However, the association between tumor FAK and VEGFR2 in tumor angiogenesis and the possible mechanisms of this remain unclear. In this study, we used a public database and human specimens to examine the association between FAK and VEGFR2. At the same time, we verified the association between FAK and VEGFR2 through several experimental methods, such as quantitative real-time polymerase chain reaction, Western blotting, and next-generation sequencing. In addition, we used the endothelial cell model, zebrafish, and xenograft animal models to investigate the role of FAK in TNBC angiogenesis. We found that FAK and VEGFR2 were positively correlated in patients with TNBC. VEGFR2 and several other angiogenesis-related genes were regulated by FAK. In addition, FAK regulated VEGFR2 and VEGF protein expression in TNBC cells. Functional assays showed that FAK knockdown inhibited endothelial tube formation and zebrafish angiogenesis. An animal model showed that FAK inhibitors could suppress tumor growth and tumor vascular formation. FAK promotes angiogenesis in TNBC cells by regulating VEGFR2 expression. Therefore, targeting FAK could be another antiangiogenic strategy for TNBC treatment.
48
Subhan, Md Abdus, Farzana Parveen, Hassan Shah, Satya Siva Kishan Yalamarty, Janaína Artem Ataide, and Valdimir P. Torchilin. "Recent Advances with Precision Medicine Treatment for Breast Cancer including Triple-Negative Sub-Type." Cancers 15, no. 8 (April 8, 2023): 2204. http://dx.doi.org/10.3390/cancers15082204.
Анотація:
Breast cancer is a heterogeneous disease with different molecular subtypes. Breast cancer is the second leading cause of mortality in woman due to rapid metastasis and disease recurrence. Precision medicine remains an essential source to lower the off-target toxicities of chemotherapeutic agents and maximize the patient benefits. This is a crucial approach for a more effective treatment and prevention of disease. Precision-medicine methods are based on the selection of suitable biomarkers to envision the effectiveness of targeted therapy in a specific group of patients. Several druggable mutations have been identified in breast cancer patients. Current improvements in omics technologies have focused on more precise strategies for precision therapy. The development of next-generation sequencing technologies has raised hopes for precision-medicine treatment strategies in breast cancer (BC) and triple-negative breast cancer (TNBC). Targeted therapies utilizing immune checkpoint inhibitors (ICIs), epidermal growth factor receptor inhibitor (EGFRi), poly(ADP-ribose) polymerase inhibitor (PARPi), antibody–drug conjugates (ADCs), oncolytic viruses (OVs), glucose transporter-1 inhibitor (GLUT1i), and targeting signaling pathways are potential treatment approaches for BC and TNBC. This review emphasizes the recent progress made with the precision-medicine therapy of metastatic breast cancer and TNBC.
49
Jagadish, Nirmala, Sonika Devi, Namita Gupta, Vitusha Suri, and Anil Suri. "Knockdown of A-kinase anchor protein 4 inhibits proliferation of triple-negative breast cancer cells in vitro and in vivo." Tumor Biology 42, no. 4 (April 2020): 101042832091447. http://dx.doi.org/10.1177/1010428320914477.
Анотація:
Triple-negative breast cancers are the most aggressive subtypes with poor prognosis due to lack of targeted cancer therapy. Recently, we reported an association of A-kinase anchor protein 4 expression with various clinico-pathological parameters of breast cancer patients. In this context, we examined the effect of knockdown of A-kinase anchor protein 4 on cell cycle, apoptosis, cellular proliferation, colony formation, migration, and invasion in triple-negative breast cancer cells. We also examined the synergistic cytotoxic effect of paclitaxel on A-kinase anchor protein 4 downregulated triple-negative breast cancer cells. Knockdown of A-kinase anchor protein 4 resulted in significant reduction in cellular growth and migratory abilities. Interestingly, we also observed enhanced cell death in A-kinase anchor protein 4 downregulated cells treated with paclitaxel. Knockdown of A-kinase anchor protein 4 in cell cycle resulted in G0/G1 phase arrest. Knockdown of A-kinase anchor protein 4 also led to increased reactive oxygen species generation as a result of upregulation of NOXA and CHOP. In addition, levels of cyclins, cyclin-dependent kinases, anti-apoptotic molecules, and mesenchymal markers were reduced in A-kinase anchor protein 4 downregulated cells. Moreover, downregulation of A-kinase anchor protein 4 also caused tumor growth reduction in in vivo studies. These data together suggest that A-kinase anchor protein 4 downregulation inhibits various malignant properties and enhances the cytotoxic effect of paclitaxel, and this combinatorial approach could be useful for triple-negative breast cancer treatment.
50
Mohammadhosseinpour, Sepideh, Alexx Weaver, Meenakshi Sudhakaran, Linh-Chi Ho, Tra Le, Andrea I. Doseff, and Fabricio Medina-Bolivar. "Arachidin-1, a Prenylated Stilbenoid from Peanut, Enhances the Anticancer Effects of Paclitaxel in Triple-Negative Breast Cancer Cells." Cancers 15, no. 2 (January 7, 2023): 399. http://dx.doi.org/10.3390/cancers15020399.
Анотація:
Triple-negative breast cancer (TNBC) is one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. To this end, the cytotoxic effects of the prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3), and non-prenylated resveratrol (RES) were evaluated in human TNBC cell lines as potential adjuvants for paclitaxel (Pac). A-1, alone or in combination with Pac, showed the highest cytotoxicity in TNBC cells. Apoptosis was further evaluated by measuring key apoptosis marker proteins, cell cycle arrest, and intracellular reactive oxygen species (ROS) generation. Furthermore, the cytotoxic effect of A-1 combined with Pac was also evaluated in a 3D spheroid TNBC model. The results showed that A-1 decreased the Pac IC50 approximately 2-fold in TNBC cells. The synergistic combination of A-1 and Pac arrested cells in G2/M phase and activated p53 expression. In addition, the combined treatment increased intracellular ROS generation and induced apoptosis. Importantly, the combination of A-1 with Pac inhibited TNBC spheroid growth. Our results demonstrated that A-1 in combination with Pac inhibited cell proliferation, induced apoptosis through mitochondrial oxidative stress, and reduced TNBC spheroid growth. These findings underscore the impactful effects of the prenylated stilbenoid A-1 as a novel adjuvant for Pac chemotherapy in TNBC treatment.