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Chi, Ya-Hui, Chun-Ping Chang, Teng-Kuang Yeh, Chiung-Tong Chen, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai i in. "Abstract 5806: Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus". Cancer Research 84, nr 6_Supplement (22.03.2024): 5806. http://dx.doi.org/10.1158/1538-7445.am2024-5806.
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Abstract Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A (AURKA) inhibitor that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer (BC) cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC- overexpressing xenografts including SCLC, triple-negative breast cancer (TNBC), hepatocellular carcinoma and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Chiung-Tong Chen, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chen-Lung Huang, Ya-Ping Chen, Hong Zhuang. Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus [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 5806.
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Chi, Ya-Hui, Chun-Ping Chang, Teng-Kuang Yeh, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen i in. "Abstract 523: Targeting myc-amplified cancers with a novel prodrug inhibiting aurora A kinase". Cancer Research 83, nr 7_Supplement (4.04.2023): 523. http://dx.doi.org/10.1158/1538-7445.am2023-523.
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Abstract Upregulation of Aurora kinases has been associated with increased tumor progression, and thus they are appealing targets for the development of anti-cancer therapies. In addition to have a critical role in cell cycle regulation, Aurora kinases have been shown to stabilize MYC-family oncoproteins for the maintenance of malignancy. Aurora kinase inhibitors such as Alisertib has demonstrated compelling anti-tumor efficacies; however, the reported side effects including serious haematological disturbances have limited its risk-benefit ratio in clinical use. In this study we discovered a novel pyrimidine-based Aurora kinase inhibitor compound A that degraded MYC- and MYCN- oncoproteins with better potency than Alisertib. The acyl-based prodrug design leads to the discovery of compound B which was able to regress MYC- or MYCN- overexpressing tumor xenografts including small cell lung cancer, neuroblastoma, hepatocellular carcinoma and medulloblastoma using a once-a-week (QW) oral dosing regimen. Pharmacokinetic studies revealed that the tumor/plasma ratio of compound B was about 20 at 24 h post drug administration, and the active compound remained detectable in the tumors after 7 days. No significant haematological or liver/kidney biochemical aberration was observed in mice treated with up to 500 mg/kg of DBPR728 on a QW dosing regimen in a 21-day cycle. The unique pharmacokinetic and molecular properties of compound B hold potential clinical promise for treating MYC- and MYCN- amplified tumors with manageable on-target haematological adverse effects caused by Aurora kinase inhibition. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chiung-Tong Chen. Targeting myc-amplified cancers with a novel prodrug inhibiting aurora A kinase [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 523.
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Ball, Alexander, Yung Lin Hsieh, Chun Kai Huang, Sega Huang, Ping Kuan Hsieh, Shang Ru Wu, Yue Yun Chang, Jiming Liu, Po Shin Peng i Chia Yi Lin. "Abstract 1325: Novel recombinant rabbit monoclonal antibodies for cancer biology research". Cancer Research 83, nr 7_Supplement (4.04.2023): 1325. http://dx.doi.org/10.1158/1538-7445.am2023-1325.
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Abstract Recombinant monoclonal antibodies (rAbs) are superior tools for cancer biology research as they offer distinct advantages over standard polyclonal and hybridoma-generated monoclonal antibody reagents. Recombinant technology produces antibodies that can be defined at the primary sequence level and are characterized by consistent performance and supply. These rAb features are in stark contrast to traditional polyclonal and hybridoma-generated monoclonal antibodies, whose lack of dependability has been widely documented as a primary reason for data irreproducibility plaguing biomedical research. In an effort to respond to this challenge, GeneTex has established a recombinant antibody production platform combined with more rigorous validation protocols. The goal is to develop reliable recombinant rabbit monoclonal antibodies for reproducible performance in various experimental applications utilized routinely by cancer biologists. GeneTex’s rAb production protocol is based on the approach described by Starkie et al. (2016). This involves a multi-parameter fluorescence-activated single cell sorting (FACS)-based methodology to identify and isolate antigen-specific IgG+ memory B cells obtained from an immunized rabbit. The heavy and light chain variable region genes from selected cells are PCR-amplified and cloned into plasmids to produce full-length heavy and light chains for a single IgG. These constructs are subsequently introduced together into mammalian cells for expression, meaning that natural pairing of the chains is maintained. This manufacturing strategy allows application-specific testing (e.g., for western blot (WB), immunohistochemistry (IHC), and immunocytochemistry (ICC/IF), etc.) of clones during the antibody production process. Validation of antibodies is performed inhouse and, when possible, in relationships with academic or industry/pharma institutions where ideal samples and reagents are frequently more available. This recombinant monoclonal antibody production platform has created a series of well-validated antibodies against many important targets for cancer biology research. This includes reagents to study tumor immunobiology (e.g., PD-L1), hormone receptors (e.g., ER alpha and androgen receptor variants like ARV7), oncogenic RAS protein mutants (e.g., RAS G12D), transcription factors (e.g., NRF2), and epithelial-mesenchymal transition (EMT) (e.g., E-cadherin), among many others. Extensive validation for multiple applications was performed, with knockdown or CRISPR-based knockout cell lysates employed when possible to establish specificity. In summary, GeneTex is utilizing a FACS-based recombinant rabbit monoclonal antibody production approach to generate and thoroughly validate antibody reagents that will hopefully facilitate reproducible cancer biology research. Citation Format: Alexander Ball, Yung Lin Hsieh, Chun Kai Huang, Sega Huang, Ping Kuan Hsieh, Shang Ru Wu, Yue Yun Chang, Jiming Liu, Po Shin Peng, Chia Yi Lin. Novel recombinant rabbit monoclonal antibodies for cancer biology research [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 1325.
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Li, Ning, Peng Jiang, Yuzhen Huang, Yuan TU, Wei Kong, Shan Jiang, Jingni Zhang i in. "Estrogen Receptor- And Progesterone Receptor-Positive Thresholds in Predicting the Recurrence of Early Low-Risk Endometrial Cancer". Clinical Medicine Insights: Oncology 16 (styczeń 2022): 117955492211032. http://dx.doi.org/10.1177/11795549221103200.
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Background: Estrogen receptors (ER) and progesterone receptors (PR) have important prognostic value in endometrial cancer, but there is no recognized positive immunohistochemical threshold for predicting the recurrence of early low-risk endometrial cancer. The purpose of this study was to clarify the optimal positive thresholds of the immunohistochemical parameters the ER and PR in early low-risk endometrial cancer. Methods: A total of 332 patients with stage IA endometrial cancer were enrolled from the First Affiliated Hospital of Chongqing Medical University and People’s Hospital of Sha ping ba District in Chongqing between January 2013 and December 2018. First, univariate and multivariate Cox regression analyses were used to analyze the correlation between various clinical factors and the prognosis of early low-risk endometrial cancer. Then, the receiver operating characteristic curve (ROC curve) and Youden index were used to determine the positive thresholds of ER and PR. Results: The positive thresholds of ER and PR for predicting the recurrence of early low-risk endometrial cancer were 12% and 8%, respectively. Multivariate analysis showed that ER ( P = 0.004), PR ( P = 0.026), and p53 ( P = 0.021) were risk factors for the prognosis of patients with early low-risk endometrial cancer. The recurrence-free survival and the overall survival in the low ER group and PR group were much lower than those in the high ER group and PR group ( P < 0.001 of all). Conclusions: ER and PR positive thresholds of 12% and 8%, respectively, are the most suitable for predicting the recurrence of early low-risk endometrial cancer.
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Bondebjerg, Ib. "Kritisk teori, æstetik og receptionsforskning". MedieKultur: Journal of media and communication research 4, nr 7 (26.01.1988): 26. http://dx.doi.org/10.7146/mediekultur.v4i7.765.
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Det er receptionsforskningens uomtvistelige fortjeneste, at den har sat focus på modtagernes oplevelser og vurderinger. Brugerne tages tilsyne- ladende alvorligt, i modsætning til den kritiske teori (Frankfurterskolen m.v.), der i debatten om receptionsforskningen er blevet beskyldt for at være formynderisk: Den tager stilling til æstetisk og indholdsmæssig kvalitet på brugernes vegne. I denne artikel forsøger Ib Bondebjerg at fastholde en del næsten glemte, men fundamentale nuancer (ikke mindst mht. tekstens status i forhold til oplevelsen) i både den kritiske teori, semiotikken og dele af receptions- forskningen. Hermed bidrages til den diskussion om hvem der skal fast- lægge den kulturelle og æstetiske værdi i et medieprodukt som tages op af både Jensen, Schrøder og Skovmand i dette nummer. Indirekte viser Bondebjerg, at der sker en afpolitisering af medierne, hvis de alene eksisterer i en uproblematiseret relation mellem afsender og modtager. Populært TV konstrueres jo netop så det fremtræder lyst- og spændings- fyldt og kommer herved til at virke som et passivt spejl for modtagerne. Hvis kunsten forråder det smertefulde og tabuiserede, bliver den ufarlig. Mediernes eneste formål bliver da at igangsætte et på forhånd kalkuleret ping-pong-spil mellem den enkeltes erfaringer, oplevelser og fantasier. Heroverfor stiller Bondebjerg den demokratiske radikalisme hvor æstetik- ken udgør et kampområde. Kunsten er med andre ord en politisk agent, hvor både afsenderen, modtageren og samfundet selv aktivt er med i forandringsprocessen. - "Perspektivet er at gøre modtagerne til kvalifi- cerede producenter i videste forstand".
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Hou, Sharon S. J., i Huang Wei-liang. "Huo-yu te feng-hung: Yu Kuang-chung tso-p'in p'ing-lun chi (Huo-yu de feng-huang)---(Yu Guang-zhong zuo pin ping-lun ji)". Chinese Literature: Essays, Articles, Reviews (CLEAR) 7, nr 1/2 (lipiec 1985): 201. http://dx.doi.org/10.2307/495212.
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Agger, Gunhild. "Reklamen som pastiche. Om Dansk Sygeplejeråds annoncekampagne efteråret 1986". MedieKultur: Journal of media and communication research 5, nr 10 (27.03.1989): 19. http://dx.doi.org/10.7146/mediekultur.v5i10.808.
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Der er flere og flere medieproducenter, der anser modtagerne for at besidde en vis tekstuel intelligens. Fra detektivpasticher som Dick Spanner og Batman over den konstant genreparodierende "Moon- lighting" (De heldige helte) til Poul og Nulles respektløse faktion "I sandhedens Tjeneste" leges der med betydningsdannelsen. Seerne/læserne indbydes til selv at spille ping-pong med billeder og tekst. Gunhild Agger analyserer her denne tendens, sådan som den kom- mer til udtryk inden for reklamen: Anker Jørgensen som James Bond, og kondomer til Prinsessen på Ærten! Mest indgående beskæftiger hun sig med Dansk Sygeplejeråds brug af myten om sygeplejersken i en annoncekampagne op mod overenskomstforhandlingerne i 1987. Gunhild Agger nøjes ikke med en indholdsanalyse af annoncerne, men beskriver hele kampagnen: Dansk Sygeplejeråds hensigter med frem- stødet, kampagnens lancering over for den tre-dobbelte målgruppe, læsernes formodede reception, og kampagnens politiske og holdnings- mæssige effekter.
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Quroturohman, Denis. "PENETRATION TESTING DALAM FORENSIK DIGITAL PADA JARINGAN FAKULTAS TEKNIK UNIVERSITAS IBN KHALDUN BOGOR DENGAN PING OF DEATH". Jurnal Inovatif : Inovasi Teknologi Informasi dan Informatika 4, nr 2 (3.11.2021): 81. http://dx.doi.org/10.32832/inova-tif.v4i2.5812.
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<p><em>Network forensics is a computer security investigation to find sources of the attack s on the network by examining data log evidence, identifying, analyzing, and reconstructing the incidents. Types of attack s againist a computer or server on the network by spending resources that are owned by the computer until computer is not able to function properly, thus indirectly preventing other users to obtain access to network services that were attack ed is Distributed Denial of Service attack (DDoS). Network Forensics Research conducted in Research Laboratory of Information Engineering Master of Ahmad Dahlan University Yogyak arta. Detection of attacks carried out by Winbox RouterOS v3,6 where the software shows resources, attack er (IP Address), data pack ets, and when attack doing. Simulated attack s carried out by LOIC software to determine performance of safety system in computer network . To anticipate DDoS attack s,then developed a computer network security system.</em></p>
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Wang, Ping, Mariam Hassan i Anjan Chatterjee. "1493. The Incremental Burden of Nontuberculous Mycobacterial Lung Disease (NTMLD) among Patients with chronic obstructive pulmonary disease (COPD): Hospitalizations and ER Visits among US Medicare Beneficiaries". Open Forum Infectious Diseases 7, Supplement_1 (1.10.2020): S748—S749. http://dx.doi.org/10.1093/ofid/ofaa439.1674.
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Abstract Background NTMLD is a rare mycobacterial infection characterized by worsening lung function and increased healthcare resource burden. Many patients with NTMLD have comorbid respiratory diseases such as COPD. Management of NTMLD in patients with COPD may not get adequate attention as clinical management of COPD is often prioritized. There is a lack of data quantifying the incremental burden of NTMLD among patients with COPD. We assessed the incremental burden of NTMLD in patients with comorbid COPD by comparing their healthcare resource utilization (HCRU), in terms of hospitalizations and emergency room (ER) visits, to matched COPD patients without NTMLD. Methods A retrospective cohort study was conducted using the US Medicare claims database (2010-2017). COPD patients with NTMLD were matched 1:3 to COPD patients without NTMLD (controls) by age and gender. HCRU was assessed in terms of hospitalizations (all-cause, respiratory related and COPD related) as well as ER visits (with and without subsequent hospitalization) over a 12-month follow-up period. Incremental burden of NTMLD was assessed by comparing the HCRU between COPD patients with NTMLD and controls using univariate and multivariate analyses adjusting for baseline comorbidities. Results A total of 4,010 COPD patients with NTMLD were matched to 12,030 controls. In univariate analyses, a significantly higher proportion of COPD patients with NTMLD had hospitalizations and ER visits compared to controls (Fig 1(A)); the number of hospitalizations and ER visits were also higher among patients with NTMLD (Fig 2(A)). This incremental burden was also reflected in subsequent multivariate analyses after adjusting for baseline comorbidities. As an example, respiratory-related hospitalizations in COPD patients with NTMLD had Odds Ratio of 2.5 (95%CI 2.2-2.7) and Incident Rate Ratio (IRR) of 2.3 (95%CI 2.1-2.4) compared to controls (Fig 1(B), 2(B)). Figure 1: Proportion of Patients (A) and Odds Ratio (B) of Hospitalizations and ER Visits over a 12-month follow-up period among COPD patients with NTMLD vs. matched COPD patients without NTMLD. Figure 2: Per Patient Rate (A) and Incidence Rate Ratio (B) of Hospitalization and ER Visits over a 12-month follow-up period among COPD patients with NTMLD vs. matched COPD patients without NTMLD. Conclusion COPD patients with NTMLD have a significantly higher disease burden due to hospitalizations and ER visits compared to COPD patients without NTMLD. These findings suggest the substantial incremental burden that NTMLD adds to existing COPD in patients and highlight the urgent need for attention and appropriate management. Disclosures Ping Wang, PhD, Insmed Incorporated (Employee) Mariam Hassan, PhD, B. Pharm, Insmed Incorporated (Employee) Anjan Chatterjee, MD, MPH, Insmed Incorporated (Employee)
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Chen, Mei-Kuang, Grace DeAlessandro, Tuyen Bui i Khandan Keyomarsi. "Abstract PO2-04-14: Dual Inhibition of WEE1 and PKMYT1 Synergistically Overcomes CDK4/6 Inhibitor Resistance in Breast Cancer". Cancer Research 84, nr 9_Supplement (2.05.2024): PO2–04–14—PO2–04–14. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-04-14.
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Abstract Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are approved for the treatment of advanced estrogen receptor-positive, HER2-negative (ER+ve) breast cancer when combined with endocrine therapy. However, the emergence of resistance to CDK4/6 inhibitors poses a significant clinical challenge. This study investigates the mechanisms underlying CDK4/6 inhibitor resistance and identifies a common occurrence of high replication stress in triple-negative breast cancer (TNBC) and CDK4/6 inhibitor-resistant ER+ve breast cancers. While ER+ve breast cancer patients have benefited from targeted therapy, TNBC patients, particularly those without germline BRCA1/2 or PALB2 mutations, lack effective treatment options. TNBC and CDK4/6 inhibitor-resistant ER+ve breast cancer cells exhibit an increased dependence on cell cycle arrest to repair replication stress-induced DNA damage. Failure to exit the cell cycle results in excessive DNA damage, thereby limiting their proliferative potential. Based on these findings, we hypothesize that dual inhibition of WEE1 and PKMYT1, two kinases involved in G2/M cell cycle transition and crucial for cell cycle arrest and DNA damage repair, could synergistically inhibit tumor growth. Although WEE1 and PKMYT1 share a common function in promoting G2/M cell cycle transition through CDK1 phosphorylation, their functions are not entirely redundant, suggesting that targeting both kinases may elicit a synergistic response. Recent clinical trials have shown resistance to WEE1-targeted monotherapies, emphasizing the need for combining WEE1 inhibitors with other agents, such as PKMYT1 inhibitors. We demonstrate the synergistic effects of WEE1 inhibitor (MK1775/AZD1775) and PKMYT1 inhibitor (RP6306) in a panel of TNBC and ER+ve breast cancer cells with acquired palbociclib resistance (PalboR). Combination treatment with both inhibitors leads to excessive unrepaired DNA damage, as indicated by increased γH2AX foci following 48 hours of combination treatment, whereas single-agent treatments induce significantly lower levels of DNA damage. Furthermore, we observed the AZD1775/RP6306 combination decreases the expression of the DNA repair protein Rad51 in PalboR cells. To evaluate the clinical potential of dual WEE1 and PKMYT1 inhibition, we generated organoids from metastatic breast cancer lesions of patients who had progressed on CDK4/6 inhibitors for ex vivo studies. Our results demonstrate that dual inhibition of WEE1 and PKMYT1 is more effective than single-agent treatments in eliminating CDK4/6 inhibitor-resistant organoids. Additionally, using patient-derived xenograft mouse models from patients who had progressed on palbociclib and endocrine treatment, we show that the AZD1775/RP6306 combination exhibits superior tumor suppression effects compared to single agents. Overall, this study highlights the potential therapeutic benefits of dual inhibition of WEE1 and PKMYT1 in overcoming CDK4/6 inhibitor resistance in TNBC and ER+ve breast cancer patients. These findings provide a rationale for future clinical trials aimed at exploring the clinical utility of this combination therapy. Citation Format: Mei-Kuang Chen, Grace DeAlessandro, Tuyen Bui, Khandan Keyomarsi. Dual Inhibition of WEE1 and PKMYT1 Synergistically Overcomes CDK4/6 Inhibitor Resistance in Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-14.
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Lee, Pony Yu-Ling, Marvin A. Aberin, Chien-Chang Shen, Kun-Yuan Lin, Chao Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya Wen Hung, Xin-Guo Hsu i Shu-Ping Wang. "Abstract 5953: Reshaping the tumor microenvironment: new application of tamoxifen in triple negative breast cancer immunomodulation". Cancer Research 83, nr 7_Supplement (4.04.2023): 5953. http://dx.doi.org/10.1158/1538-7445.am2023-5953.
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Abstract Tamoxifen is a widely known estrogen receptor (ER) modulator which has been employed in adjuvant treatment of ER+ breast cancer for over 30 years. Interestingly, clinical observations reveal that tamoxifen is capable of inducing regression of some tumors lacking ER expression whereas tamoxifen is also capable of increasing host resistance against cancer in an ER-independent mechanism. These findings suggest the immunomodulatory effects of tamoxifen may be ER-independent, but little is known about the underlying mechanism and the potential clinical implication. Recently, we identified a novel mechanism by which tamoxifen exerts its DNA-damaging potential by re-shaping the unfavorable tumor microenvironment in breast cancer. A long-term tamoxifen administration induces downregulation of the chromatin ‘‘reader’’ RACK7/ZMYND8, which acts as a suppressor of interferon-stimulated genes (ISGs, including cytokines and chemokines) and CEACAM1 in both ER+ and triple negative breast cancer (TNBC) cells. To investigate the immunomodulatory effects of tamoxifen in conjunction with RACK7-knockdown, the orthotopic murine TNBC 4T1 model was employed to investigate tamoxifen-mediated cellular modulation in TNBC. The control and RACK7-knockdown 4T1 cells are orthotopically implanted into the mammary fat pad of female BALB/c mice. Peripheral cytokines/chemokines and high-content biomarker studies (multiplex immunoassays, flow cytometry, and single-cell RNA sequencing) are deployed to obtain insights into the mechanistic rationale behind the immunomodulatory effects of tamoxifen and/or RACK7-knockdown. The tamoxifen-mediated cellular modulation evokes cytokine/chemokine secretion and further induces T-cell infiltration into tumor area. However, tumor reduction was limited due to extensive T-cell exhaustion from interaction of CEACAM1 and TIM-3, a “checkpoint” receptor expressed in CD4+ and CD8+ T cells. The expression patterns of CEACAM1 and PD-L1 in 4T1 tumor cells and that of TIM-3 and PD-1 in CD4+ and CD8+ T-cells correlate with intra-tumor infiltration of T-cells and tumor cell growth. Therefore, targeting the interaction between CEACAM1 and TIM-3 to overcome T-cell exhaustion is crucial for the new therapeutic role of tamoxifen treatment in TNBC breast cancer in conjugation with RACK7-knockdown. Altogether, our findings provide direct evidence to support a new therapeutic opportunity by targeting CEACAM1-TIM-3 interaction in the tamoxifen-mediated tumor immune microenvironment for improving immune checkpoint blockade therapy in breast cancer. Citation Format: Pony Yu-Ling Lee, Marvin A. Aberin, Chien-Chang Shen, Kun-Yuan Lin, Chao Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya Wen Hung, Xin-Guo Hsu, Shu-Ping Wang. Reshaping the tumor microenvironment: new application of tamoxifen in triple negative breast cancer immunomodulation. [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 5953.
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Li, Hui-Ping, Qingyuan Zhang, Ruyan Zhang, Yaxin Liu i Xianjun Hu. "Abstract PO4-04-01: Antitumor activity and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER and HER2 both positive metastatic breast cancer: A phase Ib study". Cancer Research 84, nr 9_Supplement (2.05.2024): PO4–04–01—PO4–04–01. http://dx.doi.org/10.1158/1538-7445.sabcs23-po4-04-01.
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Abstract Abstract PURPOSE Sacibertinib (Hemay022) is a novel irreversible tyrosine kinase inhibitor (TKI) blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study aimed to explore the safety and efficacy of sacibertinib plus endocrine therapy in patients with estrogen receptor-positive ( PATIENTS AND METHODS Using a phase 1b 3+3 dose escalation and expansion study design, patients with ER+/HER2+ MBC were treated with sacibertinib (200mg-500mg daily) plus endocrine therapy including exemestane, letrozole, fulvestrant. The safety, pharmacokinetic and clinical efficacy, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and progression-free survival (PFS) were assessed. RESULTS A total of 55 ER+/HER2+ MBC patients pretreated with chemotherapy and anti-HER2 therapy were enrolled in the study between March, 2018 and July, 2021. The incidence of ORR ranged from 17.6% to 42.9%, DCR ranged from 63.0% to 86.8%, CBR ranged from 42.3% to 69.7%, and the overall median PFS was 9.0 (95% CI, 5.5 ~ 11.00) months. In the 400 mg Sacibertinib plus exemestane cohort (N = 18), ORR was 38.9% (7/18), DCR was 72.2%(13/18), CBR was 66.7%(12/18), and median PFS was 8.9 months; In the 500 mg Sacibertinib plus exemestane cohort (N = 12), ORR was 25.0%(3/12), DCR was 100.0%(12/12), CBR was 50.0%(6/12), and median PFS was 9.0 months. The ORR, CBR, and DCR were better in the 400 mg and above dose cohorts than in the 200 mg and 300 mg cohorts. The DCR of the 500 mg combined with exemestane cohort was better than that of the other dose cohorts. Sacibertinib plus endocrine therapy was well-tolerated without dose-limiting toxicities. The most frequent grade 3 adverse events included diarrhoea (9.1%), leucopenia(5.5%), neutropenia (3.6%). One (1.8%) had grade 4 hydropericardium. CONCLUSION Sacibertinib plus endocrine therapy had a favorable safety profile and antitumor activity in patients with ER+/HER2+ MBC, 400-500mg daily showed more efficacy, supporting further assessment in randomized studies. This figure showed response of Sacibertinib plus endocrine therapy in ER+/HER2+ metastatic breast cancer. Citation Format: Hui-Ping Li, Qingyuan Zhang, Ruyan Zhang, Yaxin Liu, Xianjun Hu. Antitumor activity and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER and HER2 both positive metastatic breast cancer: A phase Ib study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-01.
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Sun, Yu, i Longhai Zhang. "Shakespeare across the Taiwan Strait: A Developmental Perspective". Multicultural Shakespeare: Translation, Appropriation and Performance 20, nr 35 (30.12.2019): 115–31. http://dx.doi.org/10.18778/2083-8530.20.09.
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Shakespeare studies in Mainland China and Taiwan evolved from the same origin during the two centuries after Shakespeare being introduced into China in the early nineteenth century. Although Shakespeare was first seen on the Taiwan stage in the Japanese language during the colonial period, it was after Kuomintang moved to Taiwan in 1949 that Shakespeare studies began to flourish when scholars and theatrical experts from mainland China, such as Liang Shih-Chiu, Yu Er-Chang, Wang Sheng-shan and others brought Chinese Shakespeare to Taiwan. Since the 1980s, mainland Shakespeareans began to communicate actively with their colleagues in Taiwan. With the continuous efforts of Cao Yu, Fang Ping, Meng Xianqiang, Gu Zhengkun, Yang Lingui and many other scholars in mainland China and Chu Li-Min, Yen Yuan-shu, Perng Ching-Hsi and other scholars in Taiwan, communications and conversations on Shakespeare studies across the Taiwan Strait were gradually enhanced in recent years. Meanwhile, innovations in Chinese adaptations of Shakespeare have resulted in a new performing medium, Shake-xiqu, through which theatrical practitioners on both sides explore possibilities of a union of Shakespeare and traditional Chinese theatre. This paper studies some intricate relationship in the history of Shakespeare studies in mainland China and Taiwan from a developmental perspective and suggests opportunities for positive and effective co-operations and interactions in the future.
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Li, Hui-Ping, Qingyuan Zhang, Ruyan Zhang, Yaxin Liu, Chang Liu i Xianjun Hu. "Abstract PO2-27-11: Antitumor efficacy and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER+ and HER2+ metastatic breast cancer: A phase Ib study". Cancer Research 84, nr 9_Supplement (2.05.2024): PO2–27–11—PO2–27–11. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-27-11.
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Abstract PURPOSE Sacibertinib (Hemay022) is a novel irreversible tyrosine kinase inhibitor (TKI) blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study aimed to explore the safety and efficacy of sacibertinib plus endocrine therapy in patients with estrogen receptor-positive (ER+) and HER2-positive (HER2+) >metastatic breast cancer (MBC). PATIENTS AND METHODS Using a phase 1b 3+3 dose escalation and expansion study design, patients with ER+/HER2+ MBC were treated with sacibertinib (200mg-500mg daily) plus endocrine therapy including exemestane, letrozole, fulvestrant . The safety, pharmacokinetic (PK) and clinical efficacy, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and progression-free survival (PFS) were assessed. (Clinical Trials.gov identifier: NCT03308201). RESULTS A total of 55 ER+/HER2+ MBC patients pretreated with chemotherapy and anti-HER2 therapy were enrolled in the study between March, 2018 and July, 2021. Fifty-five patients were included in safety analysis and 51 patients were assessed for efficacy analysis. Sacibertinib plus endocrine therapy was well-tolerated without dose-limiting toxicities. The overall median PFS was 9.0 months [95% confidence interval (95% CI), 5.5 ~ 11.0]. The ORR, CBR, and DCR were better in the 400 mg and 500mg dose cohorts than in the 200 mg and 300 mg cohorts. The DCR of the 500 mg combined with the exemestane cohort was better than that of cohorts of other doses. In the 400 mg sacibertinib plus exemestane cohort (N = 18), ORR was 38.9% (7/18) , DCR was 72.2%(13/18), CBR was 66.7%(12/18), and median PFS was 8.9 months (95%CI, 2.7 ~ 16.4 ) ; In the 500 mg sacibertinib plus exemestane cohort (N = 12), ORR was 25.0% (3/12), DCR was 100%(12/12), CBR was 50.0%(6/12), and median PFS was 9.0 months (95%CI, 2.1~NA. Treatment-emergent AEs (TEAEs) were mostly within grades 1–2. The most frequent grade 3 TEAE was diarrhea (9.1%). One (1.8%) had grade 4 abnormal liver function. CONCLUSIONS Sacibertinib plus endocrine therapy had a favorable safety profile and antitumor activity in patients with ER+/HER2+ MBC, 400 -500mg sacibertinib daily showed more efficacy, supporting further assessment in randomized studies. Summary of efficacy data(EAS) NOTE. NA, not available (because cannot be calculated) Treatment-Emergent Adverse Events Occurring in ≥ 10% of Patients in the Safety Population Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Waterfall plot of best change rate in target-lesion size from baseline Citation Format: Hui-Ping Li, Qingyuan Zhang, Ruyan Zhang, Yaxin Liu, Chang Liu, Xianjun Hu. Antitumor efficacy and safety of sacibertinib (Hemay022) in combination with endocrine therapy in patients with ER+ and HER2+ metastatic breast cancer: A phase Ib study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-11.
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Yu, Kun, Tenghui Chen, Manav Korpal, Ping Zhu, Zhaojie Zhang, Lihua Yu i Yonghong Xiao. "Abstract 4123: Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients". Cancer Research 82, nr 12_Supplement (15.06.2022): 4123. http://dx.doi.org/10.1158/1538-7445.am2022-4123.
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Abstract Background Real-world data (RWD) has been increasingly used for drug development. RWD coupled with genomic data provides an opportunity to identify the association between certain genomic alterations and response to current standard of care (SOC). Such analyses may help identify predictive biomarkers to select patients who will benefit most from SOC, and/or potential therapeutic nodes that can be pharmacologically targeted to overcome resistance to SOC. Methods We obtained Flatiron CGDB Breast Cancer (as of Q3 2020 release) data set. This data set includes clinical and genomic data from 6,918 breast cancer patients. Time to treatment discontinuation (TTD) was used as real world outcome. We performed two types of genomic-outcome association analysis: 1) Use Cox proportional hazards regression model to identify which baseline mutation (mutation occurred prior to the treatment) could predict the outcome; and 2) use Fisher exact test to identify which mutations are enriched in post-treatment tumors samples, compared to pre-treatment tumor samples. Result We found TP53 mutation is associated with shorter TTD for Palbociclib + Aromatase inhibitor (AI); Palbociclib + Fulvestrant; and endocrine monotherapy. It is consistent with the reports that TP53 mutation is poor prognostic factor (ref). Interestingly, ESR1 mutation is associated with shorter TTD for Palbociclib + AI and AI monotherapy; but not associated with TTD for Palbociclib + Fulvestrant or Fulvestrant monotherapy. On the other hand, MYC amplification is associated shorter TTD for Palbociclib + Fulvestrant or Fulvestrant monotherapy. We found that genes associated with Palbociclib + Endocrine are by and large same as those associated with endocrine monotherapy; suggesting the association is largely driven by endocrine treatment. Comparison of post-treatment vs. pre-treatment analysis found that ESR1 mutation is enriched in post treatment of AI; but not Fulvestrant. Conclusion We demonstrated that real-world clinicogenomic data could identify the biologically meaningful genomic biomarkers that are associated with real world response. This study warrants the further investigation of novel genomic biomarkers identified from the analysis. Citation Format: Kun Yu, Tenghui Chen, Manav Korpal, Ping Zhu, Zhaojie Zhang, Lihua Yu, Yonghong Xiao. Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4123.
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Li, Hui-Ping, Guohong Song, Hanfang Jiang, Xu Liang, Xiaojia Wang, Hua Yang, Lili Zhang i Youzhi Tong. "Abstract PS15-07: Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic Study". Cancer Research 84, nr 9_Supplement (2.05.2024): PS15–07—PS15–07. http://dx.doi.org/10.1158/1538-7445.sabcs23-ps15-07.
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Abstract Abstract Background: Resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a major obstacle to the management of hormone-receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (mBC). Targeting the AR signaling pathway has been demonstrated with promising results in this population. This phase Ic study aimed to assess the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) characteristics of the combination of proxalutamide, a high-affinity AR antagonist, with ETs in androgen receptor (AR)+/HR+/HER2- mBC. Methods: Patients in part 1 regimen-finding phase received proxalutamide plus specific ETs (letrozole [cohort A], exemestane [cohort B], or fulvestrant [cohort C]) and were assessed for dose-limiting toxicity (DLT), PK, PD, and anti-tumor activity. Part 2 expansion phase evaluated the safety and efficacy of proxalutamide plus fulvestrant. The primary endpoint was safety and tolerability. Results: Between June 18, 2019, and Sep 15, 2022, 38 (18 in part 1 and 20 in part 2) patients were treated. Efficacy analysis indicated that the ORR was 16.7% (2/12, 95% CI, 2.1%-48.4%) for cohort C and 15.0% (3/20; 95% CI, 3.2%-37.9%) for part 2. Patients achieved a median progression-free survival (PFS) of 6.4 months (95% CI, 2.7-19.3) in cohort C while an mPFS of 11.0 months (95% CI, 5.5- not estimable) in part 2. In part 1, no DLTs were reported. Grade 3 or more treatment-emergent adverse events (TEAEs) were observed in 11 (29.7%) patients (7 [18.9%] in part 1 and 4 [10.8%] in part 2) and mainly included neutrophil count decreased (8.1%) and platelet count decreased (5.4%). Seven (18.9%) had serious AEs (4 [10.8%] in part 1 and 3 [8.1%] in part 2)[1]. PD results showed a greater reduction of estradiol in cohort C compared with that in cohort B. In addition, proxalutamide was absorbed rapidly into the body with the plasma concentrations of proxalutamide and metabolites reaching a nearly steady state on day 29. Patients with AR/ER of ≤1 seemed to achieve longer PFS over those of >1 (8.4 months vs. 4.1 months). Conclusions: These findings suggested favorable clinical outcomes and safety profiles of the combination of proxalutamide and fulvestrant in AR+/HR+/HER2- mBC patients who have progressed on the first-line therapy, and maybe with better efficacy in patients with lower AR/ER ratio. Trial registration: NCT20191063 Citation Format: Hui-Ping Li, Guohong Song, Hanfang Jiang, Xu Liang, Xiaojia Wang, Hua Yang, Lili Zhang, Youzhi Tong. Proxalutamide plus Endocrine Therapies in Women with HR+/HER2-/AR+ Metastatic Breast Cancer: A Phase Ic Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-07.
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Lu, Haizhen, Dong Kuang, Lili Jiang, Jingping Yun, Qingxin Xia, Jian Wang, Pei Duan i in. "Abstract 5463: The PD-L1 protein expression in Chinese patients with recurrent or metastatic head and neck squamous cell carcinoma: A multi-center retrospective study". Cancer Research 83, nr 7_Supplement (4.04.2023): 5463. http://dx.doi.org/10.1158/1538-7445.am2023-5463.
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Abstract Programmed death-ligand 1 (PD-L1) is a trans-membrane protein and co-inhibitory factor of the immune response. PD-L1 can combine with its receptor (PD-1) to reduce the proliferation of PD-1-positive cells and induce apoptosis. Therefore, PD-L1 was employed as a prognostic marker and a target for anti-cancer immunotherapy in blocking the PD-1 and PD-L1 checkpoints. PD-L1 is highly expressed in various malignancies, including head and neck squamous cell carcinoma (HNSCC). HNSCC is the sixth most common cancer worldwide, with high incidence and mortality rates in China. Although PD-L1 expression has been widely investigated, the PD-L1 expression status in Chinese HNSCC patients (pts) is largely unrevealed. The primary objective of this study was to determine the prevalence of PD-L1 expression with the Combined Positive Score (CPS) ≥20 in Chinese pts with recurrent or metastatic (R/M) HNSCC. The secondary objectives were to determine the prevalence of CPS≥1 in pts with R/M HNSCC and to study the difference in the demographic characteristics, clinicopathological parameters, treatment status, and other available biomarkers between the PD-L1 CPS≥20 group and the PD-L1 CPS<20 group. This study was a multi-center retrospective analysis of data from six centers in China from August 9, 2021, to February 28, 2022. Pts with histologically/cytologically confirmed diagnoses of R/M HNSCC were included. PD-L1 expression was assessed by IHC using the 22C3 PharmDx assay (Agilent, Santa Clara, CA, USA) and was determined using a CPS. The Chi-square test, Fisher’s exact test, or Wilcoxon rank sum test would be used to compare the prevalence of these variables among pts between the PD-L1 CPS≥20 group and the PD-L1 CPS<20 group. Out of 406 enrolled pts with R/M HNSCC, 402 testing pts were included in the final analysis. For all testing R/M HNSCC pts, 168 pts (41.8% [95% CI 36.92-46.78]) had PD-L1 expression with CPS ≥20. In addition, 337 pts (83.8% [95% CI 79.86-87.29]) had PD-L1 expression (CPS≥1). For the testing pts, there were statistically significant differences in variables of gender (P < 0.001), smoking habit (P = 0.0138 for non-smokers versus current smokers), and primary tumor site (P < 0.001 for hypopharynx versus oral cavity and P = 0.0304 for larynx versus oral cavity) between the PD-L1 CPS≥20 group and the PD-L1 CPS<20 group. In summary, in Chinese R/M HNSCC pts, most pts (83.8%) had PD-L1 expression, and two-fifths (41.8%) had PD-L1 expression with CPS ≥20. Prevalence of PD-L1 among Chinese pts with R/M HNSCC was consistent with that reported in the global KEYNOTE-048 study. PD-L1 expression was significantly associated with gender, smoking history and primary tumor site. Our findings of the variables related to the PD-L1 expression levels can supply adjuvant evidence for clinical practice and are a solid basis for future research on immunotherapy. Citation Format: Haizhen Lu, Dong Kuang, Lili Jiang, Jingping Yun, Qingxin Xia, Jian Wang, Pei Duan, Ping Zhou, Shengbing Zang, Yiping Jin, Xiangnan Jiang, Jielin Li, Wenmin Tang, Jiansong Zhou, Jihua Chen, Jianming Ying. The PD-L1 protein expression in Chinese patients with recurrent or metastatic head and neck squamous cell carcinoma: A multi-center retrospective study. [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 5463.
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Zhao, Tianying, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Bing Zhang, Xingyi Guo i in. "Abstract 1716: A proteome-wide association study identifies putative causal proteins for breast cancer". Cancer Research 84, nr 6_Supplement (22.03.2024): 1716. http://dx.doi.org/10.1158/1538-7445.am2024-1716.
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Abstract Background: Genome-wide association studies (GWAS) have identified over 200 breast cancer risk associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue in relation to breast cancer risk. Methods: We profiled the proteome in breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank. Protein expression levels were log2 transferred and then normalized via quantile and inverse-rank transformations. The elastic net method was used to build statistical models to predict protein expression levels via genetic variants. The prediction models were then applied to the GWAS summary statistics data of 133,384 breast cancer cases and 113,789 controls to assess the associations of genetically predicted protein expression levels with breast cancer risk overall and its sub-types using the S-PrediXcan method. Results: A total of 6,388 proteins were detected in the normal breast tissue samples from 120 women with a high detection false discovery rate (FDR). Among the 5,823 proteins detected in more than 80% of participants, prediction models were successfully built for 2,041 proteins with R>0.1 and P<0.05. Among these 2,041 proteins, six proteins were significantly associated with overall breast cancer risk at an FDR P< 0.05. Among these six proteins, the corresponding genes for proteins DCTN3 and DDX6 were located at least 500kb away from the GWAS-identified breast cancer risk variants. Both DCTN3 and DDX6 were associated with a decreased risk of breast cancer with P values of 8.46 × 10−4 and 2.27 × 10−4, respectively. The corresponding genes for the remaining four proteins, LMNA, LSP1, RPS6KA5, and DNAJA3, were located in previously GWAS-identified breast cancer risk loci. After adjusting for GWAS-identified risk variants, the associations for LMNA and RPS6KA5 were still significant (P=2.54 × 10−7 and 2.79 × 10−5, respectively), however, the associations for LSP1 and DNAJA3 became weaker with P values of 0.65 and 2.10 × 10−4 respectively.Stratification analyses by breast cancer subtypes identified three proteins, LMNA, LSP1, and NCKAP1L, associated with luminal A, luminal B, and ER-positive subtypes. NCKAP1L was located at least 500kb away from risk loci. After adjusting for GWAS-risk variants, the associations for LMNA were still significant (P=2.58 × 10−5 and 4.08 × 10−6 for luminal A and ER-positive respectively). Conclusion: We conducted the first breast-tissue-based PWAS and identified seven proteins associated with breast cancer, including six proteins that were not previously implicated. These findings help improve our understanding of the underlying genetic mechanism of breast cancer development. Citation Format: Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Bing Zhang, Xingyi Guo, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long. A proteome-wide association study identifies putative causal proteins for breast cancer [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 1716.
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Wen, Kuang-Yi, Suzanne Miller, Aruna Padmanabhan, Rita Smith, Emmanuel Lapitan i Lori Goldstein. "Abstract B119: Effect of a smart pill bottle and text messaging-based intervention on medication adherence and side effect management in African American women with breast cancer new to endocrine therapy". Cancer Epidemiology, Biomarkers & Prevention 32, nr 1_Supplement (1.01.2023): B119. http://dx.doi.org/10.1158/1538-7755.disp22-b119.
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Abstract Background For women with hormone receptor-positive breast cancer (BCa), approximately 75-80% of all BCa cases, long-term use of endocrine therapy has been demonstrated to improve disease free survival. However, data reported that non-adherence rates range from 28% to 59%, and African American (AA) women had lower odds of being adherent to endocrine therapy than other racial/ethnic groups, suggesting that medication adherence might be an important level for targeting racial disparities in AA BCa outcomes. Emerging adherence-promoting interventions using technologies to provide at-home medication management support, however, few studies have formally assessed their effects in minority groups. The objective of this study was to evaluate the impact of an interactive text messaging (TXT) intervention and a smart pill bottle (SPB) on adherence to endocrine therapy and symptom management among AA women with early stage BCa. Method This prospective and random assignment study recruited 48 AA women with early stage ER+ or PR+ BCa who completed active treatments and were new to endocrine therapy. Participants were randomized to 1:1: between the txt2adhere and control groups. The txt2adhere group received interactive text messages three times a week, that were culturally tailored addressing barriers on the cognitive, affective interpersonal and symptom levels. The intervention group also received a SPB with light and chimes reminders. The control group received an identical SPB with all alerts deactivated. Patient adherence was calculated by % days adherent over the study time. The study was 3 months and patient-reported outcomes were collected at 1-month, 2-month and 3-month. A post-intervention interview was conducted to understand participant’s satisfaction and feedback. Results Forty-eight women were enrolled with 22 randomized in the txt2adhere group and 26 in the control group; 4 patients in the txt2adhere and 3 in the control were lost of follow up. Participants are in average 57 years old; 71% had an annual household income of $45K and lower; and 67% had a stage I BCa. Overall, the txt2adhere group has a 91% adherence rate at the end of 3-month study compared with 89% in the control group. Post-intervention interviews revealed the utility and feasible of the intervention, areas for TXT content improvement in symptom management such as joint pain and hot flashes were also identified. Conclusion In this study, a culturally-sensitive TXT intervention equipped with a SPB were associated with increased medication adherence, which need to be tested in a fully powered study. This pilot provides preliminary data on the feasibility of adherence technology used in an underserved AA population. Citation Format: Kuang-Yi Wen, Suzanne Miller, Aruna Padmanabhan, Rita Smith, Emmanuel Lapitan, Lori Goldstein. Effect of a smart pill bottle and text messaging-based intervention on medication adherence and side effect management in African American women with breast cancer new to endocrine therapy [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B119.
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Kubler, Kirsten, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi i in. "Abstract GS2-09: Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations". Cancer Research 82, nr 4_Supplement (15.02.2022): GS2–09—GS2–09. http://dx.doi.org/10.1158/1538-7445.sabcs21-gs2-09.
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Abstract Tamoxifen is widely used in the adjuvant treatment of estrogen receptor–positive (ER+) breast cancer and is an important drug for pre-menopausal women and post-menopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit in improving relapse-free and overall survival in these patients, an adverse effect of tamoxifen is a 2- to 7-fold increased risk of uterine cancer (UC) after 2-5 years of treatment. To date, the mechanism of tamoxifen-driven tumorigenesis is not well understood, and preventive approaches are lacking. Here, to molecularly characterize tamoxifen-associated uterine cancers (TA-UCs) and gain insights into their unique evolution, we performed whole-exome sequencing of 21 TA-UCs (discovery cohort) and droplet digital PCR (ddPCR) of an additional 40 TA-UCs (validation cohort) obtained from the ‘Tamoxifen Associated Malignancies: Aspects of Risk’ (TAMARISK) study. In addition, we used in vivo mouse models to: (i) further investigate tamoxifen-activated molecular pathways that may be involved in TA-UC tumorigenesis; and (ii) offer mechanistic insights. Overall, we discovered that TA-UCs were genomically similar to non–TA-UCs from The Cancer Genome Atlas (TCGA) project, with one profound exception: TA-UCs are characterized by a lower-than-expected frequency of mutations in two highly prevalent UC driver genes in the PI3K pathway: PIK3CA (14% [3/21] vs 48% [265/554] in non–TA-UC; P=0.003, Fisher’s exact test; Q=0.02, Benjamini-Hochberg FDR) and PIK3R1 (0%, [0/21] vs 31% [174/554]; P=0.001; Q=0.01). We used ddPCR in the independent TA-UC validation cohort and confirmed the low frequency of mutations in PIK3CA (7.5% [3/40] vs 21% [144/685] in control UCs from the Dana-Farber contribution to the AACR GENIE project; P=0.04). We next performed mouse in vivo studies and demonstrated that tamoxifen activated the PI3K pathway and increased cell proliferation in normal mouse uterine tissue through paracrine and autocrine effects, both of which were abrogated by the PI3K inhibitor alpelisib. Taken together, we describe a distinct and novel pathway of carcinogenesis in which tamoxifen acts as a driver event in the uterus and promotes tumor development in a mutation-independent manner. Indeed, tamoxifen may increase the risk of UC by activating the PI3K pathway, which can substitute for the early acquisition of oncogenic PIK3CA or PIK3R1 mutations observed in non–TA-UC tumors. Furthermore, the ability of a PI3K inhibitor to reduce cell proliferation in our mouse model raises the possibility that downregulating the PI3K pathway may prevent or significantly reduce TA-UC development, offering a potential future therapeutic and prevention strategy for specific high-risk patients undergoing tamoxifen therapy. Citation Format: Kirsten Kubler, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi, Avery S Feit, Gabriella Cohen, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra Nederlof, Harry Hollema, Quang-Dé Nguyen, Marian JE Mourits, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-09.
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Jabado, Omar, Suzana Couto, Jordan Blum, Patrick Franken, Patricia Coutinho de Souza, Maria Jure-Kunkel, Nora Pencheva, Brandon Higgs, Kate Sasser i Mark Fereshteh. "238 Molecular dissection of tumor-immune microenvironment factors associated with response to checkpoint inhibitor therapy in non-small cell lung cancer patients using nanostring digital spatial profiling". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (listopad 2020): A255—A256. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0238.
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BackgroundUnderstanding the dynamics of immune cells in the lung tumor microenvironment following immune checkpoint inhibitor (ICI) therapy is important for developing therapies tailored to patients with progressive disease. We sought to characterize protein and mRNA biomarkers in the tumor and stromal microenvironment in such patients with the Nanostring Digital Spatial Profiling (DSP) platform. DSP technology allows highly multiplexed profiling of proteins and RNA in a spatially resolved manner.MethodsFFPE non-small lung adenocarcinoma biopsies from 18 patients were sourced commercially (Capital Biosciences, MD). Patients had surgical resection of tumors then adjuvant chemotherapy. Upon progression, patients received monotherapy ICI (nivolumab or pembrolizumab). Once progressed on ICI, biopsies were performed and patients were then treated with platinum-doublet or single agent chemotherapy and followed until progression and/or death. Best overall response (BOR) and progression free survival (PFS) was available for ICI. FFPE tumors were sectioned and stained with anti-Pan-Cytokeratin, anti-PDL1 and anti-4-1BB (CD137) using standard immunofluorescence techniques. Twelve circular regions of ~400 um in diameter containing tumor (PanCK+) and stromal (PanCK-) areas were selected per patient (figure 1). The technology uses a photocleavable DNA barcode strategy to multiplex antibodies and RNA in-situ hybridization probes. The GeoMX instrument was used to generate counts for 58 proteins and 84 RNAs on serial sections. Data normalization, linear modeling and survival analysis was conducted in R.ResultsLymphoid and myeloid markers were more abundant in stroma, indicating the microenvironment is diverse and confirming the DSP platform can segment adjacent cells. High levels of PDL1 protein in the tumor were correlated with T cell markers in the stroma (CD3, CD8, ICOS, IDO, OX40L) and inversely correlated with granulocytic (CD66b) and angiogenesis markers (CD34). We focused outcomes analysis on ICI response (9 PD/9 PR). OX40L protein was higher in patients with partial response and associated with delayed progression (figure 2). CD74 protein was associated with progressive disease during ICI therapy. CSF1R, CD4 and PECAM1 mRNA expression levels in stroma trended with progressive disease.Abstract 238 Figure 1Immunofluorescence staining and segmentation of NSCLC tumorAbstract 238 Figure 2Association of OX40L abundance in stroma with PFS using Kaplan-Meier analysisConclusionsIn this study we recapitulated the role of OX40L as a marker for response to ICI1 and CSF1R and PECAM1 in non-response to ICI.2. 3 CD74 is a receptor for the pro-inflammatory cytokine (MIF) however CD74 ectodomain shedding may function as a decoy receptor.4 These findings highlight how DSP can be used to probe the tumor microenvironment to identify pathways specific to NSCLC non-response for therapeutic target and biomarker development.Ethics ApprovalSubjects provided informed consent to Capital Biosciences for genetic and protein analysis.AcknowledgementsLiang Zhang, Adrienne Whitman, Jennifer Hart, JingJing Gong of Nanostring Technologies.ReferencesMassarelli E, Lam VK, Parra ER, et al. High OX-40 expression in the tumor immune infiltrate is a favorable prognostic factor of overall survival in non-small cell lung cancer. J Immunother Cancer 2019;7(1):351.Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 2017;5(1):53.Kuang BH, Wen XZ, Ding Y, et al. The prognostic value of platelet endothelial cell adhesion molecule-1 in non-small-cell lung cancer patients. Med Oncol 2013;30(2):536.Schröder B. The multifaceted roles of the invariant chain CD74-More than just a chaperone. Biochim Biophys Acta 2016;1863(6 Pt A):1269–1281.
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Aberin, Marvin A., Yu-Ling (Pony) Lee, Xin-Guo Hsu, Chen-Yang Shen, Yao-Ming Chang, Kun-Yuan Lin, Chandan Guha i Shu-Ping Wang. "Abstract 3646: New functional role of tamoxifen in breast cancer immunomodulation: role of RACK7 in activation of type I interferon signaling and CEACAM1/TIM-3-dependent immunosuppression". Cancer Research 83, nr 7_Supplement (4.04.2023): 3646. http://dx.doi.org/10.1158/1538-7445.am2023-3646.
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Abstract Despite advancements of immunotherapy against various cancers, breast cancer still retains poor response to immune checkpoint blockade (ICB) therapy. Therefore, the identification of promising target or new strategy to enhance ICB therapy in breast cancer is crucial. Here, we uncover that the DNA-damaging potential of tamoxifen (TAM) can shape the unfavorable but ready-to-fire tumor immune microenvironment in breast cancer. We discover that a long-term TAM administration unexpectedly induces JAK/STAT signaling and Type I interferon (IFN)-stimulated gene expression to promote T-cell infiltration. Furthermore, TAM also induces the expression of CEACAM1, which acts as an alternative T-cell inhibitory ligand via binding to TIM-3, a “checkpoint” receptor expressed on CD4+ and CD8+ T cells. The chromatin ‘‘reader’’ RACK7/ZMYND8, which functions as a transcriptional repressor of IFN-stimulated gene (ISG) and a critical factor in DNA repair, is found to be downregulated upon tamoxifen exposure and involved in the tamoxifen-mediated cellular modulation. We demonstrate that TAM in conjunction with RACK7-knockdown (KD) triggers robust upregulation of ISGs and CEACAM1 in both estrogen receptor-positive (ER+) and triple negative breast cancer (TNBC) cells. This immunomodulatory effect lead by loss of RACK7 is specific to TAM treatment, and is not observed when combined with other endocrine therapeutics. TAM combined with RACK7-KD promotes mitochondrial DNA damage, which leads to accumulation of cytosolic DNA and subsequent activation of the cGAS/STING pathway. The murine breast orthotopic models with TS/A, EO771 and 4T1 cells further demonstrate that TAM-mediated immunomodulatory in conjunction with RACK7-KD evokes cytokine/chemokine secretion and further induces T-cell infiltration into tumor microenvironment. However, the tumor killing effect is limited due to promotion of T-cell exhaustion from CEACAM1-TIM-3 interaction between tumor and T cells. Thus, our study indicates that targeting CEACAM1-TIM-3 interaction is crucial for TAM-mediated tumor immune response. This brings promising therapeutic approach with TAM by combining RACK7-KD with blockage to CEACAM1-TIM-3 interaction in breast cancer. The resistance of tamoxifen treatment may be overcome, and RACK7 may serve as both a therapeutic target and a biomarker to enable ICB therapy. Citation Format: Marvin A. Aberin, Yu-Ling (Pony) Lee, Xin-Guo Hsu, Chen-Yang Shen, Yao-Ming Chang, Kun-Yuan Lin, Chandan Guha, Shu-Ping Wang. New functional role of tamoxifen in breast cancer immunomodulation: role of RACK7 in activation of type I interferon signaling and CEACAM1/TIM-3-dependent immunosuppression. [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 3646.
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Huang, Lisi, Xin Du, Jianyu Weng, Peilong Lai, Zesheng Lu, Ping Wu, Suijing Wu, Chengwei Luo, Xin Huang i Suxia Geng. "Comparison of the 5 Year Medical Outcome and Quality of Life of Patients with Chronic Myeloid Leukemia Treated with Imatinib or Allogeneic Transplant". Blood 126, nr 23 (3.12.2015): 2118. http://dx.doi.org/10.1182/blood.v126.23.2118.2118.
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Abstract Comparison of the 5 year Medical Outcome and Quality of Life of Patients with Chronic Myeloid Leukemia treated with Imatinib or Allogeneic Transplant Jianyu Weng1*, Lisi Huang1*, Peilong Lai1, Zesheng Lu1, Ping Wu1, Suijing Wu1, Chengwei Luo1, Wei Ling1, Chenxin Deng1, Xin Huang1, Suxia Geng1, Xin Du1? 1Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China. *These authors contributed equally to this work.? Corresponding author: Xin Du, MD, Ph.D. 106. Zhongshan Er Rd, Guangzhou, 510080, P.R. China E-mail: miyadu@hotmail.com Phone: (86)-20-83827812-62122 Fax: (86)-20-83889772 Abstract To evaluate and compare the long-term medical outcome and health-related quality of life (HRQOL) of patients with CML in chronic phase (CML-CP) who received imatinib or an allogeneic hematopoietic stem cell transplant (allo-HSCT) using retrospective analysis and an embedded cross-sectional study. CML-CP patients who received imatinib or transplantation from January 4, 2004 to October 10, 2011 in the Department of Hematology at Guangdong General Hospital (GGH) were enrolled in this study. A total of 131 patients, including 90 and 41 in the imatinib and allo-HSCT groups, respectively, were enrolled. The two groups including HRQOL investigation were well matched for gender, marital status, employment status, educational background, and Sokal score at diagnosis. There were no significant differences in the five-year EFS, PFS and OS between the two groups. The HRQOL was measured using EORTC QLQ-C30. Those questions include five multi-item function scales (Physical, Role, Emotional, Cognitive and Social Functioning), a combined Global Health Status/QOL scale, and a number of individual items (appetite loss, dyspnea, diarrhea, constipation, sleep disturbances, and financial impact). In terms of HRQOL, with the exception of social functioning (64.9 vs. 77.5, P=0.035), there was no significant difference in many of the HRQOL scores between the imatinib and transplant groups: global HRQOL, role function, physical function, emotional function and cognitive function. However, symptoms including nausea/vomiting (14.8 vs. 3.2, P=0.013), diarrhea (18.4 vs. 2.5, P=0.001), and financial difficulty (56.9 vs. 33.3, P=0.023) more negatively impacted the imatinib group (P<0.05). Persistent cGVHD reduced the HRQOL of the allo-HSCT group, compared with the non-cGVHD and historic cGVHD group. Although imatinib and transplantation have similar long-term medical outcomes, allo-HSCT provides better social function, moderate symptoms, and lower financial burden. Thus, the role of allo-HSCT for CML-CP should be reevaluated in developing countries in the era of TKIs. Keywords: chronic myeloid leukemia; quality of Life CONFLICT OF INTEREST The authors declare no conflict of interest. ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant No. 81270648, 81300446 and 81370665), Science and Technology Planning Project of Guangzhou (Grant No.201400000003-4, 201400000003-1). Disclosures No relevant conflicts of interest to declare.
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Liang, Yuehua, Hui Ping Li i Zehui Yun. "Abstract C035: Chemotherapy plus HER2-targeted therapy versus endocrine therapy plus HER2-targeted therapy as first-line treatment in patients with HR+/HER2+advanced breast cancer: A real-world trial". Molecular Cancer Therapeutics 22, nr 12_Supplement (1.12.2023): C035. http://dx.doi.org/10.1158/1535-7163.targ-23-c035.
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Abstract Purpose:This study is a real-world research to compare the efficacy of using chemotherapy plus anti-HER2 therapy versus endocrine therapy plus anti-HER2 therapy as first-line treatment for HR+/HER+ advanced breast cancer patients, aiming at providing a better treatment option for patients. Patients and methods: This study enrolled patients with advanced breast cancer who had complete medical records and were treated in the breast oncology department of Peking University Cancer Hospital from October 2010 to October 2022. These patients were pathologically confirmed with HR+/HER2+ and underwent first-line treatment with anti-HER2 therapy + endocrine therapy (HE group) or anti-HER2 therapy + chemotherapy (with/without endocrine maintenance therapy) (HC group). HER2 positive was defined as HER2+++ or HER2++ on immunohistochemical staining of tumor tissue and fluorescence in situ hybridization (FISH) testing showing HER2 gene amplification in patients. HR+ was considered when more than 1% of tumor cells expressed estrogen receptor (ER) and/or progesterone receptor (PR). The primary endpoints being investigated are progression-free survival (PFS) and overall survival (OS). The second endpoint is objective response rate (ORR) and clinical benefit rate (CBR). Results:From October 2010 to October 2022, a total of 181 patients who met the inclusion criteria were enrolled in the study. Among them, 18 patients received endocrine therapy + anti-HER2 therapy in the first-line treatment stage, while 163 patients received chemotherapy + anti-HER2 therapy (70 patients underwent endocrine maintenance therapy). The median follow-up time was 67 months. The median PFS (mPFS) of the patients in HC group and the HE group were 14.32 months (95% confidence interval (CI) 12.83-15.81) and 9.78 months (95%CI 4.48-15.8), respectively (p=0.299), and no significant statistical difference was observed. Similarly, no significant statistical difference was achieved in the median OS (mOS) of the HC group and the HE group patients, with 126.87 months (95%CI 102.08-151.658) versus 96.00 months (95%CI 78.41-113.59) (p=0.076). In the HC group, the mPFS of patients who received endocrine maintenance therapy and those who did not receive endocrine therapy were 16.24 months (95%CI 12.11-20.37) and 12.36 months (95%CI 10.26-14.46), respectively. The ORR of the two groups of patients were 46.6% and 16.7% (p=0.0015), respectively. Conclusion: The analysis demonstrated that the combination of anti-HER2 therapy with endocrine therapy is not inferior to the combination of anti-HER2 therapy with chemotherapy as first-line treatment for HR+/HER2+ advanced breast cancer. It provides compelling evidence to support the selection of endocrine therapy plus HER2-targeted therapy as a first-line treatment strategy that that enhances the quality of life for patients without shortening their survival time. Citation Format: Yuehua Liang, Hui Ping Li, Zehui Yun. Chemotherapy plus HER2-targeted therapy versus endocrine therapy plus HER2-targeted therapy as first-line treatment in patients with HR+/HER2+advanced breast cancer: A real-world trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C035.
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Puca, Loredana, Michele S. Dowless, Carmen M. Perez-Ferreiro, Maria Jesus Ortiz-Ruiz, Gregory P. Donoho, Andrew Capen, Lysiane Huber i in. "Abstract P4-08-02: LOXO-783: A potent, highly mutant selective and brain-penetrant allosteric PI3Kα H1047R inhibitor in combination with standard of care (SOC) treatments in preclinical PI3Kα H1047R-mutant breast cancer models". Cancer Research 83, nr 5_Supplement (1.03.2023): P4–08–02—P4–08–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-p4-08-02.
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Abstract Background Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Early generation PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor that is currently in phase 1 testing. Preclinically, LOXO-783 as a single agent is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms, and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant breast cancer models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. Here we report the efficacy of LOXO-783 with SOC treatments in preclinical breast cancer models. Methods Cell proliferation assays and in vivo studies to evaluate combination effects were performed in various PI3Ka H1047R mutant HR+, HER2- and triple negative breast cancer models. For each combination in vitro, a combination index (CI) based on the Loewe Additivity Method was calculated (CI>2 antagonism, 0.5>CI< 2 additivity, CI< 0.5 synergy). For the in vivo studies, the Bliss Independence Method was used to evaluate the statistical significance of the combination effects. Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R-mutant T47D model. LOXO-783 also demonstrated an additive effect in combination with these endocrine therapies in vivo. Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib. Moreover, LOXO-783 plus abemaciclib demonstrated an additive effect in vitro (CI at 50% inhibition = 0.61), and in T47D xenograft and PDX models in vivo. Combinations of LOXO-783 with abemaciclib plus imlunestrant resulted in a mean tumor regression of –48.1%; LOXO-783 with abemaciclib plus FUL showed mean tumor regression of –43.9% in T47D xenografts. Similar efficacy was not observed in the absence of LOXO-783 (mean tumor regression was –7.3% with abemaciclib plus imlunestrant, and 3.2% with abemaciclib plus FUL). We observed comparable results in PDX models. These data collectively demonstrate the additive effect of LOXO-783 with SOC treatments. Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo. Conclusions LOXO-783 shows additive effects when combined with SOC in breast cancers harboring the PI3Kα H1047R-mutation (as single or double in-cis mutations) in both HR+ and triple negative settings. LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705). Citation Format: Loredana Puca, Michele S. Dowless, Carmen M. Perez-Ferreiro, Maria Jesus Ortiz-Ruiz, Gregory P. Donoho, Andrew Capen, Lysiane Huber, Sarah M. Bogner, Dongling Fei, Jason R. Manro, Chun Ping Yu, Wei Guo Xu, Rui Wang, Shuang Chen, Mark A. Hicks, Parisa Zolfaghari, Andrew Faber, Raymond Gilmour, Monica D. Ramstetter, Matthew T. Chang, Maria Jose Lallena, Xuequian Gong, David M. Hyman, Lillian M. Smyth, Barbara J. Brandhuber, Barry S. Taylor, Anke Klippel. LOXO-783: A potent, highly mutant selective and brain-penetrant allosteric PI3Kα H1047R inhibitor in combination with standard of care (SOC) treatments in preclinical PI3Kα H1047R-mutant breast cancer models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-02.
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Luo, Ting, Xiaorong Zhong, Ping He, Dan Zheng, Yan Cheng i Kunrui Zhu. "Abstract PO4-18-03: Combined Treatment with Pyrotinib and Chrysin Synergistically Improve the Autophagy Level in HER2-Positive Breast Cancer by Regulating the miR-16-5p/ZBTB16/G6PD Axis". Cancer Research 84, nr 9_Supplement (2.05.2024): PO4–18–03—PO4–18–03. http://dx.doi.org/10.1158/1538-7445.sabcs23-po4-18-03.
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Abstract Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, which consists of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis outcome, the efficacy of pyrotinib as monotherapy remain largely restricted due to its acquired resistance. Therefore, we aim at identifying a potent antitumor drug incorporated with pyrotinib for amplifying therapeutic efficacy for treating HER2-positive BC. Here, we reported a novel incorporation of pyrotinib in combination with chrysin, and explored its antitumor efficacy and the underlying mechanisms on HER2+ breast cancer. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce apoptosis and inhibit BT-474 and SK-BR-3 tumor cells, and suppressed in vivo tumor growth in tumor-bearing mice models. This may be mechanistically attributed to the induction of enhanced endoplasmic reticulum stress to increase the autophagy level. Furthermore, it was demonstrated that the combined treatment with pyrotinib and chrysin induced ubiquitination and G6PD degradation by regulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Besides, we identified that miR-16-5p is a potential upstream regulatory target of ZBTB16. Blocking miR-16-5p overexpression could inhibit HER2-positive tumorigenesis and significantly potentiate the efficacy of pyrotinib in combination with chrysin. Together, these findings demonstrate the utility of combined treatment with pyrotinib and chrysin as a potential option in the target treatment of HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis. The miR-16-5p/ZBTB16/G6PD axis plays a crucial role in the pyrotinib plus chrysin-enabled anti HER2-positive BC Fig.1 a Cell viability of SK-BR-3 cells received various treatments. b Detection of cell cycle arrest of SK-BR-3 cells after various treatments. c Schematic diagram of the established protocol of the animal models. Photograph of resected tumor tissues, tumor volume (d), and tumor weight (e) of mice in different treatment groups during the whole testing period. f H&E, Ki67, and Tunel immunohistochemical staining of tumor sections of mice in various treatment groups. g Autophagy flux of SK-BR-3 cells labeled with mRFP-GFP-LC3 in the different treatment groups. h Expression level of ER stress markers in SK-BR-3 cells after various treatments via RT-qPCR and western blot. *P <0.05, compared with control group (DMSO), #P <0.05, compared with chrysin group, & P<0.05, compared with pyrotinib group. i Western blot analysis of the expression of G6PD in different treatment groups. j Fluorescence images of SK-BR-3 cells subjected to G6PD overexpression for the detection of autophagy level. k Ubibrowser database predicting the E3 ubiquitin ligases that may be involved in the regulation of G6PD ubiquitination. l Western blot analysis of G6PD protein half-life in SK-BR-3 cells with ZBTB16 silence. Cells were co-incubated with cycloheximide (CHX, 50μg/ml) for the indicated time. m Determination of the ubiquitination of G6PD in cells pretreated with 10 μM MG-132 for 3 h. Cells were transfected with ubiquitin after different treatments. The ubiquitinated G6PD was subjected to immunoprecipitation before western blot with ubiquitin antibody. n Dual-luciferase report verifying the targeting of ZBTB16 and miR-16-5p. o Transmission electron microscopy images of autophagosomes of tumors in various treatment groups (× 20000). p Immunohistochemical staining images of tumor slices for the determination of G6PD. q Schematic diagram for the underlying mechanism of pyrotinib combined chrysin against HER2-positive BC. Citation Format: Ting Luo, Xiaorong Zhong, Ping He, Dan Zheng, Yan Cheng, Kunrui Zhu. Combined Treatment with Pyrotinib and Chrysin Synergistically Improve the Autophagy Level in HER2-Positive Breast Cancer by Regulating the miR-16-5p/ZBTB16/G6PD Axis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-03.
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Grzegorczyk, Adrian, i Marcin Mamajek. "A 70 W thulium-doped all-fiber laser operating at 1940 nm". Photonics Letters of Poland 11, nr 3 (30.09.2019): 81. http://dx.doi.org/10.4302/plp.v11i3.928.
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An all-fiber thulium-doped fiber laser operating at a wavelength of 1940 nm is reported. A maximum output continuous-wave power of 70.7 W with a slope efficiency of 59%, determined with respect to the absorbed pump power, was demonstrated. The laser delivered almost a single-mode beam with a beam quality factor of < 1.3.Full Text: PDF ReferencesM. N. Zervas and C. A. Codemard, "High Power Fiber Lasers: A Review", IEEE J. Sel. Top. Quantum Electron. 20, 0904123 (2014). CrossRef D. J. Richardson, J. Nilsson, and W. A. Clarkson. "High power fiber lasers: current status and future perspectives [Invited]", J. Opt. Soc. Am. B 27, B63 (2010). CrossRef J. Swiderski, A. Zajac, and M. Skorczakowski, "Pulsed ytterbium-doped large mode area double-clad fiber amplifier in MOFPA configuration", Opto-Electron. Rev. 15, 98 (2007). CrossRef M. Eckerle et al. "High-average-power actively-modelocked Tm3+ fiber lasers", Proc. SPIE 8237, 823740 (2012). CrossRef J. Swiderski, D. Dorosz, M. Skorczakowski, and W. Pichola, "Ytterbium-doped fiber amplifier with tunable repetition rate and pulse duration", Laser Phys. 20, 1738 (2010). CrossRef P. Grzes and J. Swiderski, "Gain-Switched 2-μm Fiber Laser System Providing Kilowatt Peak-Power Mode-Locked Resembling Pulses and Its Application to Supercontinuum Generation in Fluoride Fibers", IEEE Phot. J. 10, 1 (2018). CrossRef S. Liang et al. "Transmission of wireless signals using space division multiplexing in few mode fibers", Opt. Express 26, 6490 (2018). CrossRef J. Swiderski, M. Michalska, and P. Grzes, "Broadband and top-flat mid-infrared supercontinuum generation with 3.52 W time-averaged power in a ZBLAN fiber directly pumped by a 2-µm mode-locked fiber laser and amplifier", Appl. Phys. B 124, 152 (2018). CrossRef F. Zhao et al. "Electromagnetically induced polarization grating", Sci. Rep. 8, 16369 (2018). CrossRef J. Sotor et al. "Ultrafast thulium-doped fiber laser mode locked with black phosphorus", Opt. Lett. 40, 3885 (2015). CrossRef M. Olivier et al. "Femtosecond fiber Mamyshev oscillator at 1550 nm", Opt. Lett. 44, 851 (2019). CrossRef J. Swiderski and M. Michalska, "Over three-octave spanning supercontinuum generated in a fluoride fiber pumped by Er & Er:Yb-doped and Tm-doped fiber amplifiers", Opt. Laser Technol. 52, 75 (2013). CrossRef C.Yao et al. "High-power mid-infrared supercontinuum laser source using fluorotellurite fiber", Optica 5, 1264 (2018). CrossRef J. Swiderski and M. Maciejewska, "Watt-level, all-fiber supercontinuum source based on telecom-grade fiber components", Appl. Phys. B 109, 177 (2012). CrossRef O. Traxer and E. X. Keller, "Thulium fiber laser: the new player for kidney stone treatment? A comparison with Holmium:YAG laser", World J. Urol., 1-12 (2019). CrossRef M. Michalska, et al. "Highly stable, efficient Tm-doped fiber laser—a potential scalpel for low invasive surgery", Laser Phys. Lett. 13, 115101 (2016). CrossRef R. L. Blackmon et al. "Thulium fiber laser ablation of kidney stones using a 50-μm-core silica optical fiber", Opt. Eng., 54, 011004 (2015). CrossRef A. Zajac et al. "Fibre lasers – conditioning constructional and technological", Bull. Pol. Ac.: Tech. 58, 491 (2010). CrossRef C. Guo, D. Shen, J. Long, and F. Wang, "High-power and widely tunable Tm-doped fiber laser at 2 \mu m", Chin. Opt. Lett. 10, 091406 (2012). CrossRef F. Liu et al. "Tandem-pumped, tunable thulium-doped fiber laser in 2.1 μm wavelength region", Opt. Express 27, 8283 (2019). CrossRef H. Ahmad, M. Z. Samion, K. Thambiratnam, and M. Yasin, "Widely Tunable Dual-Wavelength Thulium-doped fiber laser Operating in 1.8-2.0 mm Region", Optik 179, 76 (2019). CrossRef N. M. Fried, "Thulium fiber laser lithotripsy: An in vitro analysis of stone fragmentation using a modulated 110‐watt Thulium fiber laser at 1.94 µm", Lasers Surg. Med. 37, 53 (2005). CrossRef N. M. Fried, "High‐power laser vaporization of the canine prostate using a 110 W Thulium fiber laser at 1.91 μm", Lasers Surg. Med. 36, 52 (2005). CrossRef E. Lippert et al. "Polymers Designed for Laser Applications-Fundamentals and Applications", Proc. SPIE 6397, P639704 (2006). CrossRef N. Dalloz et al. "High power Q-switched Tm3+, Ho3+-codoped 2μm fiber laser and application for direct OPO pumping", Proc. SPIE 10897, 108970J (2019). CrossRef N. J. Ramírez-Martinez, M. Nunez-Velazquez, A. A. Umnikov, and J. K. Sahu, "Highly efficient thulium-doped high-power laser fibers fabricated by MCVD", Opt. Express 27, 196 (2019). CrossRef T. Ehrenreich et al. "1-kW, All-Glass Tm:fiber Laser", Proc. SPIE 7580, 758016 (2010). DirectLink L. Shah et al. "Integrated Tm:fiber MOPA with polarized output and narrow linewidth with 100 W average power", Opt. Express 20, 20558 (2012). CrossRef H. Zhen-Yue, Y. Ping, X. Qi-Rong, L. Qiang, and G. Ma-Li, "227-W output all-fiberized Tm-doped fiber laser at 1908 nm", Chin. Phys. B 23, 104206 (2014). CrossRef
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Nielsen, Klaus Bo. "Xunzis ritualanalyse". Religionsvidenskabeligt Tidsskrift, nr 51 (29.02.2008). http://dx.doi.org/10.7146/rt.v0i51.1715.
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Denne artikel undersøger en oldkinesisk filosofs syn på ritualernes praksis i samspil med moderne sociologiske forståelser af religion. Den ritualteoretiker, jeg her vil beskæftige mig med, er de er n kinesiske forfatter Xunzi eller Xun Kuang (310-230 f. Kr.). I hans afhandling om ritualer (Li Lun) går han videre end blot at beskrive den rituelle akt, og anlægger en mere distanceret indstilling til ritualet og skitserer dermed en sociologisk baseret ritualteori, som har lighedspunkter med klassiske positioner som Durkheim, Radcliff-Brown og Rappaport. Det er i dette lys, at Xunzis ritualteori fortjener at blive taget alvorligt.
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Pileberg, Silje. "Stabile tal for sjølvmord i Noreg". Suicidologi 25, nr 3 (25.01.2021). http://dx.doi.org/10.5617/suicidologi.8543.
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Yang, Fang, Yonghui Yu i Hong Liu. "Mechanism of Action of Yikun Yitong Ping-Containing Serum on Mast Cells and its Possible Involvement in Endometriosis-Related Dysmenorrhea". Natural Product Communications 19, nr 2 (luty 2024). http://dx.doi.org/10.1177/1934578x241229929.
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Background Previously, we showed that Yikun Yitong Ping (YKYTP) can effectively and safely relieve endometriosis-related dysmenorrhea; however, the underlying mechanism remained unclear. This study aimed to assess the effects of YKYTP-containing serum on rat basophilic leukemia cell line, as mast cells (MCs) analog, and investigate the mechanisms by which YKYTP alleviates endometriosis-related dysmenorrhea. Method In this study, YKYTP drug-containing serum was used to treat rat basophilic leukemia cell line (RBL2H3). The effect of YKYTP-containing serum on the expression of ER-α, ER-β, NGF, and NGFRp75 in RBL2H3 cells was evaluated using enzyme-linked immunosorbent assay, quantitative real-time polymerase reaction, and Western blotting. Results Different concentrations (5%-40%) of YKYTP-containing serum reduced ER expression in RBL2H3 cells, and the optimum concentration was 40%. Compared to the blank group, the expression of ER and NGF significantly increased in the E2 group ( P < .01). After co-administration with YKYTP-containing serum, the expression of ER-α, ER-β, NGF, and P75 significantly decreased ( P < .01). Conclusion YKYTP-containing serum can efficiently inhibit the expression of ER-α, ER-β, NGF, and P75 in RBL2H3 cells. YKYTP may alleviate endometriosis-related dysmenorrhea by downregulating ER expression in MCs.
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Dung, Nguyen Thi, Hoang Van Thanh i Nguyen Dinh Lam. "Influences of Growth Durations on Characteristics of NaYF4:(Yb,Tm) Upconversion Materials". VNU Journal of Science: Natural Sciences and Technology 35, nr 4 (23.12.2019). http://dx.doi.org/10.25073/2588-1140/vnunst.4965.
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NaYF4:(Yb,Tm) upconversion materials were synthesized by the simple hydrothermal method. Growth duration was varied from 4h to 12h under a growth temperature of 150oC. The structural, optical and surface morphology characteristics of the NaYF4:(Yb,Tm) UC materials were investigated. The XRD and SEM results illustrated that the NaYF4:(Yb,Tm) materials were transformed from the multiple phases (hexagonal and cubic) to the single-phase (hexagonal prism) as growth duration being longer than 8h with the average diameter and length of these prisms being about 0.5 µm and 2 µm, respectively. Under 980 nm laser excitation, the NaYF4:(Yb,Tm) emits at peaks of 450 nm (1D2→ 3F4), 475 nm (1G4→3H6), 647 nm (1G4→3F4) and 697 nm (3F3→3H6), with the highest emission belonging to NaYF4:(Yb,Tm) grown for 8h.
Keywords: NaYF4:(Yb,Tm), upconversion materials, photoluminescence, growth duration, hydrothermal method.
References
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