NPJ Breast Cancer最新文献

{"title":"RAD51-based homologous recombination deficiency is associated with treatment response and survival in early breast cancer.","authors":"Alba Llop-Guevara, Benedetta Pellegrino, Isabel Pimentel, Guillermo Villacampa, Cinzia Solinas, Sara Torres-Esquius, Nicoletta Campanini, Sara Simonetti, Chiara Tommasi, Olga Serra, Matilde Corianò, Daniela Boggiani, Maria Michiara, Roberta Minari, Beatrice Bortesi, Elena Rapacchi, Maria Vittoria Dieci, Matteo Lambertini, Gabriele Zoppoli, Alessio Schirone, Chiara Casarini, Elisabetta Cretella, Laura Cortesi, Enrico Maria Silini, Cristina Saura, Karen Willard-Gallo, Anais Boisson, Antonino Musolino, Violeta Serra, Judith Balmaña, Cristina Cruz","doi":"10.1038/s41523-026-00920-5","DOIUrl":"10.1038/s41523-026-00920-5","url":null,"abstract":"<p><p>Advances in breast cancer (BC) therapy are limited by the absence of well-established biomarkers for DNA-damage targeted treatments. We evaluated the predictive and prognostic value of homologous recombination repair (HRR) deficiency (HRD) by RAD51 nuclear foci and stromal tumour-infiltrating lymphocytes (TILs) in early-stage BC patients with suspected germline susceptibility. Among 291 patients, HRD by RAD51 was found in 78.4% of tumours, and 69.8% had low TILs (<30%). In 178 patients treated with neoadjuvant chemotherapy, pathologic complete response (pCR) was higher in those with HRD vs HRR-proficient (HRP) tumours (52.3% vs 36.4%); RAD51 remained independently associated with pCR (p = 0.03). Overall survival (OS) favoured HRD, with 5-year OS of 89.2% vs 82.8% in HRP (p = 0.009), with stronger evidence in triple-negative TILs-low disease (p = 0.005). These findings support RAD51-based HRD assessment as a predictive and prognostic biomarker that may guide treatment decisions in early-stage BC.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13079792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracking response to neoadjuvant systemic therapy through circulating tumor DNA analysis in breast cancer.","authors":"Antonio Marra, Sarah H Kim, Fresia Pareja, Thais Basili, David B Solit, Sarat Chandarlapaty, George Plitas, Jorge S Reis-Filho, Britta Weigelt, Tari A King, David N Brown","doi":"10.1038/s41523-026-00921-4","DOIUrl":"10.1038/s41523-026-00921-4","url":null,"abstract":"<p><p>Neoadjuvant systemic therapy (NST) is a standard treatment approach for patients with early-stage breast cancer, particularly those with stage II-III disease and aggressive subtypes such as HER2-positive and triple-negative breast cancer. While NST improves surgical outcomes and provides prognostic information, accurately assessing preoperative treatment response remains a clinical challenge. Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker for monitoring disease dynamics and guiding therapeutic decisions. In this study, we aimed to evaluate whether ctDNA analysis in patients with stage II-III breast cancer (n = 20) could serve as a surrogate for invasive biopsies in molecular profiling and as a tool for monitoring response to NST. At baseline, ctDNA was detectable in the majority of patients by droplet digital (dd)PCR (15/18, 83%) and all patients with longitudinal follow-up had ctDNA clearance after NST (13/13; 100%). A positive correlation was observed between the allele fraction in ctDNA, histologic grade and molecular subtype, suggesting that ctDNA levels may be influenced by tumor biology. None of the three patients with undetectable baseline ctDNA had distant relapse, regardless of whether they achieved pathologic complete response (pCR), compared to 5/15 (33%) with detectable baseline ctDNA. These findings suggest that ctDNA assessment at baseline may provide additional prognostic information to define the risk of patients after NST. While ctDNA shows promise in capturing tumor burden and biological characteristics, its role in predicting pCR and long-term outcomes requires further investigation.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant pembrolizumab plus chemotherapy in older patients with early-stage triple-negative breast cancer: real-world insights from neo-real/GBECAM-0123.","authors":"Mariana Carvalho Gouveia, Romualdo Barroso-Sousa, Laura Lapuchesky, Laura Testa, Monique Celeste Tavares, Flávia Cavalcanti Balint, Carlos Henrique Dos Anjos, Débora de Melo Gagliato, Mayana Lopes de Brito, Giuliana Colucci, Daniele Assad-Suzuki, Daniela Dornelles Rosa, Noele de Jesus Barros Gomes, Natalia Cristina Cardoso Nunes, Isadora Martins de Sousa, Matheus de Oliveira Andrade, Fernanda Madasi, Jose Bines, Mariana Savignano, Rafael Dal Ponte Ferreira, Candice Lima Santos, Maira Tavares, Mariana Ribeiro Monteiro, Zenaide Silva de Souza, Ana Maria Ulbricht Gomes, Bruna M Zucchetti, Anezka Ferrari, Maria Marcela Fernandes Monteiro, Poliana Albuquerque Signorini, Solange Sanches, Paulo M Hoff, Claudio Paletta, Maria Del Pilar Estevez-Diz, Renata Colombo Bonadio","doi":"10.1038/s41523-026-00919-y","DOIUrl":"10.1038/s41523-026-00919-y","url":null,"abstract":"<p><p>The KEYNOTE-522 regimen is the standard of care for stage II-III triple-negative breast cancer (TNBC). However, older patients were underrepresented in the pivotal trial. We evaluated the effectiveness and safety of this regimen in patients aged ≥65 years enrolled in the Neo-Real/GBECAM-0123 multicenter real-world study conducted across institutions in Brazil and Argentina. Among 724 patients, 80 (11%) were aged ≥65 years and presented distinct baseline characteristics, including lower frequencies of grade 3 tumors, Ki67 ≥ 50%, and germline BRCA1/2 mutations, alongside a higher prevalence of impaired performance status. The pathologic complete response (pCR) rate in older patients was 54.9% in comparison with 64.5% in younger patients, although age was not independently associated with pCR in multivariable analysis, including other relevant baseline variables. Older patients experienced a significantly higher toxicity burden, with increased rates of treatment discontinuation, dose reductions, treatment delays, hospitalizations, and grade ≥3 neutropenia. Taken together, these data indicate that older patients with TNBC harbor distinct biological and clinical features with numerically lower pCR rates, and that the increased toxicity burden underscores the need for personalized treatment strategies and dedicated research in this population.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13066152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity and immune microenvironment of early invasive estrogen receptor-positive breast cancer reveal an immune-rich subset.","authors":"Drashti Jain, Linda Liao, Vida Talebian, Megan Hopkins, Mary Anne Quintayo, Cheryl Crozier, Jane Bayani, Alison M Cheung, Martin Yaffe, John Bartlett, Melanie Spears","doi":"10.1038/s41523-025-00875-z","DOIUrl":"10.1038/s41523-025-00875-z","url":null,"abstract":"<p><p>Approximately 80% of all breast cancer cases are estrogen receptor-positive (ER+). This subtype is known to have distant recurrences in a subset of patients after adjuvant endocrine therapy, partially due to the heterogeneity of the disease. ER+ breast cancer has been generally classified as an immune-cold disease. Thus, to better inform treatment decisions and to consider the prospect of immunotherapy, the immune microenvironment needs to be thoroughly characterized. In this study, the proteome and transcriptome of the tumour and tumour microenvironment (TME) were characterized using the GeoMx Digital Spatial Profiler (DSP) and NanoString's BC360 gene expression panel. Spatially resolved tumour and TME across a patient's lumpectomy demonstrated substantial heterogeneity in the expression of commonly targeted immune and tumour proteins. Results from this study demonstrated heterogeneity across the tumour and TME in ER+ breast cancer, which may be reflective of a variable immune response.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer.","authors":"Dobrin Draganov, Zhen Han, Aamir Rana, Nitasha Bennett, Darrell J Irvine, Peter P Lee","doi":"10.1038/s41523-026-00908-1","DOIUrl":"10.1038/s41523-026-00908-1","url":null,"abstract":"","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":"12 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The landscape of the intestinal microbiome among patients with newly diagnosed invasive breast cancer and ductal carcinoma in situ (DCIS).","authors":"Sarah L Sammons, Thomas M Kuntz, Molly DiLullo, Xochitl C Morgan, Alyssa Martin, Melissa E Hughes, Tasnim Rahman, Romualdo Barroso-Sousa, Esther Ritah Ogayo, Julia Giordano, Sean Ryan, Adrienne G Waks, Ilana Schlam, Jennifer Ligibel, Nancy U Lin, Ana C Garrido-Castro, Elizabeth A Mittendorf, Sara M Tolaney","doi":"10.1038/s41523-026-00922-3","DOIUrl":"10.1038/s41523-026-00922-3","url":null,"abstract":"<p><p>The intestinal microbiome shapes immune responses and is associated with patient outcomes in cancer following immunotherapy. We evaluated differences between the intestinal microbiome profiles of patients with early-stage invasive breast cancer (BC) and ductal carcinoma in situ (DCIS) by subtype using whole genome metagenomic sequencing. There were no significant differences in microbiome composition between DCIS and invasive BC as measured by alpha diversity (p = 0.20, ANOVA) or beta diversity (p = 0.52, PERMANOVA). Within invasive BC, patients with hormone receptor-positive (HR + )/HER2 + BC differed significantly in beta diversity relative to other subtypes (p < 0.05), with differences in six species (q < 0.25). Bacteroides ovatus was significantly more abundant in patients with stage III BC vs. stage I (p = 0.0003). Functional pathway analysis using HUMAnN3 revealed stage-specific enrichment of amino acid biosynthesis and nucleotide-related pathways. Altogether, these findings highlight potential microbial signatures associated with BC subtype and stage.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13066469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"No evidence for genotype-treatment interactions with breast cancer endocrine therapy adverse effects in UK Biobank.","authors":"Kinan Mokbel, Michael N Weedon, Victoria Moye, Katherine S Ruth, Leigh Jackson","doi":"10.1038/s41523-026-00923-2","DOIUrl":"10.1038/s41523-026-00923-2","url":null,"abstract":"<p><p>Breast cancer is the most commonly diagnosed cancer worldwide. Earlier studies have demonstrated that breast cancer patients with particular genomic variants are more susceptible to adverse drug effects (ADEs) when they are receiving endocrine therapy. However, to establish a robust body of evidence with regard to the potential utility and predictive value of these variants, findings from these reports require replication. This study aimed to validate previously reported associations between genomic variants and medically important adverse drug effects (MIADEs) using UK Biobank (UKBB). In 2729 female participants who had received endocrine therapy in the UKBB, no statistically significant genotype-treatment interactions were observed for the outcomes examined after correction for multiple testing. Power was limited for modest interactions involving low-frequency variants and less frequent outcomes, whereas power was high to detect larger interaction effects in common-variant scenarios. Accordingly, the findings do not provide robust evidence to support previously reported pharmacogenomic associations in this dataset, and current evidence does not support the use of pharmacogenomic testing for individualised endocrine therapy selection in clinical practice.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Socioeconomic disparities in long-term heart failure risk of trastuzumab with or without anthracyclines in early-stage breast cancer: a SEER-Medicare database analysis.","authors":"Karissa Britten, Marla Lipsyc-Sharf, Eric H Yang, Susan McCloskey, Mina S Sedrak, Mediget Teshome, Julia LaBarbera, Aditya Bardia, Nicholas McAndrew","doi":"10.1038/s41523-025-00883-z","DOIUrl":"10.1038/s41523-025-00883-z","url":null,"abstract":"<p><p>While it is well-established that cardiovascular disease and congestive heart failure (CHF) are increased among breast cancer survivors, little is known about how systemic therapy use, medical comorbidities, and socioeconomic factors interact to influence long-term cardiac outcomes. In this study, we performed an analysis of the SEER-Medicare database, including more than 200,000 patients with early-stage breast cancer. Using available zip code and census data, patient disease characteristics and cardiac outcomes were stratified by socioeconomic variables. Overall, patients of Black, Hispanic, and American Indian/Alaskan Native race/ethnicity had an increased incidence of large, high-grade tumors and nodal involvement as compared to White and Asian American/Pacific Islander (AAPI) patients. Lower per capita income (PCI), higher percentage of population living in poverty, lower level of education, and not speaking English at home were also associated with increased tumor size, grade, and nodal stage. Adjusting for cardiac covariates and cancer therapy type, a multivariate socioeconomic model revealed that Black patients had a higher risk of CHF and AAPI patients had a lower risk compared to White patients. Further adjusting for race/ethnicity, patients living in a zip code in the lowest quartile of PCI also had a higher risk of CHF compared to those in the highest quartile.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13043732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic analysis to uncover the mechanism of radiosensitization of AR-positive triple-negative breast cancers with AR inhibition.","authors":"Breanna McBean, Benjamin Hauk, Anna R Michmerhuizen, Benjamin C Chandler, Andrea M Pesch, Lynn M Lerner, Douglas Gurdak, Connor Ward, Priyanka Rana, Reine Abou Zeidane, Vesna Mercer, Mingfang Tao, Ethan Hochmuth, Kassidy M Jungles, Stephanie The, Meilan Liu, Daniel E Spratt, Alan P Boyle, Lori J Pierce, Corey W Speers","doi":"10.1038/s41523-026-00916-1","DOIUrl":"10.1038/s41523-026-00916-1","url":null,"abstract":"<p><p>The androgen receptor (AR) has been identified as a driver of tumor growth and radioresistance in triple-negative breast cancers (TNBC), though the mechanistic role of AR in response to radiation therapy (RT) remains unknown. Here, we demonstrate that inhibition with the second-generation anti-androgen, apalutamide, but not darolutamide, is sufficient to radiosensitize AR+ TNBC models (rER: 1.34-1.41; rER: 0.96-1.11, respectively). Cells with low AR expression were not radiosensitized by AR inhibition (rER: 0.96-1.03). Mechanistically, while stimulation with the AR-agonist R1881 is sufficient to induce nuclear translocation of AR in AR+ TNBC cells, AR inhibition with enzalutamide, apalutamide, or darolutamide blocked AR nuclear translocation. When cells are treated with R1881+RT, nuclear translocation of AR was induced at similar or greater levels compared to R1881 alone in AR+ TNBC cells. Combination treatment of RT with enzalutamide reduced nuclear localization of AR (32-39% reduction) compared to RT alone. Transcriptional evaluation with RNA-Seq after AR stimulation and RT demonstrated changes in the MAPK/ERK signaling pathway, among others. Overexpression of ERK reduces the radiosensitizing ability of second-generation anti-androgens, suggesting that AR-mediated radioresistance may be due, at least in part, to downstream MAPK/ERK signaling. These findings suggest that AR-mediated radioresistance is at least partially due to downstream MAPK/ERK signaling. Together this work builds on the mechanistic understanding of AR-mediated radioresistance in AR+ TNBC which may expose vulnerabilities in resistance to combination treatment with AR inhibition and RT.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13039478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147284546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trimester of diagnosis affects tumor characteristics and survival in breast cancer during pregnancy: first results from the STURGATE collaboration.","authors":"Carsten F J Bakhuis, Leo Gkekos, Paul J van Diest, Elsken van der Wall, Irma Fredriksson, Carmen van Dooijeweert, Anna L V Johansson","doi":"10.1038/s41523-026-00918-z","DOIUrl":"10.1038/s41523-026-00918-z","url":null,"abstract":"<p><p>Breast cancer diagnosed during pregnancy (PrBC) more often shows unfavorable disease characteristics compared to non-pregnant young breast cancer patients. Previous PrBC research suggests marked differences in tumor characteristics and survival between the gestational trimesters of diagnosis. To investigate this, data of two national retrospective PrBC cohorts from Sweden (1992-2018) and the Netherlands (1988-2022) were harmonized and pooled. PrBC patients were matched for age and year of diagnosis to three non-PrBC patients (controls) per country. Frequencies were pooled and compared using non-parametric tests, while fixed effect meta-analysis with stepwise multivariable Cox models was applied for overall survival. PrBC patients diagnosed in the first trimester resembled the non-PrBC controls. In contrast, second and third trimester diagnoses were associated with significantly more aggressive features, including higher rates of triple negative subtype, higher histologic grade, and more advanced stage at presentation compared to controls. Following adjustment for these features and treatment, overall survival remained significantly worse in PrBC patients compared to non-PrBC controls. This association was pronounced in the second and third trimesters but did not reach statistical significance after full adjustments. Altogether, the persistent worse survival for PrBC and the differences between the trimesters suggest trimester-specific biological influences on tumor behavior and survival.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}