Cancer Science最新文献

Geographical Discrepancy in Medical Care Access Among Children, Adolescents, and Young Adults With Cancer in Japan, 2016-2019.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-04-02 DOI: 10.1111/cas.70069

Anna Tsutsui, Yoshitaka Murakami, Takako Fujimaki, Masayuki Endo, Yuko Ohno

{"title":"Geographical Discrepancy in Medical Care Access Among Children, Adolescents, and Young Adults With Cancer in Japan, 2016-2019.","authors":"Anna Tsutsui, Yoshitaka Murakami, Takako Fujimaki, Masayuki Endo, Yuko Ohno","doi":"10.1111/cas.70069","DOIUrl":"https://doi.org/10.1111/cas.70069","url":null,"abstract":"In Japan, cancer control measures have been developed in specialized hospitals for children (0-14 years), and adolescents and young adults (15-39 years) patients with cancer. We investigated geographical discrepancies between residential addresses and cancer treatment hospitals in patients aged 0-39 in Japan between 2016 and 2019. Using Japan's National Population-Based Cancer Registry data (n = 99,968), we classified the cases into 10 diagnostic groups and four age groups: 0-14, 15-19, 20-29, and 30-39. Using five types of hospital groups, we examined the origin-destination relationships between patients' residences and hospitals at the prefecture and Secondary Medical Area (SMA) levels via cross-tabulation, summarizing the results using descriptive statistics and heat maps. Generalized Estimating Equation analysis was performed to investigate the factors associated with receiving treatment outside the residential prefecture based on individual data. The median percentage of patients receiving treatment within their residential prefecture was 81.82% or higher across age groups and hospital groups. At the SMA level, the percentage ranged from 0% to 57.00% (median)-minimum 0.0% and maximum 100.0%. Model analysis revealed that patients with retinoblastoma (adjusted risk ratio: 5.45) and those living in metropolitan (Tokyo: 3.73, Osaka: 2.00) and non-metropolitan and depopulated (1.67) areas were significantly more likely to travel outside their residential prefectures. These findings reveal that Japan faces geographical discrepancies in access to cancer care, particularly for specific cancer types and areas. These findings can inform targeted interventions to support equitable access to specialized cancer care for young Japanese patients.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-04-01 DOI: 10.1111/cas.70058

Hiromi Muraoka, Hiromi Kazuno, Akihiro Hashimoto, Hiroshi Sootome, Shuichi Ohkubo

{"title":"Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells.","authors":"Hiromi Muraoka, Hiromi Kazuno, Akihiro Hashimoto, Hiroshi Sootome, Shuichi Ohkubo","doi":"10.1111/cas.70058","DOIUrl":"https://doi.org/10.1111/cas.70058","url":null,"abstract":"Heat shock protein 90 (HSP90) plays a crucial role in the maintenance of protein homeostasis in cancer cells. Inhibition of HSP90 is anticipated to exert anticancer activities by reducing levels of HSP90 client proteins. Pimitespib (TAS-116) has emerged as a potent ATP-competitive inhibitor of both HSP90α and β, demonstrating favorable therapeutic properties in preclinical models. Notably, pimitespib is the first HSP90 inhibitor approved for the treatment of advanced gastrointestinal stromal tumors in Japan. Poly(ADP-ribose) polymerase (PARP) inhibitors target cancers susceptible to the homologous recombination (HR) pathway and are used for treating various types of tumors, particularly those harboring defects in HR repair pathways within DNA damage repair (DDR) such as mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively). However, PARP inhibitors have shown limited efficacy in HR-proficient tumors, and the development of resistance to PARP inhibitors via restoration of DDR systems poses a significant challenge. In this study, we explored the potential of pimitespib to enhance PARP inhibitor activity. In PARP inhibitor-insensitive breast cancer cell lines, pimitespib impaired HR pathway function by promoting the proteasome-mediated degradation of proteins involved in HR, such as BRCA1, BRCA2, and Rad51 homologous 1 (RAD51). Consequently, pimitespib enhanced antitumor activity and DNA damage induced by PARP inhibitors in vitro. In human breast cancer xenograft mouse models, pimitespib downregulated RAD51 proteins and augmented the antitumor effects of PARP inhibitors. These findings highlight the potential of pimitespib as a therapeutic agent in combination with PARP inhibitors to treat PARP inhibitor-insensitive cancers.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to "Loss of Polarity Protein Par3, via Transcription Factor Snail, Promotes Bladder Cancer Metastasis".

IF 5.7 2区医学

Cancer Science Pub Date : 2025-04-01 DOI: 10.1111/cas.70073

引用次数: 0

Comparative Net Survival Analysis of Men and Women With Breast Cancer in Japan: A Population-Based Study.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-31 DOI: 10.1111/cas.70068

Daisy Sibale Mojoo, Isao Oze, Hiroshi Tsuge, Yukari Taniyama, Yuriko N Koyanagi, Sayaka Yamamoto, Megumi Hori, Kayo Nakata, Hiromi Sugiyama, Isao Miyashiro, Izumi Oki, Yoshikazu Nishino, Yuri Ito, Kota Katanoda, Akiko Shibata, Tomohiro Matsuda, Keitaro Matsuo, Hidemi Ito

{"title":"Comparative Net Survival Analysis of Men and Women With Breast Cancer in Japan: A Population-Based Study.","authors":"Daisy Sibale Mojoo, Isao Oze, Hiroshi Tsuge, Yukari Taniyama, Yuriko N Koyanagi, Sayaka Yamamoto, Megumi Hori, Kayo Nakata, Hiromi Sugiyama, Isao Miyashiro, Izumi Oki, Yoshikazu Nishino, Yuri Ito, Kota Katanoda, Akiko Shibata, Tomohiro Matsuda, Keitaro Matsuo, Hidemi Ito","doi":"10.1111/cas.70068","DOIUrl":"https://doi.org/10.1111/cas.70068","url":null,"abstract":"While male breast cancer (MBC) remains a rare and understudied disease, comparatively little is known about its prognosis in contrast to female breast cancer (FBC). There is a paucity of large population-based studies comparing the prognosis of MBC patients to FBC patients in Japan. This study analyzed 181,540 breast cancer cases, 1058 (0.6%) males and 180,482 (99.4%) females, from 12 prefectures in Japan diagnosed between 1993 and 2011. Five- and ten-year net survival (NS) were estimated and stratified by sex, period, age, stage, and histological groups. Excess hazard ratios (EHR) were adjusted for period, age, stage, and histological group. Cochran's Q test was utilized to assess heterogeneity across these factors. The overall 5- and 10-year NS estimates for MBC patients were 90.7% (95% CI: 86.3%-93.7%) and 83.7% (95% CI: 72.2%-90.8%), respectively, while those for FBC patients were 88.3% (95% CI: 88.1%-88.5%) and 79.1% (95% CI: 78.7%-79.4%), respectively. The survival of MBC patients was comparable to that of FBC patients, with EHR of 0.88 [95% CI: 0.70-1.09] and 0.86 [95% CI: 0.69-1.07] for 5- and 10-year survival, respectively. Heterogeneity analysis revealed no significant sex-based differences in survival across these strata. This study offers a comprehensive analysis of breast cancer survival in Japanese men and women and enhances understanding of MBC prognosis relative to FBC.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual Targeting of Aurora-A and Bcl-xL Synergistically Reshapes the Immune Microenvironment and Induces Apoptosis in Breast Cancer.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-30 DOI: 10.1111/cas.70072

Mingxue Liu, Jing Guo, Weiyong Liu, Zhenye Yang, Fazhi Yu

{"title":"Dual Targeting of Aurora-A and Bcl-xL Synergistically Reshapes the Immune Microenvironment and Induces Apoptosis in Breast Cancer.","authors":"Mingxue Liu, Jing Guo, Weiyong Liu, Zhenye Yang, Fazhi Yu","doi":"10.1111/cas.70072","DOIUrl":"https://doi.org/10.1111/cas.70072","url":null,"abstract":"The Aurora-A kinase inhibitor MLN8237 has shown efficacy in clinical trials for advanced breast cancer; however, its use as a monotherapy is limited by significant side effects and modest efficacy. Therefore, combining MLN8237 with other agents at lower doses may provide a viable alternative. In this study, we evaluated the combination of MLN8237 with the BH3 mimetic ABT263 for the treatment of triple-negative breast cancer (TNBC). We found that this combination significantly suppressed tumor growth and metastasis in immunocompetent syngeneic mouse models, whereas its efficacy was attenuated in immunodeficient xenograft models. Mechanistic studies revealed that the combination enhanced anti-tumor immunity by increasing the presence of CD8+ T cells and NK cells, while reducing the number of immunosuppressive cells in the tumor microenvironment. This shift resulted in elevated levels of IFN-γ and granzyme B, which activated the extrinsic apoptotic pathways in cancer cells. Notably, the combination treatment did not affect tumor cell proliferation but promoted apoptosis with minimal toxicity. Furthermore, the synergistic effect of MLN8237 and ABT263 in inducing intrinsic apoptosis was primarily driven by the inhibition of the AKT-Mcl-1 and Bcl-xL survival pathways in cultured tumor cells. Together, these findings support the MLN8237-ABT263 combination as an effective treatment strategy for TNBC, promoting both immune-mediated extrinsic apoptosis and inactivation of Bcl-xL/Mcl-1-dependent intrinsic anti-apoptotic pathways.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to "Celastrol Induces Proteasomal Degradation of FANCD2 to Sensitize Lung Cancer Cells to DNA Crosslinking Agents".

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-29 DOI: 10.1111/cas.70066

引用次数: 0

A Multicenter Phase II Trial of Nimustine Hydrochloride Administered via Convection-Enhanced Delivery in Children With DIPG.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-27 DOI: 10.1111/cas.70054

Ryuta Saito, Masayuki Kanamori, Yoshiki Arakawa, Yohei Mineharu, Yasuo Aihara, Kentaro Chiba, Toshihiro Kumabe, Ichiyo Shibahara, Yukihiko Sonoda, Kenichiro Matsuda, Manabu Kinoshita, Aya Sato, Fumiaki Takahashi, Teiji Tominaga

{"title":"A Multicenter Phase II Trial of Nimustine Hydrochloride Administered via Convection-Enhanced Delivery in Children With DIPG.","authors":"Ryuta Saito, Masayuki Kanamori, Yoshiki Arakawa, Yohei Mineharu, Yasuo Aihara, Kentaro Chiba, Toshihiro Kumabe, Ichiyo Shibahara, Yukihiko Sonoda, Kenichiro Matsuda, Manabu Kinoshita, Aya Sato, Fumiaki Takahashi, Teiji Tominaga","doi":"10.1111/cas.70054","DOIUrl":"https://doi.org/10.1111/cas.70054","url":null,"abstract":"Diffuse intrinsic pontine glioma (DIPG) is a very challenging-to-treat pediatric malignant tumor, with a median survival time of < 12 months. Convection-enhanced delivery (CED) allows for direct drug administration into the tumor site, showing potential as a novel therapeutic approach. This study evaluated the efficacy of CED of nimustine hydrochloride (ACNU) in children with DIPG. This phase 2, single-arm, multicenter study enrolled patients aged 3-21 years and diagnosed with DIPG. The investigational treatment commenced 1 month after completing radiotherapy (local 50-60 Gy). The treatment involved stereotactic brain surgery for catheter placement, followed by ACNU administration via a CED catheter at a concentration of 0.75 mg/mL for 2-3 days until a cumulative dose of 7 (±0.3) mL was achieved. The primary endpoint was the 1-year survival rate. From April 2018 to March 2020, 21 children were enrolled in the trial and treated, with 20 evaluable for the primary endpoint. The 1-year survival rate from the start of radiotherapy was 60%, and the median survival time was 15 months. The response rate was analyzed in 20 patients, with one complete response (CR), six partial responses (PR), nine stable diseases, and four progressive diseases, resulting in a response rate of 35% (CR + PR). The CED of ACNU in the brainstem of children with DIPG after radiotherapy appears to be an effective therapeutic strategy. This approach warrants further development as a treatment for children with DIPG. This study is registered with jRCT (No. jRCT2021190003).","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Real-World Data Analysis of Genomic Alterations Detected by a Dual DNA-RNA Comprehensive Genomic Profiling Test.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-26 DOI: 10.1111/cas.70071

Kousuke Watanabe, Miho Ogawa, Aya Shinozaki-Ushiku, Shuichi Tsutsumi, Kenji Tatsuno, Hiroyuki Aburatani, Hidenori Kage, Katsutoshi Oda

{"title":"Real-World Data Analysis of Genomic Alterations Detected by a Dual DNA-RNA Comprehensive Genomic Profiling Test.","authors":"Kousuke Watanabe, Miho Ogawa, Aya Shinozaki-Ushiku, Shuichi Tsutsumi, Kenji Tatsuno, Hiroyuki Aburatani, Hidenori Kage, Katsutoshi Oda","doi":"10.1111/cas.70071","DOIUrl":"https://doi.org/10.1111/cas.70071","url":null,"abstract":"GenMineTOP, the first dual DNA-RNA comprehensive genomic profiling (CGP) test in Japan, was approved for reimbursement in 2023. To evaluate its clinical utility, we analyzed 1356 cases from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database. Oncogenic genomic alterations were identified in 91.5% of cases. Somatic mutations were the most prevalent, followed by amplifications and fusion/exon skipping events. The DNA panel, covering 737 genes, detected not only alterations relevant to therapeutic decisions but also those providing insights into tumor biology. Among the latter, frequently observed examples included mutations in KMT2C (n = 28) and ARID1B (n = 24), and amplifications in GLI1 (n = 14) and YAP1 (n = 10), which are not included in other CGP tests approved in Japan. The RNA panel identified 105 fusion events, including 11 NTRK fusions (0.8%), of which five were NTRK3 fusions: two with the well-known ETV6-NTRK3 fusion and three with non-ETV6 partners. Forty-nine of these fusions were diagnostically significant, highlighting the utility of the RNA panel. Amplification-RNA expression analyses revealed strong correlations for MDM2, CDK4, EGFR, and ERBB2. In contrast, weaker correlations observed for MYC and FGFR1 highlighted the need for careful interpretation of amplification in these genes. Cancer type significantly influenced RNA expression, with KIT and TERT mutations linked to increased expression and significant overexpression observed in ALK, FGFR3, NTRK1, NTRK3, and RET fusions. In summary, this study demonstrated the real-world clinical utility of the dual DNA-RNA CGP test and provided a valuable resource for interpreting RNA expressions.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Cancer With Bifunctional Peptides: Mechanism of Cell Entry and Inciting Cell Death.

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-26 DOI: 10.1111/cas.70065

Maria F Setiawan, Oliver Rudan, Ingo G H Schmidt-Wolf

{"title":"Targeting Cancer With Bifunctional Peptides: Mechanism of Cell Entry and Inciting Cell Death.","authors":"Maria F Setiawan, Oliver Rudan, Ingo G H Schmidt-Wolf","doi":"10.1111/cas.70065","DOIUrl":"https://doi.org/10.1111/cas.70065","url":null,"abstract":"Antimicrobial peptides have gained much attention in clinical research due to their extensive possibilities of application beyond antimicrobial use. The modification of antimicrobial peptides enables the peptides to target particular cancer cells, improving the specificity and efficiency of the treatment. In this study, TP2-D-Tox, a derivative of TP-D-Tox, demonstrated a superior anti-tumor activity towards renal carcinoma, Caki-2, and breast carcinoma, SK-BR-3. TP-Tox was previously reported to inhibit tumor growth in a mouse model, increasing the overall survival. TP- and TP2-D-Tox were shown to penetrate the cells via clathrin-mediated endocytosis, triggered by binding to the subunits of non-muscle myosin IIa and S100A9. HSPB1 was observed to have a protective effect towards TP2-D-Tox against the immediate proteolytic inactivation. The intracellular presence of the peptides evoked mitochondrial permeability transition, generation of reactive oxygen species, and formation of MLKL oligomers in the plasma membrane. Our investigation revealed that TP- and TP2-D-Tox induced a similar but distinctly regulated cell death in Caki-2 and SK-BR-3 cells. Both peptides established toxicity without activating any caspases, suggesting the possibility of TP- and TP2-D-Tox as a promising approach to bypass the caspase-dependent apoptosis-resistance issue impairing therapeutic responses of many cancer treatments.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differentiation of Cytotoxic CD8⁺ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?

IF 5.7 2区医学

Cancer Science Pub Date : 2025-03-25 DOI: 10.1111/cas.70055

Ryo Koyama-Nasu, Yangsong Wang, Hinata Miyano, Motoko Y Kimura

{"title":"Differentiation of Cytotoxic CD8+ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?","authors":"Ryo Koyama-Nasu, Yangsong Wang, Hinata Miyano, Motoko Y Kimura","doi":"10.1111/cas.70055","DOIUrl":"https://doi.org/10.1111/cas.70055","url":null,"abstract":"Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity. Here, we review the heterogeneity of CD8+ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8+ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8+ T cells, whereas the identification of TCF1+ stem-like CD8+ T cells has highlighted their importance in anti-tumor immunity. During tumor progression, TCF1+ stem-like CD8+ T cells differentiate into cytotoxic Tim-3+ terminally differentiated CD8+ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8+ T cell responses and showed that blocking CD69 function, either through the administration of anti-CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim-3+ terminally differentiated CD8+ T cells in both tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti-tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti-tumor CD8+ T cell response.","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0