Medical Oncology最新文献

{"title":"Targeting the Hippo and Rap1 signaling pathways: the anti-proliferative effects of curcumin in colorectal cancer cell lines.","authors":"Deema Kamal Sabir","doi":"10.1007/s12032-024-02560-w","DOIUrl":"10.1007/s12032-024-02560-w","url":null,"abstract":"<p><p>CRC has the third-highest cancer incidence and death. Many human cancers, including colorectal cancer, are connected to abnormal signaling pathway gene expression. Many human malignancies include Hippo and Rap1 signaling. This research examined curcumin's therapeutic effects on colorectal cancer cell lines' Hippo and Rap1 signaling pathway genes. The role of the above signaling pathways is considered in colorectal cancer development. No research has examined curcumin's influence on key genes in these pathways; thus, this work is meant to uncover its more precise mechanism. First, the gene expression omnibus database is queried to discover GSE8671, a dataset that contains differentially expressed genes associated in CRC formation. DAVID was used to discover the corporation of these genes and signaling pathways (Hippo and Rap1), and the cancer genome atlas (TCGA) database was utilized to select genes and assess their expression and biomarker potential. MTT, apoptosis, and quantitative PCR were used to assess whether curcumin is therapeutic for colorectal cancer cell lines. An in-silico analysis identified the dysregulation of several critical genes AXIN2, MYC, TEAD4, MET, LPAR1, and ADCY9 in colorectal cancer, highlighting their involvement in the Hippo and Rap1 signaling pathways. Experimental assessments, including MTT assays, apoptosis assays, and quantitative PCR (qPCR) analysis, demonstrated that the targeted modulation of these genes effectively inhibits cancer cell proliferation. Specifically, treatment with curcumin resulted in a significant reduction in cell viability in HT-29 and HCT-116 colorectal cancer cell lines, thereby facilitating apoptotic cell death. Furthermore, curcumin administration was associated with the upregulation of LPAR1 and ADCY9 gene expression, while concurrently downregulating AXIN2, MYC, TEAD4, and MET in both cell lines. This study reveals compelling evidence of curcumin's potent anticancer properties, highlighting its transformative influence on the Hippo and Rap1 signaling pathways within colorectal cancer cells. These findings not only underscore curcumin's potential as a therapeutic agent but also pave the way for innovative strategies in the fight against colorectal cancer.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 2","pages":"41"},"PeriodicalIF":2.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concomitant medication effects on patients with lung cancer taking immune checkpoint inhibitors a review.","authors":"Han Deng, Junxiang Zhou, Zhixi Liu, Lu Huang, Yanru Gu, Peng Chen, Hongtao Xiao","doi":"10.1007/s12032-024-02591-3","DOIUrl":"10.1007/s12032-024-02591-3","url":null,"abstract":"<p><p>In the past decade, a variety of immune checkpoint inhibitors (ICIs) are currently approved for lung cancer in the world. As a new therapeutic approach, ICIs have shown significant clinical benefits in the first-line or second-line treatment for advanced lung cancer, improving the survival and quality of life of patients. Patients need to take multiple drugs in the meantime due to their own disease or side effects during treatment. In view of drug interactions, concomitant medications have a positive or negative impact on the prognosis of lung cancer patients. In this review, we reviewed the effects of multiple drugs on the prognosis of patients with lung cancer taking ICIs. Several studies indicate that antibiotics, proton pump inhibitors (PPIs), corticosteroids, and opioid analgesics can decrease the efficacy of ICIs. Aspirin and bone-targeting drugs can enhance the efficacy of ICIs and improve the survival rate. The effects of metformin (MET), renin-angiotensin-aldosterone system inhibitors (RASI), nonsteroidal anti-inflammatory drug (NSAIDS) (except aspirin), and statins on ICIs are controversial. Future research should further explore the effects of these concomitant medications on ICIs and develop personalized prescriptions based on the specific needs of patients.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 2","pages":"40"},"PeriodicalIF":2.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of the effect of zinc oxide, selenium, and silver nanoparticles on the expression level of oxidative stress-associated genes in ovarian cancer.","authors":"Fatemeh Irannejad, Shahrzad Shahbazi, Somayeh Reiisi, Razieh Heidari","doi":"10.1007/s12032-024-02593-1","DOIUrl":"10.1007/s12032-024-02593-1","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) generated by oxidative stress have emerged as critical factors in the pathophysiology of malignancies. This study investigated the antioxidant and anticancer properties of zinc (Zn), selenium (Se), and silver (Ag) nanoparticles (NPs) against the A2780 human ovarian cancer cell line. Here, the bioinformatics approach was used to determine the top differentially expressed genes associated with oxidative stress. The ZnO-, Se-, and Ag-NPs were then synthesized via a green synthesis method and subsequently characterized using techniques, such as FTIR, XRD, DLS, zeta potential analysis, FESEM, and TEM. The antioxidant capacity of the NPs was evaluated using a DPPH scavenging assay and their effect on superoxide dismutase enzyme activity was determined. HDF and A2780 cells were treated with varying concentrations of ZnO-, Se-, and Ag-NPs, and cell viability and colony formation were assessed using MTT and clonogenic assays, respectively. Additionally, qPCR was performed to analyze the expression of the candidate genes NOX4, SOD2, and NR4A4. Characterization techniques confirmed the successful synthesis of pure, crystalline, and spherical NPs. Antioxidant assays demonstrated the significant antioxidant properties of ZnO-, Se-, and Ag-NPs. In vitro studies indicated that ZnO-, Se-, and Ag-NPs effectively inhibited cell proliferation and suppressed colony formation, likely owing to the downregulation of NOX4 and upregulation of SOD2 genes. Our findings suggest that ZnO-, Se-, and Ag-NPs may serve as promising anticancer agents for ovarian cancer and NOX4 downregulation and SOD2 upregulation can be proposed as oxidative stress biomarkers; however, further experimental investigation is required to elucidate the therapeutic potential of NPs and the early detection potential of biomarkers.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 2","pages":"39"},"PeriodicalIF":2.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of potential anti-metastatic effect of metformin and caffeic acid combination therapy in breast cancer cell line in in-vitro culture model.","authors":"Halil Yavuz, Yasin Tülüce, Fuat Karakuş, Sedat Köstekci, Merve Tunçyürekli, Ahmet Yasin Keleş","doi":"10.1007/s12032-024-02592-2","DOIUrl":"10.1007/s12032-024-02592-2","url":null,"abstract":"<p><p>The invasion and metastasis of cancer cells transform localized cancers into systemic and life-threatening diseases, posing one of the most significant challenges in cancer treatment. This study tested the hypothesis that combined treatment with Caffeic acid (CA) and metformin (MTF) could inhibit or reduce effective signaling pathways involved in the proliferation, survival, and metastasis of MCF-7 breast cancer cells. Anti-proliferation analysis determined the IC50 values for MTF (4.5 mM) and CA (163 µM) after 72 h. Cell migration analysis showed that MTF and CA significantly inhibited MCF-7 cell migration by the 72nd hour, both alone and in combination, without affecting HME1 healthy cell migration from the 48th hour. Colony formation analysis revealed that CA completely inhibited colony formation in MCF-7 cells, while MTF reduced it by 19%. ELISA results indicated that neither CA nor MTF affected the levels of VEGF-A, E-cadherin, or TINAGL-1 proteins, which are involved in MCF-7 cell migration and invasion. However, MTF significantly reduced IL-1β protein levels, and CA significantly reduced IL-4 protein levels in MCF-7 cells. RT-qPCR results largely supported the ELISA findings. Overall, CA and MTF exhibited potential to inhibit MCF-7 cell apoptosis, migration, tumor microenvironment modulation, and metastasis.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 2","pages":"38"},"PeriodicalIF":2.8,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling non-coding RNAs in breast cancer: mechanistic insights and therapeutic potential.","authors":"Muqtada Shaikh, Gaurav Doshi","doi":"10.1007/s12032-024-02589-x","DOIUrl":"10.1007/s12032-024-02589-x","url":null,"abstract":"<p><p>Breast cancer remains a leading global health challenge requiring innovative, therapeutic strategies to improve patient outcomes. This review explores the pivotal roles of non-coding RNAs (ncRNAs), including long non-coding RNA, micro RNA, and circular RNA, in breast cancer biology. We highlight how these molecules regulate critical signaling pathways, influence tumor microenvironments, and contribute to treatment resistance. Our findings underscore the potential of ncRNAs as biomarkers for early diagnosis and as treatment targets for personalized treatment strategies. To pave the way for innovative cancer management approaches, we investigate the complex interactions of ncRNAs and their impact on tumor progression. This comprehensive review enhances our understanding of breast cancer biology while emphasizing the translational significance of ncRNA research in developing effective treatment strategies. Additional research and clinical studies are required to confirm the diagnostic and medicinal value of ncRNAs in breast cancer. Investigating the complex networks of ncRNA interactions and their links to other biological pathways can lead to the discovery of new treatment targets. Furthermore, leveraging advanced technologies, such as machine learning and multi-omics methods, will be critical in improving our understanding of ncRNAs biomarkers and translating these insights into impactful clinical applications.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 1","pages":"37"},"PeriodicalIF":2.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanobodies as innovative immune checkpoint modulators: advancing cancer immunotherapy.","authors":"Mohammad Hosseininejad-Chafi, Zohre Eftekhari, Akbar Oghalaie, Mahdi Behdani, Nazli Sotoudeh, Fatemeh Kazemi-Lomedasht","doi":"10.1007/s12032-024-02588-y","DOIUrl":"10.1007/s12032-024-02588-y","url":null,"abstract":"<p><p>The immune system relies on a delicate balance between attacking harmful pathogens and preserving the body's own tissues, a balance maintained by immune checkpoints. These checkpoints play a critical role in preventing autoimmune diseases by restraining excessive immune responses while allowing the immune system to recognize and destroy abnormal cells, such as tumors. In recent years, immune checkpoint inhibitors (ICIs) have become central to cancer therapy, enabling the immune system to target and eliminate cancer cells that evade detection. Traditional antibodies, such as IgGs, have been widely used in immune therapies but are limited by their size and complexity. Nanobodies (Nbs), derived from camelid heavy-chain-only antibodies, offer a promising alternative. These small, stable antibody fragments retain the antigen-binding specificity of traditional antibodies but have enhanced solubility and the ability to target otherwise inaccessible epitopes. This review explores the use of Nbs as ICIs, emphasizing their potential in cancer immunotherapy and other immune-related treatments. Their unique structural properties and small size make Nbs highly effective tools for modulating immune responses, representing a novel approach in the evolving landscape of checkpoint inhibitor therapies.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 1","pages":"36"},"PeriodicalIF":2.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baicalein, a natural flavonoid in gastrointestinal cancers treatment: recent trends and future perspectives.","authors":"Pooja Sharma, Deeksha Pal, Anita Rani Gill, Mahiti Gupta, Soniya Goyal, Poonam Bansal, Ujjawal Sharma, Darin Mansor Mathkor, Shafiul Haque, Damandeep Kaur, Hardeep SinghTuli","doi":"10.1007/s12032-024-02587-z","DOIUrl":"10.1007/s12032-024-02587-z","url":null,"abstract":"<p><p>Gastrointestinal cancer is a malignant condition of the gastrointestinal tract (GI) which affect multi-organs of digestive system, such as esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum, and anus. Gastrointestinal cancer is a 5th most common malignant cancer and 4th major cause in cancer-related mortality rate. Various significant facilities are available that have reduced the radio-resistance, chemo-resistance, and their adverse side effects. However, there are serious side effects associated with chemical and radiations during the process. Baicalein is a natural flavonoid extracted from dried roots of Scutellaria baicalensis, showing anti-cancerous property. It is also participating in inhibiting metastasis, accelerating apoptosis and elevating autophagy through inhibition of inflammation and cell proliferation. In this review, we have focused on Chemistry and pharmacokinetics of Baicalein for drug designing and clinical applications majorly in gastrointestinal cancer. Moreover, various types of cancer related to gastrointestinal, role of nanotechnology, and its synergism for reducing cancer are also discussed. Thus, the review would be beneficial to explore the role of baicalein against gastrointestinal cancer treatment.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 1","pages":"35"},"PeriodicalIF":2.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotheranostics for gynecological cancers: a path forward for Africa.","authors":"Mutia Kehwalla Aza, Anavami Suberu, Mahmood Balogun, Goodness Adegbola, Mohamed Alie Sankoh, Thomas Oyediran, Nicholas Aderinto, Gbolahan Olatunji, Emmanuel Kokori, Chinonyelum Emmanuel Agbo","doi":"10.1007/s12032-024-02582-4","DOIUrl":"10.1007/s12032-024-02582-4","url":null,"abstract":"<p><p>Nanoparticle-based therapies represent a transformative approach to managing gynecological cancers, offering targeted treatment strategies that minimize harm to healthy tissues while maximizing therapeutic efficacy. Despite their potential, implementing these advanced treatments in Africa is needed by a complex interplay of technological, economic, regulatory, and ethical challenges. This paper examines the current landscape of nanoparticle-based therapies, identifying critical barriers to their adoption, including inadequate infrastructure, high costs, and insufficient regulatory frameworks. Technological deficiencies manifest as a need for advanced nanoparticle synthesis, delivery, and diagnostics equipment, impeding research and clinical applications. Economically, the high production costs of nanoparticles, compounded by limited access to advanced diagnostic and treatment facilities, create significant financial barriers for healthcare systems and patients alike. Additionally, the regulatory environment needs to be more cohesive, characterized by a lack of established protocols and expertise to evaluate the unique properties of nanomedicines. However, opportunities for advancement exist through focused research and development initiatives. Targeted drug delivery systems, early detection methods, and immunotherapy integration are promising avenues to enhance treatment outcomes. Collaborative partnerships between African institutions and international research entities, alongside public-private collaborations, could bolster local capabilities in nanomedicine. To facilitate the integration of nanoparticle-based therapies, African governments must prioritize funding for nanomedicine research, create robust regulatory frameworks, and ensure equitable access to these innovative treatments. A concerted effort involving policy reforms, investment, and collaboration is essential for overcoming existing barriers and realizing the full potential of nanoparticle-based therapies in improving health outcomes for gynecological cancer patients across Africa.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 1","pages":"34"},"PeriodicalIF":2.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I study of neoadjuvant chemoradiotherapy with S-1 for clinically resectable type 4 or large type 3 gastric cancer in elderly patients aged 75 years and older (OGSG1303).","authors":"Masayuki Shinkai, Motohiro Imano, Masaki Yokokawa, Jin Matsuyama, Yutaka Kimura, Toshio Shimokawa, Hisato Kawakami, Taroh Satoh, Takushi Yasuda, Hiroshi Furukawa","doi":"10.1007/s12032-024-02583-3","DOIUrl":"10.1007/s12032-024-02583-3","url":null,"abstract":"<p><p>Purpose The prognosis for type 4 and large type 3 gastric cancer (GC) is extremely poor, especially in elderly patients (≥ 75 years). To improve the prognosis of these types of GC, we performed a phase I study to determine the recommended dose (RD) of S-1 combined with neoadjuvant radiotherapy. Methods Patients with clinically resectable type 4 and large type 3 GC were enrolled to successive cohorts in a conventional 3 + 3 design. Three dose levels were designed, as follows: level 0: S-1 60 mg/m²/day on Days 1-14; level 1: S-1 80 mg/m²/day on Days 1 -14; level 2: S-1 80 mg/m²/day on Days 1-14 and Days 22-35. The starting dose was level 1. Radiotherapy was delivered at a total dose of 40 Gy in fractions for 4 weeks. Results Ten patients were enrolled from July 2014 to August 2018. Six patients were registered at level 1, and one patient developed a dose limiting toxicity as gastric stenosis (grade 3). Two of four patients enrolled at level 2 developed dose limiting toxicity (inability to receive S-1 for hematological reasons). Therefore, the RD was determined as level 1. All patients underwent the protocol surgery; one patient underwent R1 resection because of positive peritoneal washing cytology. There were no treatment-related deaths, and the pathological response rate was 80%. The 5-year overall- and progression-free survival rates were both 60.0%. Conclusion The RD was determined as level 1. A phase II trial using the RD should be initiated.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 1","pages":"31"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxic effects of bee venom-loaded ZIF-8 nanoparticles on thyroid cancer cells: a promising strategy for targeted therapy.","authors":"Hasan İlhan, Dilek Kabakcı, Mücahit Seçme","doi":"10.1007/s12032-024-02584-2","DOIUrl":"10.1007/s12032-024-02584-2","url":null,"abstract":"<p><p>Thyroid cancer continues to be a notable health issue, requiring the creation of novel treatment methods to enhance patient results. The objective of this study is to investigate the potential of utilizing bee venom (BV)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanoparticles as a novel strategy for specifically targeting and treating medullary thyroid cancer cells. Due to their wide surface area and configurable pore size, ZIF-8 nanoparticles are ideal for drug delivery. Bee venom's cytotoxic capabilities are used in ZIF-8 nanoparticles to target thyroid cancer cells more effectively. ZIF-8 nanoparticles containing bee venom were tested on TT medullary thyroid cancer cell lines. The effects of these nanoparticles on cell viability, proliferation, and apoptosis were investigated. IC₅₀ value at 24 h for BV-ZIF-8 nanoparticles in TT medullary thyroid carcinoma cells was determined to be 17.19 µg/mL, while the IC₅₀ value at 48 h was determined to be 16.39 µg/mL. It has been demonstrated that nanoparticle treatment upregulates the Bax and caspase-3 genes while downregulating the Bcl-2, CCND1, and CDK4 genes. Additionally, it was observed that oxidative stress was triggered in the nanoparticle-treated group. Furthermore, an examination of its mechanisms was conducted, with a specific emphasis on the modulation of critical signaling pathways that are implicated in the progression of cancer. In thyroid cancer cells, ZIF-8 nanoparticles infused with bee venom promote programmed cell death and impair key biological processes.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 1","pages":"32"},"PeriodicalIF":2.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}