{"title":"THBS1 inhibition alleviates inflammatory response by inhibiting TGF-β and NLRP3 inflammasome in experimental murine dry eye.","authors":"Yuan Tu, Xin Gu","doi":"10.1007/s00795-025-00451-1","DOIUrl":"10.1007/s00795-025-00451-1","url":null,"abstract":"<p><p>Dry eye is a multifactorial ocular surface disease that may be accompanied by visual impairment and ocular surface damage. Thrombospondin 1 (THBS1) was found to be highly expressed in corneal epithelial cells of dry eye mouse models. Our research aimed at exploring the role and regulatory mechanism of THBS1 in dry eye mouse models. Both eyes of mice with benzalkonium chloride (BAC)-induced dry eye were subconjunctivally injected with the recombinant adeno-associated virus (AAV) vector containing the THBS1 silencing plasmid. Under a slit lamp biomicroscope, the conjunctival irritation including edema, hyperemia, and secretion was scored. Fluorescein staining was performed to evaluate corneal epithelial damage. The conjunctiva tissues were obtained for ELISA, RT-qPCR, histological staining, and western blotting. Dry eye model mice exhibited severe ocular surface damage, reduced tear secretion, conjunctival goblet cell loss, increased conjunctival inflammation, elevated THBS1 expression, and the TGF-β/NLRP3 inflammasome pathway activation. THBS1 silencing ameliorated ocular surface damage, increased tear secretion, attenuated conjunctival goblet cell loss, mitigated conjunctival inflammation, and repressed the TGF-β/NLRP3 inflammasome pathway activation in dry eye mice. THBS1 silencing protects mice against dry eye by inhibiting TGF-β/NLRP3 inflammasome-mediated inflammatory response.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"93-105"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482446","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":"Loss of Fbxw7 disrupts lipid homeostasis and autophagy in hepatocellular carcinoma cells.","authors":"Yoshihiro Hayashi, Yumiko Yamamoto, Ichiro Murakami","doi":"10.1007/s00795-026-00457-3","DOIUrl":"10.1007/s00795-026-00457-3","url":null,"abstract":"<p><p>Fbxw7, a substrate recognition subunit of the SCF ubiquitin ligase complex, regulates the proteasomal degradation of multiple cancer-related and metabolic proteins. To elucidate its role in hepatic lipid homeostasis, we established Fbxw7 knockdown (FKD) Huh-7 cells and analyzed associated morphological and molecular alterations. Lipid droplets were evaluated by BODIPY staining and transmission electron microscopy, while metabolic and autophagy-related factors were examined using immunocytochemistry, Western blotting, and RT-PCR. FKD resulted in marked lipid droplet accumulation and upregulation of lipogenic genes, accompanied by increased levels of both precursor and mature sterol regulatory element-binding protein 1 (SREBP-1) with prominent nuclear localization. In three-dimensional spheroid cultures, FKD cells exhibited extensive vacuolar degeneration, reduced LC3B expression, and p62 accumulation, whereas LAMP-1 expression remained unchanged. Low-vacuum scanning electron microscopy further revealed rough, granular deposits on the spheroid surface, suggesting structural deterioration associated with impaired autophagy. Treatment with the autophagy inducer Tat-Beclin1 partially restored LC3B expression and attenuated lipid droplet accumulation. Collectively, these findings indicate that Fbxw7 plays a critical role in maintaining hepatocellular homeostasis through coordinated regulation of lipid metabolism and autophagic degradation. Loss of Fbxw7 disrupts this balance, leading to characteristic metabolic and morphological alterations in hepatocellular carcinoma cells.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"146-152"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13222321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comprehensive analysis of DNA repair, morphological remodeling and immune-gene expression in patient-derived biliary tract carcinoma organoids following ionizing radiation.","authors":"Ken Okuda, Shunji Haruna, Toshihide Muramatsu, Kohei Tateno, Mayu Isono, Kunihiro Miyazaki, Takahiro Oike, Haruka Okami, Takehiko Yokobori, Keiji Suzuki, Kensuke Otsuka, Akiko Takahashi, Yoshimasa Saito, Atsushi Shibata","doi":"10.1007/s00795-026-00456-4","DOIUrl":"10.1007/s00795-026-00456-4","url":null,"abstract":"<p><p>Biliary tract carcinoma (BTC) is a malignancy with poor prognosis. Current molecular targeted therapies benefit only a limited subset of patients, underscoring the need for novel approaches, such as combining DNA-damaging chemoradiotherapy with an immune checkpoint inhibitor. Although cellular responses following chemoradiotherapy-induced DNA damage are essential, they remain poorly understood in the context of three-dimensional tumor structures. This study aimed to investigate the effects of ionizing radiation, a DNA-damaging cancer therapy, on patient-derived BTC organoids. DNA repair and gene expression regulation was integrally examined by immunofluorescence and RNA-Seq analysis following 10 Gy of X-rays. X-ray irradiation caused significant morphological changes. In addition, X-ray irradiation upregulated extracellular matrix-related gene expression as revealed by RNA sequencing. DNA damage response analysis indicated that non-homologous end joining was the primary repair pathway in patient-derived BTC organoids. Moreover, X-ray irradiation activated immune-related pathways, such as cGAS/STING, RIG-I/MDA-5, and JAK/STAT, suggesting potential immune activation following radiotherapy. Our study revealed that DNA damage response altered the tumor structure and modulated the expression of multiple genes, including extracellular matrix- and immune-related genes. Studies using in vitro organoid models can be useful for investigating three-dimensional cellular responses after DNA-damaging cancer therapies, such as chemoradiotherapy.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"134-145"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157793","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":"Primary renal parenchymal squamous cell carcinoma mimicking abscess: value of trans-urinary tract fine-needle aspiration in preoperative evaluation: a case report and literature review.","authors":"Yusuke Ono, Masaki Murata, Akira Takasawa, Rena Morita, Makoto Osanai","doi":"10.1007/s00795-025-00449-9","DOIUrl":"10.1007/s00795-025-00449-9","url":null,"abstract":"<p><p>Primary squamous cell carcinoma (SCC) of the renal parenchyma is exceedingly rare, with only seven cases reported to date. We report a 72-year-old woman with recurrent cystitis, gross hematuria, and a right renal mass. Imaging studies revealed a necrotic lesion in the renal parenchyma, initially suggestive of an abscess. Despite percutaneous drainage and antibiotic therapy, there was no clinical improvement. Trans-urinary tract fine-needle aspiration (FNA) provided preoperative cytologic evidence of malignancy with features consistent with SCC, and histopathologic examination of the nephrectomy specimen, supported by immunohistochemistry, confirmed primary renal parenchymal SCC. The patient subsequently underwent radical nephrectomy, and histopathological examination confirmed a primary SCC of the renal parenchyma without renal pelvic involvement. Although surgical treatment was performed promptly, metastatic spread to lymph nodes, vertebrae, and lungs was detected within months, and the patient died 18 months postoperatively. This case highlights the importance of considering SCC in the differential diagnosis of abscess-like renal lesions, particularly when they fail to respond to antibiotics. In selected patients, trans-urinary tract FNA offers a rapid, minimally invasive means to obtain cytologic material, which can prevent delays and facilitate timely management, potentially improving outcomes in similarly challenging cases. Additional studies will clarify diagnostic and therapeutic strategies.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"153-159"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186231","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":"Relationship between nutritional indicators and clinicopathological factors, including immune cell densities in the tumor microenvironment, in patients with colorectal cancer.","authors":"Natsuko Sakaida, Rin Yamada, Kota Arima, Kohei Yamashita, Norihisa Hanada, Daiki Yoshii, Yukio Fujiwara, Chihiro Nakashita, Seiya Shimoda, Masaaki Iwatsuki, Yoshihiro Komohara","doi":"10.1007/s00795-025-00454-y","DOIUrl":"10.1007/s00795-025-00454-y","url":null,"abstract":"<p><p>We retrospectively analyzed 116 cases of colorectal cancer (CRC) to evaluate the relationship between nutritional indicators (NIs) and clinicopathological features, including immune cell infiltration in the tumor microenvironment. The geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), Controlling Nutritional Status (CONUT) score, and neutrophil-to-lymphocyte ratio (NLR) were assessed. Immune cell densities (CD3, CD8, Foxp3, Iba1, CD163) were quantified by immunohistochemistry. Poor NIs were associated with older age, lower body mass index, advanced tumor stage, elevated tumor markers, and reduced immune cell infiltration. Specifically, low GNRI and high mGPS correlated with reduced Foxp3-positive cells; low PNI with reduced Foxp3- and CD20-positive cells; and high NLR with reduced CD3-, CD8-, CD20-, and Iba1-positive cells. The GNRI- and mGPS-abnormal groups showed significantly reduced Foxp3-positive cells, and the CONUT-abnormal group exhibited decreased CD3- and CD20-positive cells. Patients with abnormal NLR had significantly worse cancer-specific survival. However, it was not identified as an independent prognostic factor in the multivariate analysis. Nutritional impairment in CRC patients is linked not only to poor clinical outcomes, but also to a tumor-promoting microenvironment characterized by diminished immune cell infiltration. Assessing NIs may help guide nutritional and therapeutic strategies to improve prognosis.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"113-123"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934073","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":"Novel autoantibodies in autoimmune hepatitis: from diagnostic challenges to molecular and spatial pathology.","authors":"Kazumichi Abe, Jun Wada, Manabu Hayashi, Tatsuro Sugaya, Naoto Abe, Masashi Fujita, Hiromasa Ohira","doi":"10.1007/s00795-026-00459-1","DOIUrl":"10.1007/s00795-026-00459-1","url":null,"abstract":"<p><p>Autoimmune hepatitis (AIH) lacks a single disease-specific diagnostic test, particularly in acute-onset or seronegative cases with normal IgG levels. Recent progress in high-throughput autoantibody profiling has enabled systematic and unbiased identification of novel autoantibodies, offering new insights into disease diagnosis and underlying pathogenic mechanisms. This review summarizes emerging autoantibodies in AIH, primarily focusing on antibodies identified through proteome-wide approaches. We highlight anti-docking protein 2 (DOK2) antibodies, identified using a human protein microarray and validated by ELISA, immunohistochemistry, and imaging mass cytometry. These antibodies exhibit high diagnostic performance, including in patients with IgG-normal and ANA-negative AIH, and are correlated with disease activity. Spatial analyses revealed that DOK2 was expressed predominantly in hepatic macrophages and subsets of T cells, providing mechanistic insight into immune regulation in AIH. These findings illustrate how integrative serological and molecular morphology approaches can refine AIH diagnosis and deepen the understanding of disease pathogenesis.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"85-92"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513213","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":"Rapid liquid-based cytology improves carcinoma cell detection in intraoperative effusion cytology.","authors":"Masaki Satou, Mutsumi Sato, Chiaki Momma, Hiroko Suzuki, Hiromi Hayasaka, Haruka Saito, Naomi Sato, Fumiyoshi Fujishima, Yasuhiro Nakamura","doi":"10.1007/s00795-025-00455-x","DOIUrl":"10.1007/s00795-025-00455-x","url":null,"abstract":"<p><p>This study evaluated the utility of rapid liquid-based cytology with a shortened fixation time for intraoperative effusion cytology compared to conventional smears. Despite widespread use, intraoperative applications of liquid-based cytology are understudied; no quantitative paired comparison of rapid liquid-based cytology and conventional smears under identical constraints has been reported. We therefore tested whether rapid liquid-based cytology enriches diagnostically informative cells during time-limited reads, supporting more reliable reporting. We retrospectively analyzed 67 effusion (17 adenocarcinoma-positive and 50 adenocarcinoma-negative) samples collected between May, 2019 and February, 2024. Smear area, nucleated cell counts per field and slide, atypical cell counts, and atypical cell aggregates were quantified for paired preparations and compared using the Wilcoxon signed-rank test. Rapid liquid-based cytology yielded a markedly small smear area with significantly high nucleated cell counts per field, and conventional smears yielded high total nucleated cell counts per slide. Rapid liquid-based cytology also revealed significantly high numbers of atypical cells and aggregates. Subgroup analyses based on specimen characteristics (mesothelial-dominant, blood-dominant, and mixed) confirmed that rapid liquid-based cytology yielded high per-field nucleated cell counts in all groups. These results suggest that rapid liquid-based cytology concentrates diagnostic cells into a small standardized smear area, supporting timely reporting.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"124-133"},"PeriodicalIF":1.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998647","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":"Effect of conditioned medium derived from a clone cell of epithelial rests of Malassez on enamel crystallization in tooth germs.","authors":"Dembereldorj Bolortsetseg, Yoshihito Kurashige, Maria Mielnik-Błaszczak, Syed Taufiqul Islam, Yusuke Fujita, Sayaka Sakakibara, Erika Minowa, Hiroyo Yoshimoto, Yoshihiro Abiko, Masato Saitoh","doi":"10.1007/s00795-025-00444-0","DOIUrl":"10.1007/s00795-025-00444-0","url":null,"abstract":"<p><p>We have previously isolated the epithelial rests of Malassez (ERM) clone cells with strong Amelx expression, named as ERM-2, from the crude ERM cells. In the present study, we examined whether conditioned medium (CM) derived from cultured ERM-2 promotes the crystallization of immature enamel in tooth germs. Tooth germs from postnatal day 3 mice were incubated with ERM-2 conditional medium (CM). ERM-2 cells were transfected with si-RNA targeting specific enamel matrix proteins (EMPs). After 2 days of incubation, each CM was collected and employed to culture the tooth germs. The surface layers of the enamel structure were examined with a scanning electron microscope (SEM). Tooth germs cultured with ERM-2 CM on days 3 and 7 showed elongation and densification of the columnar structures in SEM analysis. The columnar structures became denser and aggregated forming a HAP-like hexagonal columnar structure 14 days after culture in ERM-2 CM. In contrast, no clear columnar structures were observed in ERM-2 CM with si-RNA of each EMPs. In conclusion, the present study demonstrated that CM derived from ERM-2 could form enamel-like structures on the surface of the tooth germ. ERM-2 may provide the possibility for the clinical use of enamel regeneration.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"42-56"},"PeriodicalIF":1.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575772","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":"Hepatocarcinogenesis prediction by liver fibrosis patterns in metabolic dysfunction-associated steatotic liver disease biopsies.","authors":"Asami Beppu, Hisamitsu Miyaaki, Satoshi Miuma, Ryu Sasaki, Masafumi Haraguchi, Masanori Fukusima, Yasuhiko Nakao, Kazuaki Tajima, Satoshi Matsuo, Yuko Akazawa, Shinji Okano, Kazuhiko Nakao","doi":"10.1007/s00795-025-00440-4","DOIUrl":"10.1007/s00795-025-00440-4","url":null,"abstract":"<p><p>This study aimed to investigate carcinogenesis-related fibrosis patterns in liver biopsy tissues from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) by comprehensively measuring and quantifying various fibrosis patterns using artificial intelligence. Liver biopsy tissues from 13 patients with advanced fibrosis at MASLD diagnosis were subjected to collagen quantification and morphological and structural fiber characteristic evaluation using FibroNest (PharmaNest, Princeton, NJ, USA), which was described using up to seven quantitative fibrosis parameters (qFPs). The collagen-fibrosis composite score (FCS), morphometric-FCS, architecture-FCS, and phenotypic-FCS (Ph-FCS) were compared between patients with and without hepatocellular carcinoma (HCC). The collagen quantification alone could not discriminate between HCC and non-HCC cases. Regarding the individual qFPs of morphological fiber characteristics, the kurtosis and skewness of fiber twists were significantly lower in HCC cases than in non-HCC cases. In HCC cases, fiber width and density kurtosis tended to be larger, whereas fiber length kurtosis tended to be smaller than those in non-HCC cases. Ph-FCS could discriminate HCC from non-HCC at a threshold of 4.2, with 85% sensitivity and 100% specificity. A combination of fiber morphology and structural characteristics predicted HCC development with higher accuracy and might help define carcinogenic risk groups among patients with MASLD.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"26-33"},"PeriodicalIF":1.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225873","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":"Evaluation of PRDM10 gene rearrangement by immunohistochemistry and molecular methods in unclassifiable undifferentiated soft tissue tumors.","authors":"Merve Aksin, Kivilcim Eren Ates, Akif Mirioglu, Tugba Toyran, Gulfiliz Gonlusen","doi":"10.1007/s00795-025-00442-2","DOIUrl":"10.1007/s00795-025-00442-2","url":null,"abstract":"<p><p>Soft tissue sarcomas are heterogenous groups of tumors that show variable morphology as well as clinical behavior. Morphological features do not always directly reflect clinical behavior. Certain mesenchymal tumors exhibit an indolent clinical course. Among them are superficial CD34-positive fibroblastic tumors characterized by PRDM10 fusion. In our study, we aimed to detect PRDM10 gene rearrangement in superficial CD34-positive fibroblastic tumors and other pleomorphic sarcomas included in its differential diagnosis by immunohistochemistry and Fluorescence in situ hybridization. Totally, 33 cases were enrolled into this study. The results showed that two cases diagnosed as superficial CD34-positive fibroblastic tumor and two cases diagnosed as undifferentiated pleomorphic sarcoma have PRDM10 gene rearrangement. Immunohistochemically, not all rearranged tumors showed PRDM10 staining that suggests a low sensitivity of PRDM10 antibody. In conclusion, we suggested that PRDM10 gene rearrangement is not limited to superficial CD34-positive fibroblastic tumors; undifferentiated pleomorphic sarcomas may exhibit this molecular alteration and immunohistochemistry has lower sensitivity than fluorescence in situ hybridization.</p>","PeriodicalId":18338,"journal":{"name":"Medical Molecular Morphology","volume":" ","pages":"20-25"},"PeriodicalIF":1.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}