International immunopharmacology最新文献

{"title":"IGFALS suppresses hepatocellular carcinoma progression by stabilizing PPAR-γ","authors":"","doi":"10.1016/j.intimp.2024.113414","DOIUrl":"10.1016/j.intimp.2024.113414","url":null,"abstract":"<div><div>IGFALS forms stable ternary complexes with insulin-like growth factors (IGF1 and IGF2) and IGF-binding proteins (IGFBP3 and IGFBP5), which prolong the half-lives of IGFs. Through immunohistochemical analysis of 90 pairs of clinical samples and bioinformatics analysis, we observed downregulation of IGFALS in hepatocellular carcinoma tissues, which was associated with poor patient prognosis. This prompted us to explore the specific molecular mechanism of action of IGFALS in the inhibition of hepatocellular carcinoma (HCC), which could be a potential new target for the treatment of HCC. In vitro experiments demonstrated that IGFALS inhibits the proliferation, invasion, and migration of hepatocellular carcinoma cells and suppresses epithelial-mesenchymal transition. Gene Set Enrichment Analysis (GSEA) revealed a positive correlation between IGFALS and the activation of the PPAR pathway. Western blotting, immunofluorescence colocalization, and co-immunoprecipitation assays confirmed that IGFALS binds to PPAR-γ and stabilizes it through deubiquitination. Inhibition of PPAR-γ reversed the anticancer effects of IGFALS. Furthermore, we showed that IGFALS/PPAR-γ upregulates the expression of HMGCS2. The tumor xenograft model supported our findings. Mass spectrometry analysis and co-immunoprecipitation assays indicated that IGFALS promotes the binding of PPAR-γ with USP9X, a deubiquitinating enzyme, thereby facilitating the deubiquitination of PPAR-γ. In conclusion, our findings demonstrate that IGFALS can suppress hepatocellular carcinoma via the PPAR-γ/HMGCS2 pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142538825","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}

{"title":"Enhanced cytotoxicity in multiple myeloma via T cells armed with bispecific T cell engager targeting B-cell maturation antigen on cancer cells and CD3 on T cells","authors":"","doi":"10.1016/j.intimp.2024.113480","DOIUrl":"10.1016/j.intimp.2024.113480","url":null,"abstract":"<div><div>Multiple myeloma (MM), a cancer of plasma cells, remains difficult to treat due to its incurability and high recurrence rates. Recent advancements in immunotherapies, such as CAR T cells, bispecific antibodies, and bispecific T cell engagers (BITEs) targeting B-cell maturation antigen (BCMA), have improved treatment options for relapsed and refractory MM (RRMM). However, these therapies face challenges, including complex manufacturing, high cost, and severe side effects. In this study, we developed a stable cell line that produces anti-BCMA × anti-CD3 BITEs and generated BITE-armed T cells (BATs) as a novel MM treatment approach. These αBCMA × αCD3 BATs specifically targeted BCMA-expressing cells, promoting T cell activation, proliferation, and cytotoxicity. BATs demonstrated superior cytotoxicity compared to unarmed T cells, likely due to enhanced antigen specificity and targeting efficiency, even at low effector-to-target ratios. The antitumor activity of BATs against BCMA-expressing cells was antigen-specific and dose-dependent. BATs also triggered T cell expansion and significant cytokine release (IL-2, TNF-α, IFN-γ) without increasing IL-6, suggesting a lower risk of cytokine release syndrome (CRS). Our findings indicate that BCMA-targeting BATs offer a promising and accessible therapeutic strategy for MM, with a simple, rapid, and cost-effective production process. These results support future development of BITE-armed T cells as a novel cancer treatment to enhance therapeutic outcomes for MM patients.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521824","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":"Natural polysaccharides: The potential biomacromolecules for treating diabetes and its complications via AGEs-RAGE-oxidative stress axis","authors":"","doi":"10.1016/j.intimp.2024.113426","DOIUrl":"10.1016/j.intimp.2024.113426","url":null,"abstract":"<div><div>Diabetes mellitus, a chronic metabolic disorder, poses a significantly public health challenge. Extensive research highlights that contemporary dietary patterns, characterized by excessive intake of sugar, fat, and protein, are major contributors to the onset and progression of diabetes. The central element to this process is the aberrant activation of the advanced glycation end products (AGEs) – receptor for AGEs (RAGE) – oxidative stress axis, which plays a pivotal role in disrupting normal carbohydrate metabolism. This pathway presents a critical target for developing interventions aimed at mitigating diabetes and its complications. In recent years, natural polysaccharides have emerged as promising agents in the prevention and treatment of diabetes, due to their ability to inhibit AGE formation, regulate RAGE expression, and modulate the AGEs-RAGE-oxidative stress axis. In this paper, we explore the pathogenic mechanism of this axis and review the therapeutic potential of natural polysaccharides in managing diabetes and its complications. Our goal is to provide new insights for the effective management of diabetes and its associated health challenges.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499811","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}

{"title":"From darkness to light: Targeting CAFs as a new potential strategy for cancer treatment","authors":"","doi":"10.1016/j.intimp.2024.113482","DOIUrl":"10.1016/j.intimp.2024.113482","url":null,"abstract":"<div><div>Cancer-associated fibroblasts (CAFs), which are the most frequent stromal cells in the tumor microenvironment (TME), play a key role in the metastasis of tumor cells. Generally speaking, CAFs in cooperation with tumor cells can secrete various cytokines, proteins, growth factors, and metabolites to promote angiogenesis, mediate immune escape of tumor cells, enhance endothelial-to-mesenchymal transition, stimulate extracellular matrix remodeling, and preserve tumor cell stemness. These activities of CAFs provide a favorable exogenous pathway for tumor progression and metastasis, and a microenvironment that allows rapid growth of tumor cells, which always lead to poor prognosis for patients. More importantly, it seems that targeting CAFs is also a potential precision therapeutic strategy in clinical practice. Hence, this review outlines the origin of CAFs, the relationship between CAFs and cancer metastasis, and targeting CAFs as a potential strategy for cancer patients, which could give some inspirations for cancer treatment in clinic.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142538762","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}

{"title":"The intestinal absorption of triptolide for the treatment of rheumatoid arthritis is mediated by transporters","authors":"","doi":"10.1016/j.intimp.2024.113440","DOIUrl":"10.1016/j.intimp.2024.113440","url":null,"abstract":"<div><div><em>Tripterygium wilfordii</em> Hook. f. is a traditional Chinese herb that is used to treat rheumatoid arthritis (RA). Triptolide (TP), an epoxidized diterpene lactone extracted from this herb, has been suggested to be the primary active and toxic component. In this work, the material basis and molecular mechanism of toxicity induced by <em>T. wilfordii</em> preparations in RA were investigated. Female rats with collagen-induced arthritis were given 500 μg·kg⁻¹ TP intragastrically or intravenously. Compared with that in the control group, the AUC_last in the CIA group was 1.7-fold greater after intragastric administration, while this value decreased 22.6 % after intravenous administration, suggesting that the absorption of TP was significantly greater in the CIA group. The results from RT-PCR and probe substrate perfusion indicated that Oatp1a5 expression was upregulated while P-glycoprotein (P-gp) expression was downregulated in the duodenums of CIA rats. Naringin, an inhibitor of Oatp1a5, decreased the P_eff of TP in the rat duodenum by 27.9 %, whereas verapamil hydrochloride, an inhibitor of P-gp, increased the P_eff by 50.8 %, suggesting that Oatp1a5 and P-gp mediate the uptake and efflux of TP in the rat duodenum, respectively. Furthermore, among the upstream nuclear receptors, the mRNA expression levels and protein expression levels of FXR and VDR were noticeably decreased. In the present study, the absorption of TP in the duodenums of CIA rats significantly increased due to the upregulation of Oatp1a5 expression and the downregulation of P-gp expression, leading to an increase in TP plasma exposure after intragastric administration. The altered expression of Oatp1a5 and P-gp may be related to FXR and VDR.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142538827","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}

{"title":"Efficacy, drug survival, safety and metabolic parameters of ixekizumab in patients with moderate-to-severe psoriasis in China: A two-year real-world study","authors":"","doi":"10.1016/j.intimp.2024.113474","DOIUrl":"10.1016/j.intimp.2024.113474","url":null,"abstract":"<div><div>Long-term, real-world studies of the efficacy and metabolic parameters of ixekizumab in difficult-to-treat areas of psoriasis are lacking. A two-year retrospective study was conducted to evaluate the long-term efficacy, safety, drug survival and metabolic parameters of ixekizumab in the real world. A total of 258 patients were enrolled. At 52 weeks, PASI 75/90/100 was achieved in 92.0 %, 79.8 % and 54.6 % of patients, respectively. The efficacy was maintained at week 104 with PASI 75/90/100 of 92.6 %, 81.5 % and 48.1 %, respectively. At week 12, sPGA 0/1 was achieved in 71.0 % of scalp psoriasis, 60.0 % of palmoplantar psoriasis and 68.8 % of genital psoriasis. The probability of drug survival at 12 and 24 months was 67.1 % and 56.3 %, respectively. The most common adverse events included local injection reactions (31.8 %), allergies (11.6 %) and infections (6.1 %). No disease activation was observed in patients with latent tuberculosis or hepatitis B/C. No hyperlipidemia or hyperglycemia was observed. This study confirmed the long-term efficacy, high drug survival and favorable safety of ixekizumab in a real-world setting.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521823","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}

{"title":"Synergistic Anti-Tumor Effects of Newcastle Disease Virus and Doxorubicin: Evidence from A Murine Breast Cancer Model","authors":"","doi":"10.1016/j.intimp.2024.113481","DOIUrl":"10.1016/j.intimp.2024.113481","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Despite the recent advances in the diagnosis and treatment of breast cancer, triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and resistance to conventional therapies. Virotherapy has emerged as a promising cancer treatment strategy, leveraging the ability of viruses to specifically target and replicate in cancerous cells. This study evaluated the oncolytic potential of a combined therapeutic strategy, utilizing Newcastle disease virus (NDV) and Doxorubicin hydrochloride (Dox) both &lt;em&gt;in vitro&lt;/em&gt; and &lt;em&gt;in vivo&lt;/em&gt;.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The &lt;em&gt;in vitro&lt;/em&gt; experiments involved exposing human and mouse TNBC cell lines (MDA-MB-231 and 4T1, respectively) to NDV and Dox, individually or in combination. Cell viability assays and flow cytometry analyses were conducted to assess the synergistic effects of NDV and Dox on regulating breast cancer cell behavior &lt;em&gt;in vitro&lt;/em&gt;. Furthermore, the immune-stimulating potential of NDV was investigated by examining its effects on dendritic cell (DC) maturation using flow cytometry and T cell proliferation. The &lt;em&gt;in vitro&lt;/em&gt; anti-tumor effects of NDV were examined in both parental and tamoxifen-resistant cancer cells to assess its efficacy against chemoresistance. Animal models of breast cancer were treated with NDV in combination with Dox. The body weight changes, tumor volume, and survival rates of the mice were monitored throughout the study. Histopathological analyses were conducted to evaluate the potential toxic effects of the treatments.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Based on the MTT results, NDV at optimal concentrations synergized the effect of Dox to reduce the viability of both MDA-MB231 and 4T1 cell lines (Isobologram combination index of less than 1). Additionally, individual treatment with NDV was able to significantly reduce the viability of patient-derived breast cancer cells, compared to the untreated control (P &lt; 0.05) without affecting the cells of normal adjacent tissue. Furthermore, a combination of NDV and Dox significantly enhanced the percentage of early and late apoptotic cells in MDA-MB-231 (P &lt; 0.0001) and late apoptotic cells in 4T1 (P &lt; 0.0001), in comparison with individual treatment with these agents. Flow cytometry results showed that, compared to wild type MDA-MB-231 cells, NDV-infected MDA-MB-231 cells were better inducers of T cell proliferation and DC maturation as evidenced by increased proliferation index (P &lt; 0.05) and elevated expression of CD1a, CD83, and CD86 (P &lt; 0.0001), respectively. Moreover, co-treatment of both wild-type and (tamoxifen) TAM-resistant MCF-7/TAMR-1 cells with TAM and NDV significantly reduce the viability of the cancer cells (P &lt; 0.0001). In tumor-bearing mice locally engrafted with 4T1 cells, combined treatment of NDV and Dox exhibited a marked reduction in median tumor volume compared to the control group, validating our &lt;","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521842","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}

{"title":"New Insights on the potential therapeutic effects of glibenclamide and Obeticholic acid against Alloxan-Induced diabetes mellitus in rat model","authors":"","doi":"10.1016/j.intimp.2024.113469","DOIUrl":"10.1016/j.intimp.2024.113469","url":null,"abstract":"<div><div>Diabetes mellitus (DM) represents a highly prevalent metabolic disorder across the globe. This study aimed to determine the ameliorative efficacy of glibenclamide (Gli) and obeticholic acid (OCA) against biochemical and pathological changes related to alloxan-induced diabetes. Twenty male Wistar rats were allocated into four groups; Control group, Diabetic group: received intraperitoneal injection of alloxan (120 mg/kg) for induction of diabetes, Diabetic + Gli group: Diabetic rats treated daily with oral Gli (5 mg/kg) and Diabetic + OCA group: Diabetic rats treated daily with oral OCA (10 mg/kg). All rats were subjected to 30 days treatments. Our results indicated that Gli successfully ameliorated hyperglycemia and dyslipidemia with a significant decline in serum pancreatic lipase activity and increased insulin level, while OCA had the same effect but without any enhancement in serum insulin levels. Additionally, the disturbances in liver function-related parameters and the evoked oxidative stress, interleukin(IL)-6 and IL-10 in the liver and pancreas were abrogated upon treatment with Gli and OCA. Furthermore, Gli and OCA increased AMP-activated protein kinase (P-AMPK), insulin receptor substrate 1 (IRS1), farnesoid X receptor (FXR), and glucagon-like peptide-1 receptor (GLP-1R) expressions and downregulated sterol regulatory element binding protein-1c mRNA expression. Besides, Gli and OCA have alleviated diabetes-induced histopathological distortions in hepatic and pancreatic tissues and enhanced the immunoexpression of insulin, and proliferating cell nuclear antigen with decreased immune reactivity of glucagon within pancreatic tissues. Gli and OCA decreased the immune reactivity of nuclear factor kappa B and increased the glycogen content of hepatic tissues. In conclusion, OCA is efficacious in the management of dyslipidemia and hyperglycemia of DM and its related oxidative stress.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499812","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}

{"title":"Immunologic role of macrophages in sepsis-induced acute liver injury","authors":"","doi":"10.1016/j.intimp.2024.113492","DOIUrl":"10.1016/j.intimp.2024.113492","url":null,"abstract":"<div><div>Sepsis-induced acute liver injury (SALI), a manifestation of sepsis multi-organ dysfunction syndrome, is associated with poor prognosis and high mortality. The diversity and plasticity of liver macrophage subpopulations explain their different functional responses in different liver diseases. Kupffer macrophages, liver capsular macrophages, and monocyte-derived macrophages are involved in pathogen recognition and clearance and in the regulation of inflammatory responses, exacerbating the progression of SALI through different pathways of pyroptosis, ferroptosis, and autophagy. Concurrently, they play an important role in maintaining hepatic homeostasis and in the injury and repair processes of SALI. Other macrophages are recruited to diseased tissues under pathological conditions and are polarized into various phenotypes (mainly M1 and M2 types) under the influence of signaling molecules, transcription factors, and metabolic reprogramming, thereby exerting different roles and functions. This review provides an overview of the immune role of macrophages in SALI and discusses the multiple roles of macrophages in liver injury and repair to provide a reference for future studies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142538828","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":"LCCP exposure leads to skin cell senescence damage by triggering oxidative stress mediated by mitochondrial Ca2+ overload","authors":"","doi":"10.1016/j.intimp.2024.113471","DOIUrl":"10.1016/j.intimp.2024.113471","url":null,"abstract":"<div><div>Currently, LCCP is widely present in environmental media as well as animal and human samples, suggesting that exposure to LCCP may have posed a threat to the health of animals and humans. Skin is one of the important pathways for LCCP exposure. To clarify the effects of LCCP exposure on the skin, we have utilized two skin cell models, HaCaT and L929, to investigate the complex impacts of LCCP exposure on skin cell senescence and its potential regulatory mechanism(s). Firstly, the expression of senescence-related markers, including SA-β-Gal staining, p16, p21, and p53 proteins, were evaluated, and the results showed that skin cell senescence occurred under the treatment of LCCP. Moreover, our findings revealed that LCCP exposure triggered the activation of the NF-κB signaling pathway, prompting an inflammatory response in skin cells. To further understand the potential molecular mechanism of skin cell senescence induced by LCCP, according to our preliminary experimental results, we hypothesized that mtROS and Ca²⁺ might have played an important role in the LCCP-induced senescence of skin cells. Based on this hypothesis, the use of mtROS and Ca²⁺ inhibitors revealed a reduction in LCCP-triggered cell senescence and oxidative stress, validating our speculation. Similarly, in vivo experiments showed that LCCP enhanced the expression of inflammatory factors in mouse skin tissue, inhibiting skin proliferation and collagen level. This discovery was consistent with the findings from in vitro experiments. In summary, our experiments emphasized that both in vitro and in vivo, exposure to LCCP could induce skin aging, potentially through oxidative stress mediated by Ca²⁺ overload, leading to skin aging damage. The research presented here establishes an important foundation for continued examination of the toxicology characteristics of LCCP.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521825","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}