Association between the Dietary Inflammatory Index and fracture risk in older adults: a systematic review and meta-analysis.

OBJECTIVE: We explored correlations between the Dietary Inflammatory Index (DII) and fracture risk in older adults. METHODS: We systematically searched MEDLINE, PubMed, Science Direct, Scopus, and CNKI for all relevant epidemiological studies published through October 16, 2023. Because observational studies were included in the meta-analysis, we used a random-effects model to pool the study-specific effect sizes and 95% confidence intervals (CIs). We assessed study quality using the Newcastle-Ottawa scale. This meta-analysis was registered in PROSPERO. RESULTS: Eight studies with 462,986 participants were included, with five cohort studies, two cross-sectional studies, and one case-control study. An analysis of heterogeneity among the eight included studies resulted in I2 = 87.1%, indicating significant between-study heterogeneity; hence, the random-effects model was adopted to generate the combined effect size. We found that the DII was positively associated with fracture (relative risk: 1.188, 95% CI: 1.043-1.354). This result was further confirmed in leave-one-out sensitivity analysis. CONCLUSIONS: Our study provides evidence suggesting that diets high in pro-inflammatory components might increase the fracture risk among older people. Decreased consumption of pro-inflammatory foods and increased consumption of anti-inflammatory foods are suggested to prevent adverse fracture outcomes. More prospective studies involving both sexes are warranted to verify the results.

Dynamic immune recovery process after liver transplantation revealed by single-cell multi-omics analysis.

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14+RNASE2+ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.

Genotype-guided model significantly improves accuracy of tacrolimus initial dosing after liver transplantation.

Background: The initial dose of tacrolimus after liver transplantation (LT) is critical for rapidly achieving the steady state of the drug concentration, minimizing the potential adverse reactions and warranting long-term patient prognosis. We aimed to develop and validate a genotype-guided model for determining personalized initial dose of tacrolimus. Methods: By combining pharmacokinetic modeling, pharmacogenomic analysis and multiple statistical methods, we developed a genotype-guided model to predict individualized tacrolimus initial dose after LT in the discovery (n = 150) and validation cohorts (n = 97) respectively. This model was further validated in a prospective, randomized and single-blind clinical trial from August, 2021 to February, 2022 (n = 40, ChiCTR2100050288). Findings: Our model included donor's and recipient's genotypes, recipient's weight and total bilirubin, which achieved an area under the curve of receiver operating characteristic curve (AUC of ROC) of 0.88 and 0.79 in the discovery and validation cohorts, respectively. We found that patients who were given tacrolimus within the recommended concentration range (RCR) (4-10 ng/mL), the new-onset metabolic syndromes are lower, especially for new-onset diabetes (p = 0.043). In the clinical trial, compared to those in experience-based (EB) group, patients in the model-based (MB) group were more likely to achieving the RCR (75% vs 40%, p = 0.025) with a more variable individualized dose (0.023-0.096 mg/kg/day vs 0.045-0.057 mg/kg/day). Moreover, significantly fewer medication adjustments were required for the MB group than the EB group (2.75 ± 2.01 vs 6.05 ± 3.35, p = 0.001). Interpretation: Our genotype-based model significantly improved the initial dosing accuracy of tacrolimus and reduced the number of medication adjustments, which are critical for improving the prognosis of LT patients. Funding: National Natural Science Foundation of China, Shanghai three-year action plan, National Science and Technology Major Project of China.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Demethylase-independent function of JMJD2D as a novel antagonist of p53 to promote Liver Cancer initiation and progression.

Background: As a histone demethylase, JMJD2D can enhance gene expression by specifically demethylating H3K9me2/3 and plays an important role in promoting colorectal cancer progression. However, its role in liver cancer remains unclear. Methods: The expression of JMJD2D was examined in human liver cancer specimens and non-tumorous liver tissues by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in liver cancer cells using small hairpin RNAs, and cells were analyzed with Western blot, real-time PCR, cell viability, colony formation, and flow cytometry assays. Cells were also grown as tumor xenografts in nude mice, and the tumor cell proliferation and apoptosis were measured by immunohistochemical analysis. The relationship between JMJD2D and p53 was studied by co-immunoprecipitation, chromatin immunoprecipitation, and electric mobility shift assay. Wild-type and JMJD2D-knockout mice were intraperitoneally injected with diethylnitrosamine (DEN) to induce liver tumors and the liver cancer initiation and progression were investigated. Results: JMJD2D was frequently upregulated in human liver cancer specimens compared with non-tumorous liver tissues. The overall survival of liver cancer patients with high JMJD2D expression was significantly decreased compared to that with low JMJD2D expression. JMJD2D knockdown reduced liver cancer cell proliferation and xenograft tumor growth, sensitized cells to chemotherapeutic drug-induced apoptosis, and increased the expression of cell cycle inhibitor p21 and pro-apoptosis gene PUMA. Genetically, JMJD2D deficiency protected mice against DEN-induced liver cancer initiation and progression. Knockout of tumor suppressor p53 significantly reduced the effects of JMJD2D knockdown on cell proliferation, apoptosis, and the expression of p21 and PUMA, suggesting that JMJD2D regulates liver cancer cell functions in part through inhibiting p53 signaling pathway. Mechanistically, JMJD2D directly interacted with p53 and inhibited p53 recruitment to the p21 and PUMA promoters in a demethylation activity-independent manner, implicating a demethylase-independent function of JMJD2D as a novel p53 antagonist. In addition, JMJD2D could activate Wnt/ß-catenin signaling to promote liver cancer cell proliferation. Conclusion: Our study demonstrates that JMJD2D can antagonize the tumor suppressor p53 and activate an oncogenic signaling pathway (such as Wnt/ß-catenin signaling pathway) simultaneously to promote liver cancer initiation and progression, suggesting that JMJD2D may serve as a novel target for liver cancer treatment.

Self-Assembled Metal-Organic Nanoparticles for Multimodal Imaging-Guided Photothermal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a high incidence of disease and the high recurrence rate is a major limitation for HCC treatment. To resolve such a challenge, multimodal imaging-guided photothermal therapy (PTT) provides a promising candidate for HCC treatment. Herein, we use a facile method to develop a novel self-assembled theranostic nanoparticle (NP) based on manganese irons (Mn2+) and indocyanine green (ICG) under the protection of poly(vinylpyrrolidone) (PVP). The fabricated NPs possess the properties of strong NIR optical absorbance, high photothermal conversion efficiency and multimodal imaging. Through intravenous injection, these NPs could highly accumulate in HepG2 tumor via the enhanced permeability and retention effect, as revealed by fluorescence/photoacoustic/magnetic resonance imaging, leading to an obviously improved in vivo therapeutic outcome. This study demonstrates that our self-assembled NPs could be a potential platform for multimodal imaging-guided PTT of HCC in future clinical therapy.

Pancreaticoduodenectomy assisted by 3-D visualization reconstruction and portal vein arterialization: A case report (a CARE-compliant article).

BACKGROUND: Three-dimensional visualization reconstruction, the 3-D visualization model reconstructed by software using 2-D CT images, has been widely applied in medicine; but it has rarely been applied in pancreaticoduodenectomy. Although the hepatic artery is very important for the liver, it has to be removed when tumor invades it. Therefore, portal vein arterialization has been used in clinic as a remedial measure, but there still is professional debate on portal vein arterialization. METHODS: Here, we report 1 case that was diagnosed with poorly differentiated adenocarcinoma of the duodenum. The tumor had large size and invaded surrounding organs and vessels. RESULTS: Preliminary diagnoses were poorly differentiated adenocarcinoma of the duodenum and viral hepatitis B. Pancreaticoduodenectomy assisted by 3-D visualization reconstruction and portal vein arterialization were performed in this case. The tumor was removed. Liver function returned to normal limits 1 week after operation. Digital subtraction arteriography showed compensatory artery branches within the liver 1 month after operation. CONCLUSION: 3-D visualization reconstruction can provide a reliable assistance for the accurate assessment and surgical design before pancreatoduodenectomy, and it is certainly worth adopting portal vein arterialization when retention of hepatic artery is impossible or conventional arterial anastomosis is required during pancreatoduodenectomy.