Vericiguat improves cardiac function and microcirculation of a male patient with Fabry disease: A case report.

Fabry disease (FD) is a rare X chromosome-linked disorder and can be easily misdiagnosed. Here, we report the case of a 69-year-old male patient with FD who developed heart failure and showed extremely high pulmonary artery pressure. His initial symptom was recurrent atrial fibrillation. The left and right atrial inner diameters were large, and the ventricular wall was thick. Gene analysis which showed GLA c.215T>C p.Met72Thr mutation and single photon emission computed tomography indicated the diagnosis of FD with coronary microvascular dysfunction. The patient was prescribed anti-heart failure drugs, including vericiguat. Following the treatment, his heart function and microvascular perfusion significantly improved, which might be due to the beneficial effects of vericiguat.

Repolarization of immunosuppressive macrophages by targeting SLAMF7-regulated CCL2 signaling sensitizes hepatocellular carcinoma to immunotherapy.

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and non-responsive advanced HCC patients identified SLAMF7 upregulation in immunotherapy-responsive HCC, and HCC patients who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy.

Chemokine CCL21 determines immunotherapy response in hepatocellular carcinoma by affecting neutrophil polarization.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is poor and great heterogeneity among individuals. Chemokines are highly correlated with tumor immune response. Here, we aimed to identify an effective chemokine for predicting the efficacy of immunotherapy in HCC. METHODS: Chemokine C-C motif ligand 21 (CCL21) was screened by transcriptomic analysis in tumor tissues from HCC patients with different responses to ICIs. The least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to construct a predictive nomogram. Neutrophils in vitro and HCC subcutaneous tumor model in vivo were applied to explore the role of CCL21 on the tumor microenvironment (TME) of HCC. RESULTS: Transcriptome analysis showed that CCL21 level was much higher in HCC patients with response to immunotherapy. The predictive nomogram was constructed and validated as a classifier. CCL21 could inhibit N2 neutrophil polarization by suppressing the activation of nuclear factor kappa B (NF-κB) pathway. In addition, CCL21 enhanced the therapeutic efficacy of ICIs. CONCLUSION: CCL21 may serve as a predictive biomarker for immunotherapy response in HCC patients. High levels of CCL21 in TME inhibit immunosuppressive polarization of neutrophils. CCL21 in combination with ICIs may offer a novel therapeutic strategy for HCC.

Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma.

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8+ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8+ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC.

RNA m6A methylation regulators in liver cancer.

Liver cancer is one of the most common cancers in the world and a primary cause of cancer-related death. In recent years, despite the great development of diagnostic methods and targeted therapies for liver cancer, the incidence and mortality of liver cancer are still on the rise. As a universal post-transcriptional modification, N6-methyladenosine (m6A) modification accomplishes a dynamic and reversible m6A modification process, which is executed by three types of regulators, methyltransferases (called writers), demethylases (called erasers) and m6A-binding proteins (called readers). Many studies have shown that m6A RNA methylation has an important impact on RNA metabolism, whereas its regulation exception is bound up with the occurrence of human malignant tumors. Aberrant methylation of m6A RNA and the expression of related regulatory factors may be of the essence in the pathogenesis and progression of liver cancer, yet the precise molecular mechanism remains unclear. In this paper, we review the current research situations of m6A methylation in liver cancer. Among the rest, we detail the mechanism by which methyltransferases, demethylases and m6A binding proteins regulate the occurrence and development of liver cancer by modifying mRNA. As well as the potential effect of m6A regulators in hepatocarcinogenesis and progression. New ideas and approaches will be given to the prevention and treatment of liver cancer through the following relevant research results.

Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma.

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+-CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.

Jianpi Antai formula prevents miscarriage by repressing M1 polarization of decidual macrophages through ubiquitination of NLRP3 mediated by MARCH7.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Antai Formula (JAF) is an ancient formula from He's gynecology, which has been used clinically for more than 30 years and has significant therapeutic effects on spontaneous abortion (SA). Both macrophage polarization and NLRP3 inflammasome correlate with the occurrence of SA in women with recurrent or threatened miscarriage. Whether JAF prevent SA via mediating activation of decidual macrophage (dMφ) and ubiquitination-associated degradation of NLRP3 remains uncertain. AIM OF THE STUDY: This study aimed to clarify the effects of JAF on pregnancy outcomes and dMφ polarization at the maternal-fetal interface in an SA mouse model, and use in vivo and invitro methods to explore whether JAF can inhibit M1 polarization of dMφ by up-regulating MARCH7-mediated NLRP3 ubiquitination, thereby preventing SA. MATERIALS AND METHODS: The CBA/J × DBA/2 mating method was used to establish an SA model and the dMφs of SA mice were isolated and cultured. Th1-, Th2-, Th17- and Treg-related cytokine levels were evaluated using ELISA. qRT-PCR was used to detect the levels of M1/M2 macrophage-related cytokine mRNA in the decidua, and western blotting was used to detect the expression of NLRP3 inflammasome-related proteins in the decidua and placenta. The expression of M1/M2 markers of dMφ was detected using flow cytometry, ASC speck formation was observed using immunofluorescence, and the ubiquitination level of MARCH7-NLRP3 was detected using co-immunoprecipitation. RESULTS: JAF increased the survival rate of fetuses and the levels of estradiol and progesterone in SA model mice. It also reduced the serum Th1 and Th17-associated cytokine levels and decidual M1 macrophage-associated cytokine levels, while elevating the M2 macrophages in SA mice. NLRP3, caspase-1, ASC, and IL-1ß protein expression in the decidua and placenta were also reduced. si-MARCH7 transfection reversed the effect of JAF on inhibiting the formation of the NLRP3 inflammasome and the activation of macrophages in dMφs of SA mice. CONCLUSION: JAF could effectively prevent and treat SA by repressing M1 polarization of dMφs through NLRP3 ubiquitination and pyroptosis inhibition, which were mediated by MARCH7.

Ferroptosis: a new promising target for hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the sixed most common malignant tumor in the world. The study for HCC is mired in the predicament confronted with the difficulty of early diagnosis and high drug resistance, the survival rate of patients with HCC being low. Ferroptosis, an iron-dependent cell death, has been discovered in recent years as a cell death means with tremendous potential to fight against cancer. The in-depth researches for iron metabolism, lipid peroxidation and dysregulation of antioxidant defense have brought about tangible progress in the firmament of ferroptosis with more and more results showing close connections between ferroptosis and HCC. The potential role of ferroptosis has been widely used in chemotherapy, immunotherapy, radiotherapy, and nanotherapy, with the development of various new drugs significantly improving the prognosis of patients. Based on the characteristics and mechanisms of ferroptosis, this article further focuses on the main signaling pathways and promising treatments of HCC, envisioning that existing problems in regard with ferroptosis and HCC could be grappled with in the foreseeable future.

Loss of α-1,2-mannosidase MAN1C1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-FIP200 interaction.

CD133 is widely used as a marker to isolate tumor-initiating cells in many types of cancers. The structure of N-glycan on CD133 is altered during the differentiation of tumor-initiating cells. However, the relationship between CD133 N-glycosylation and stem cell characteristics remains elusive. Here, we found that the level of α-1,2-mannosylated CD133 was associated with the level of stemness genes in intrahepatic cholangiocarcinoma (iCCA) tissues. α-1,2-mannosylated CD133+ cells possessed the characteristics of tumor-initiating cells. The loss of the Golgi α-mannosidase I coding gene MAN1C1 resulted in the formation of α-1,2-mannosylated CD133 in iCCA-initiating cells. Mechanistically, α-1,2-mannosylation promoted the cytoplasmic distribution of CD133 and enhanced the interaction between CD133 and the autophagy gene FIP200, subsequently promoting the tumorigenesis of α-1,2-mannosylated CD133+ cells. Analysis of iCCA samples showed that the level of cytoplasmic CD133 was associated with poor iCCA prognosis. Collectively, α-1,2-mannosylated CD133 is a functional marker of iCCA-initiating cells.

Comparative efficacy of nine exercise methods on the prognosis in chronic kidney disease patients with hemodialysis: a systematic review and network meta-analysis.

BACKGROUND: Several kinds of physical activities have been applied to improve the prognosis of patients with hemodialysis (HD). However, the comparative efficacy of physical activities on the outcomes in HD patients is still unknown. This study explored the effectiveness and safety of all exercise types in HD patients. METHODS: We searched randomized clinical trials from the PubMed, EMBASE, and Cochrane Library databases. Physical exercises interventions included resistance exercise (RE), aerobic exercise (AE), electrical muscle stimulation (EMS), range of motion (ROM), resistance exercise + aerobic exercise (RE + AE), stretching exercise (STE), respiratory muscle training (RMT), peripheral muscle training (PMT), walking exercise (WE), or usual care/sham exercise (UC/SE). Primary outcomes were six-minute walk test (6-mwt) and quality of life (QOL). Secondary outcomes were Kt/V, VO2max, hemoglobin (Hb), C-reactive protein (CRP), interleukin-6 (IL-6), and systolic and diastolic blood pressure (sbp and dbp). Frequentist network meta-analysis with multivariate random effects models provided mean with 95% confidence intervals (95%CI). RESULTS: A total of 58 eligible studies were included. AE, RMT, and RE + AE significantly improved 6-mwt compared with UC/SE. SE was the worst intervention and reduced QOL much more than the UC/SE and other exercise types. AE and RE + AE were associated with higher VO2max, while ROM and RE + AE induced higher Hb levels. All physical activities did not elevate blood pressure, CRP and IL-6. Only ROM decreased sbp/dbp. CRP is significantly lower in RE. CONCLUSION: Physical activities play a crucial role in the different outcomes of HD patients. They can be applied to specific area for their specific efficacy.

Efficacy and safety of trastuzumab deruxtecan in patients with solid tumors: a systematic review and meta-analysis of 3 randomized controlled trials.

Trastuzumab deruxtecan (T-DXd, DS-8201) is a targeted antibody-drug conjugate that specifically targets human epidermal growth factor receptor 2 (HER2). In 2019, it was approved by the US Food and Drug Administration for the treatment of HER2-positive breast cancer. However, ongoing research is exploring its potential efficacy in other solid tumors, such as non-small-cell lung cancer and colorectal cancer, as well as in tumors with low HER2 levels. It is important to examine the safety and effectiveness of trastuzumab deruxtecan in these various types of solid tumors, as some studies have raised concerns about potential serious adverse events associated with its use. In this meta-analysis, we conducted a comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) that evaluated the efficacy and safety of trastuzumab deruxtecan in solid tumors. We used RevMan 5.4 software to perform a meta-analysis, calculating odds ratios (OR), risk ratios (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs). After an exhaustive search, we identified three articles that met our inclusion criteria, which included a total of 1268 patients. The results of the meta-analysis showed that the treatment group had significantly higher overall survival (WMD=5.12, 95% CI (2.79, 7.44), P<0.0001), progression-free survival (WMD=3.45, 95% CI (0.8, 6.1), P=0.01), overall response rate (OR=6.49, 95% CI (4.90, 8.58), P<0.00001), and disease control rate (OR=4.68, 95% CI (2.78, 7.89), P<0.00001), TRAEs (RR=6.93, 95% CI (2.06, 23.25), P=0.002). However, there was no significant difference in TRAEs≥3 (RR=1.08, 95% CI (0.75, 1.56), P=0.68) between the trials. Based on the available evidence, trastuzumab deruxtecan appears to be an effective and safe treatment option for HER2-positive solid tumors. Although the number of studies included in this analysis is limited, ongoing trials are being conducted, further evaluating its potential in various solid tumors. The results of these trials will enhance our understanding of trastuzumab deruxtecan and potentially expand its applications, bringing hope to more patients with solid tumors.

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.

Dual-branch hybrid encoding embedded network for histopathology image classification.

Objective.Learning-based histopathology image (HI) classification methods serve as important tools for auxiliary diagnosis in the prognosis stage. However, most existing methods are focus on a single target cancer due to inter-domain differences among different cancer types, limiting their applicability to different cancer types. To overcome these limitations, this paper presents a high-performance HI classification method that aims to address inter-domain differences and provide an improved solution for reliable and practical HI classification.Approach.Firstly, we collect a high-quality hepatocellular carcinoma (HCC) dataset with enough data to verify the stability and practicability of the method. Secondly, a novel dual-branch hybrid encoding embedded network is proposed, which integrates the feature extraction capabilities of convolutional neural network and Transformer. This well-designed structure enables the network to extract diverse features while minimizing redundancy from a single complex network. Lastly, we develop a salient area constraint loss function tailored to the unique characteristics of HIs to address inter-domain differences and enhance the robustness and universality of the methods.Main results.Extensive experiments have conducted on the proposed HCC dataset and two other publicly available datasets. The proposed method demonstrates outstanding performance with an impressive accuracy of 99.09% on the HCC dataset and achieves state-of-the-art results on the other two public datasets. These remarkable outcomes underscore the superior performance and versatility of our approach in multiple HI classification.Significance.The advancements presented in this study contribute to the field of HI analysis by providing a reliable and practical solution for multiple cancer classification, potentially improving diagnostic accuracy and patient outcomes. Our code is available athttps://github.com/lms-design/DHEE-net.

Economic evaluation of third-line neratinib plus capecitabine versus lapatinib plus capecitabine with HER2+ metastatic breast cancer.

Background: Breast cancer (BC) is one of the most common malignant tumors in women. In addition, human epidermal growth factor receptor 2-positive (HER2+) BC is overexpressed in 25% of BC patients, resulting in the predicament of poor prognosis. Although first- and second-line treatments have been established, optimum third-line treatment is still mired in controversies for HER2+ metastatic BC (mBC). Therefore, this study analyzes the cost-effectiveness of neratinib plus capecitabine (N+C) and lapatinib plus capecitabine (L+C) over a 5-year time horizon from a payer perspective. Methods: A half-cycle corrected four-state Markov model was established to simulate the course of BC events and deaths in N+C and L+C armed patients. The data of this model were derived from NCT01808573 trail and other published literatures. One-way deterministic sensitivity analysis (DSA) was conducted to investigate the impact of variables and probabilistic sensitivity analysis (PSA) was performed based on second-order Monte Carlo simulation. In addition, subgroup analysis was performed to verify its cost-effectiveness in China. Result: The base-case results found that N+C was in dominant position in 82.70% of the generation scenarios, providing an improvement of 0.17 quality-adjusted life-years (QALYs) and a reduction of $1,861.28 compared with L+C. The ICER was $-1,3294.86/QALY, which did not exceed the willingness to pay (WTP) threshold, while in subgroup, the ICER decreased to $-2,448.17/QALY. Conclusion: This analysis indicated that the combination of neratinib plus capecitabine is likely to be cost-effective in comparison with lapatinib plus capecitabine in patients with HER2+ mBC who continues to progress during or after second-line HER2-targeted therapy. So neratinib plus capecitabine can become a third-line treatment option.

Investigation of the Mechanisms and Experimental Verification of Yulin Formula in the Treatment of Diminished Ovarian Reserve via Network Pharmacology.

Purpose: The aim of this study is to examine, using network pharmacology analysis and experimental validation, the pharmacological processes by which Yulin Formula (YLF) reduces cyclophosphamide-induced diminished ovarian reserve (DOR). Methods: First, information about the active components, associated targets, and related genes of YLF and DOR was gathered from open-access databases. The primary targets and pathways of YLF to reduce DOR were predicted using studies of functional enrichment from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein-Protein Interaction (PPI) networks. Second, we built a cyclophosphamide-induced diminished ovarian reserve (DOR) rat model to verify the primary target proteins implicated in the predicted signaling pathway to explore the mechanism of improve ovarian function of YLF. Results: 98 targets met the targets of the 82 active ingredients in YLF and DOR after searching the intersection of the active ingredient targets and DOR targets. Fourteen targets, including AKT and Caspase-3 among others, were hub targets, according to the PPI network study. The PI3K/AKT pathway was revealed to be enriched by numerous targets by the GO and KEGG enrichment studies, and it was used as a target for in vivo validation. Animal studies showed that YLF administration not only reduced the number of atretic follicles, the proportion of TUNEL-positive ovarian cells, the rate of apoptosis of granulosa cells (GCs) and the proportion of abnormal mitochondria in DOR rats, but also reversed the high expression of Caspase-3, Caspase-9, BAX, cytochrome C, PI3K and P-AKT, improving the ovarian reserve in cyclophosphamide (CTX)-induced DOR rats. Conclusion: Our research results predicted the active ingredients and potential targets of YLF-interfering DOR by an integrated network pharmacology approach, and experimentally validated some key target proteins participated in the predicted signaling pathway. A more comprehensive understanding of the pharmacological mechanism of YLF for DOR treatment was obtained.

Potential Value of FAPI PET/CT in the Detection and Treatment of Fibrosing Mediastinitis: Preclinical and Pilot Clinical Investigation.

Fibrosing mediastinitis (FM) is a rare proliferative disease within the mediastinum that leads to pulmonary hypertension, which has been regarded as a major cause of death. This study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-PET/CT in the integration of diagnosis and treatment of FM through targeting FAPI in fibrosis rats and provide a theoretical basis for clinical management of FM patients. By performing a 18F-FAPI PET/CT scan, the presence of FAPI-avid in the fibrotic lesion was determined. Through a fibrosis rat model, 18F-FAPI-74 was used for lesion imaging and 177Lu-FAPI-46 was utilized to investigate the potential therapeutic effect on FM in vivo. In addition, biodistribution analysis and radiation dosimetry were carried out. With the 177Lu-FAPI-46 pharmacokinetic data of rats as the input, the estimated dose for female adults was computed, which can provide some useful information for the safe application of radiolabeled FAPI in the detection and treatment of FM in patients. Then, major findings on the use of FAPI PET/CT and SPECT/CT in FM were presented. 18F-FAPI-74 showed a high-level uptake in FM lesions of patients (SUVmax 7.94 ± 0.26), which was also observed in fibrosis rats (SUVmax 2.11 ± 0.23). Consistently, SPECT/CT imaging of fibrosis rats also revealed that 177Lu-FAPI-46-avid was active for up to 60 h in fibrotic lesions. In addition to this robust diagnostic performance, a possible therapeutic impact was evaluated as well. It turned out that no spontaneous healing of lesions was observed in the control group, whereas there was complete healing on day 9, day 11, and day 14 in the 30, 100, and 300 MBq groups, respectively. With a significant difference in the free of event rate in the Kaplan-Meier curve among four groups (P < 0.001), a dose of 300 MBq displayed the best therapeutic effect, and no obvious damage was observed in the kidney. Furthermore, organ-absorbed doses and an effective dose (0.4320 mSv/MBq) of 177Lu-FAPI-46 presumed for patients were assumed to give a preliminary indication of its safe use in clinical practice. In conclusion, 18F-FAPI-46 PET/CT can be a potentially valuable tool for the diagnosis of FM. Of note, 177Lu-FAPI-46 may be a novel and safe radiolabeled reagent for the integration of diagnosis and treatment of FM.

Effect of the ketogenic diet on gut microbiome composition and metabolomics in polycystic ovarian syndrome rats induced by letrozole and a high-fat diet.

OBJECTIVES: The ketogenic diet (KD) is recommended to improve polycystic ovary syndrome (PCOS); however, its mechanisms of action are unclear. We aimed to study the effects and mechanisms of action of the KD on the gut microbiome and metabolites in PCOS rats and determine whether the sex hormone regulatory effects are related to modulations of the gut microbiota and metabolites. METHODS: PCOS was induced with a high-fat diet and letrozole in the rats. A KD was fed to rats for 8 wk, serum samples were collected for biochemical analysis, and the rats' fecal samples were subjected to 16S ribosomal RNA sequencing and metabolomic analysis. RESULTS: Feeding with a KD for 8 wk suppressed body weight gain, decreased luteinizing hormone and androgen levels, and improved insulin levels. Furthermore, the KD reversed the dysregulation of the gut microbiota in PCOS rats by adjusting the ratio of firmicutes and bacteroidetes. Also, the KD was involved in hormonal metabolic pathways by reducing the levels of some metabolites (such as testosterone and 7α-hydroxytestosterone) that are closely related to gut microbes. CONCLUSIONS: The KD improved the clinical phenotype and insulin resistance in PCOS rats and altered the composition of the gut microbiome and metabolites, which were associated with androgen metabolism, representing a potential mechanism for mediating the effects of the KD on sex hormone metabolism in PCOS. However, our study found contradictory effects of KD on the gut microbiome in PCOS, which need further research.

Approaching high-performance lithium storage materials of CoNiO2 microspheres wrapped coal tar pitch-derived porous carbon.

Ternary transition metal oxides (TMOs) are deemed as promising anode materials of Li-ion batteries (LIBs) owing to their large theoretical capacity and rich redox reaction. Nevertheless, the inherent semiconductor characteristic and enormous volume variation of TMOs during cycling bring about sluggish reaction kinetics, fast capacity fading, and poor rate capability. In this study, three-dimensional (3D) porous CoNiO2@CTP architectures, i.e., CoNiO2 microspheres combined with coal tar pitch-derived porous carbon, were designed and synthesized through a one-step hydrothermal method followed by a heat treatment process for the first time. The microsphere morphology increases the contact area between the anode and electrolyte, shortens the transport distance of Li+ ions, and reduces the agglomeration. The existence of the CTP layer provides rich charge transmission paths, improves the electronic conductivity of CoNiO2 and provides abundant active sites for Li+ storage. Owing to the synergistic effect of porous carbon and microsphere morphology of CoNiO2, the CoNiO2@CTP (10.0 wt%) anode shows remarkable electrochemical performance with a high charge capacity (1437.5 mA h g-1 at 500 mA g-1), good rate performance (839.76 mA h g-1 even at 1 A g-1), and remarkable cycle durability (741.4 mA h g-1 after 1000 cycles at 1 A g-1), which is significantly better than pristine CoNiO2. This study not only provides a simple strategy for high-value utilization of CTP but also offers cost-effective CoNiO2@CTP architectures for high-performance LIBs.

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development. METHODS: Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1+ macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing. RESULTS: Single-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1+ macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1+ macrophage-enriched HCCs were characterized by high infiltration of CD8+ T cells with increased programmed death-1 (PD-1) expression. PPT1+ macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1- macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model. CONCLUSIONS: PPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1+ macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.