Search

The programmed cell death 1 (PD-1) immune checkpoint of co-inhibitory signaling plays crucial roles in controlling the magnitude and duration of T cell activation to limit tissue damage and maintain self-tolerance. Cancer cells hijack the co-inhibitory pathway and escape immune surveillance by overexpressing the PD-1 ligand PD-L1. Immune checkpoint inhibitors, such as PD-1 blocking antibody have been approved for tumor immunotherapy. However, not all patients can benefit from PD-1 monotherapy. Combination immunotherapy based on PD-1 axis blockade substantially improves clinical anti-tumor efficacy. In this review, we briefly summarize the current progress on the mechanisms of PD-1-mediated inhibition of T cell activation and strategies for cancer combination immunotherapy.

This paper systematically investigates the structure, stability, and electronic properties of niobium carbide clusters, NbmCn (m = 5, 6; n = 1–7), using density functional theory. Nb5C2 and Nb5C6 possess higher dissociation energies and second-order difference energies, indicating that they have higher thermodynamic stability. Moreover, ab initio molecular dynamics (AIMD) simulations are used to demonstrate the thermal stability of these structures. The analysis of the density of states indicates that the molecular orbitals of NbmCn (m = 5, 6; n = 1–7) are primarily contributed by niobium atoms, with carbon atoms having a smaller contribution. The composition of the frontier molecular orbitals reveals that niobium atoms contribute approximately 73.1% to 99.8% to NbmCn clusters, while carbon atoms contribute about 0.2% to 26.9%.

The geometrical structures, relative stabilities, and electronic and magnetic properties of niobium carbon clusters, Nb7Cn (n = 1–7), are investigated in this study. Density functional theory (DFT) calculations, coupled with the Saunders Kick global search, are conducted to explore the structural properties of Nb7Cn (n = 1–7). The results regarding the average binding energy, second-order difference energy, dissociation energy, HOMO-LUMO gap, and chemical hardness highlight the robust stability of Nb7C3. Analysis of the density of states suggests that the molecular orbitals of Nb7Cn primarily consist of orbitals from the transition metal Nb, with minimal involvement of C atoms. Spin density and natural population analysis reveal that the total magnetic moment of Nb7Cn predominantly resides on the Nb atoms. The contribution of Nb atoms to the total magnetic moment stems mainly from the 4d orbital, followed by the 5p, 5s, and 6s orbitals.

Premature ovarian insufficiency is a multi-factor gynecological disease that has become a major global health problem. In recent years, several trials have explored the treatment of premature ovarian insufficiency using Chinese herbal medicine and acupuncture, but the efficacy and safety of this combination remains controversial. This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of combining Chinese herbal medicine with acupuncture to treat premature ovarian insufficiency. From eight different databases, we retrieved randomized controlled trials wherein Chinese herbal medicine and acupuncture had been compared with western medicine in the treatment of premature ovarian insufficiency. The bias risk assessment stipulated by the Cochrane Collaboration's tool was utilized to evaluate the quality of the chosen randomized controlled trials. This meta-analysis was executed with the help of Review Manager 5.3 and Stata 10.0. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A total of 10 randomized controlled trials involving 594 premature ovarian insufficiency patients were included in the analysis. Compared with western medicine, co-treatment with acupuncture and Chinese herbal medicine exhibited a significantly higher total effective rate (relative risk: 1.21; 95% confidence interval: 1.12–1.31; P

Abstract Background Diabetes has become a major public health problem in China. A better understanding of diabetes determinants and urban-rural differences is essential to crafting targeted diabetes prevention measures for the elderly living in both urban and rural areas. This study aimed to compare rural-urban differentials in prevalence and lifestyle determinants of pre-diabetes and diabetes among the elderly in southwest China. Methods A cross-sectional health interview and examination survey was conducted among individuals aged ≥ 60 years in both a rural and urban area of China. Anthropometric measurements, including height, weight, and waist circumference, as well as blood pressure and fasting blood glucose measurements were taken. Associated risk factors for pre-diabetes and diabetes were evaluated using multivariate logistic regression analysis. Results In total, 1,624 urban residents and 1,601 rural residents consented to participate in the study. The urban prevalence of pre-diabetes and diabetes (46.8% and 24.7%, respectively), was higher than the rural prevalence (23.4% and 11.0%, respectively, P

Abstract Background Rheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms. Methods Single-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR+ memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of SIGIRR in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-α production in CD4 T cells. Results SIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPβ/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis. Conclusion Taken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.

Aims: Shenghua Decoction (SHD) is a well-known classic herbal formula documented in traditional Chinese medicine (TCM) that has been widely applied during the postpartum period in Chinese communities for several years. We conducted this systematic review and meta-analysis to explore the influence of SHD as an adjuvant treatment for early medical abortion using a combination of mifepristone followed by misoprostol. Methods: This systematic review and meta-analysis was reported using 2020 PRISMA guidelines. Eight databases were searched from their establishment to February 28, 2022, for randomized controlled trials (RCTs): PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, the Chinese BioMedical database, the Chinese Scientific Journal Database, and the Wanfang database. The Grading of Recommendations Assessment, Development, and Evaluation estimated the quality of evidence. Results: Sixteen RCTs involving 3016 patients were included in the meta-analysis. Overall, compared with no treatment as the control group after early medical abortion, patients treated with SHD were associated with a higher complete abortion rate (RR: 1.14; 95% CI: 1.10 – 1.18; P

The growth behavior, stability, electronic and magnetic properties of the Gd2Sin− (n = 3–12) clusters are reported, which are investigated using density functional theory calculations combined with the Saunders ‘Kick’ and the Artificial Bee Colony algorithm. The lowest-lying structures of Gd2Sin− (n = 3–12) are all exohedral structures with two Gd atoms face-capping the Sin frameworks. Results show that the pentagonal bipyramid (PB) shape is the basic framework for the nascent growth process of the present clusters, and forming the PB structure begins with n = 5. The Gd2Si5− is the potential magic cluster due to significantly higher average binding energies and second order difference energies, which can also be further verified by localized orbital locator and adaptive natural density partitioning methods. Moreover, the localized f-electron can be observed by natural atomic orbital analysis, implying that these electrons are not affected by the pure silicon atoms and scarcely participate in bonding. Hence, the implantation of these elements into a silicon substrate could present a potential alternative strategy for designing and synthesizing rare earth magnetic silicon-based materials.

Ascites is one of the most common complications of cirrhosis, and there is a dearth of knowledge about ascites-related pathologic metabolism. In this study, 122 alcoholic liver disease (ALD) patients, including 49 cases without ascites, 18 cases with mild-ascites, and 55 cases with large-ascites (1) were established according to the International Ascites Club (2), and untargeted metabolomics coupled with pattern recognition approaches were performed to profile and extract metabolite signatures. A total of 553 metabolites were uniquely discovered in patients with ascites, of which 136 metabolites had been annotated in the human metabolome database. Principal component analysis (PCA) analysis was used to further identify 21 ascites-related fingerprints. The eigenmetabolite calculated by reducing the dimensions of the 21 metabolites could be used to effectively identify those ALD patients with or without ascites. The eigenmetabolite showed a decreasing trend during ascites production and accumulation and was negatively related to the disease progress. These metabolic fingerprints mainly belong to the metabolites in lipid metabolism and the amino acid pathway. The results imply that lipid and amino acid metabolism disturbance may play a critical role in the development of ascites in ALD patients and could be a potent prognosis marker.

Abstract Background Asthma is a common complex chronic, inflammatory polygenic disease with heterogeneous manifestations, affecting individuals of all age groups and posing an immense burden on healthcare resources. A number of studies have identified the association between a disintegrin and metalloprotease 33 (ADAM33) polymorphisms and asthma risk, however, the results still remain inconclusive. The objective of the present study was to identify the effect of ADAM33 variants in asthma susceptibility. Methods Eligible case-control studies published between January 2000 and June 2018 was searched and retrieved from online electronic databases. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the effect. Results A total of 63 case-control studies were finally screened out, including 13,280 asthma patients and 13,340 controls. Eleven SNPs of ADAM33 gene were identified. Our results detected a significant association between ADAM33 T2, Q1, F + 1 and AA genotype of T + 1 polymorphisms and asthma risk in total population. Subgroup analysis by ethnicities showed that the alleles and genotypes of T2, Q1 and F + 1 polymorphisms were associated with asthma susceptibility among Asian populations, while V4 polymorphism was associated with asthma among Caucasian populations. Subgroup analysis by ages showed that T2, F + 1 and ST + 4 polymorphisms were associated with childhood asthma, while Q1 and V4 polymorphisms were associated with asthma risk in adults. Subgroup analysis by asthma severity showed that only the G allele of ADAM33 T1 polymorphism was associated with the severity of asthma when compared with the controls. In addition, T2, Q1 and F + 1 polymorphisms of ADAM33 were significantly associated with increased the asthma risk in Chinese asthma patients. Conclusions Our results found that T2, Q1 and F + 1 polymorphisms of ADAM33 gene might contribute to asthma risk. Future well-designed case-control studies with large population and more ethnicities are still needed to estimate the association.

Objective This meta-analysis investigated the analgesic effects of erector spinae plane block (ESPB) in patients undergoing breast surgery. Methods PubMed, Embase, Web of Science, and the Cochrane Library were searched from database establishment to January 31, 2020. Two reviewers independently extracted the data. The primary outcomes were pain scores and opioid consumption during the first 24 hours after surgery. The risk of bias of the included studies was assessed according to the Cochrane Handbook. Results Six randomized controlled trials of 415 patients were included. Compared with the control value, the pain score was significantly lower in the ESPB group at different time points postoperatively. Patients who underwent ESPB required lower opioid consumption (standardized mean difference = −2.02, 95% confidence interval [CI] = −2.85 to −1.20, I 2 = 91%. The rates of postoperative nausea (risk ratio [RR] = 0.79, 95% CI = 0.48–1.30, I 2 = 47%) and postoperative vomiting (RR = 0.76, 95% CI = 0.30–1.96, I 2 = 33%) did not differ between the groups. The quality of evidence was low or very low. Conclusions ESPB significantly alleviated pain and reduced opioid consumption after breast surgery. Further research is needed to expand its clinical application. PROSPERO registration number CRD42020167900

Objective Perioperative shivering (POS) is a common complication in patients undergoing spinal anaesthesia. The present study investigated the efficacy of 5-HT3 receptor antagonists in preventing POS following spinal anaesthesia.Design Systematic review and meta-analysis.Data sources Pubmed, Embase, the Web of Science and Cochrane Library were searched from database establishment on 31 July 2019.Eligibility criteria Randomised controlled trials that reported the effects of 5-HT3 receptor antagonists in the prevention of POS in patients after spinal anaesthesia.Data extraction and synthesis Two reviewers independently extracted data. The primary outcome of the present study was the incidence of POS. The risk of bias for the included studies was assessed according to the Cochrane Handbook. The quality of primary outcome was evaluated by Grading of Recommendations Assessment, Development and Evaluation. Trial sequential analysis for the primary outcome was performed to reduce the type 1 error caused by repeated meta-analysis and the required information size was calculated.Results A total of 13 randomised controlled trials consisting of 1139 patients were included. The overall incidence of POS was significantly lower in the 5-HT3 receptor antagonists group (risk ratio 0.31; 95% CI 0.26 to 0.38; p

Objective Previous studies reported the effect of dexmedetomidine on intrathecal anesthesia. In this review, we explored the impact of dexmedetomidine as an adjunct for lumbar anesthesia in patients undergoing cesarean section. Methods Two authors searched eligible random controlled trials in electronic databases, including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, the Chinese BioMedical database, Chinese Scientific Journal Database, and the Wanfang database. Results Ten trials comprising 970 patients were included in this review. Intrathecal dexmedetomidine significantly reduced the onset time of sensory block (standardized mean difference (SMD), −1.50, 95% confidence interval (CI) −2.15, −0.85, I 2 = 92%) and motor block (SMD −0.77, 95% CI −1.50, −0.49, I 2 = 60%) and prolonged the block duration time (sensory block: SMD 2.02, 95% CI 1.29, 2.74, I 2 = 93%; motor block: SMD 1.90, 95% CI 1.07, 2.74, I 2 = 94%). Patients who received dexmedetomidine showed a lower incidence of shivering. No significant difference was reported for the neonatal Apgar score and other complications. Conclusion The use of intrathecal dexmedetomidine during cesarean section can shorten the onset time of spinal anesthesia and enhance the effect of local anesthetic. It has no significant impact on neonates and there were no other adverse events.

Objective Postoperative delirium (POD) is a perennial and distressing complication in older patients, and it may be caused by various factors. This study aimed to determine whether serum melatonin levels are associated with POD in older patients who undergo major abdominal surgery. Methods We collected serum samples from patients undergoing major abdominal surgery. Melatonin was measured by enzyme-linked immunosorbent assay and delirium was assessed by the Confusion Assessment Method after surgery. We classified the patients into the POD group and non-POD group. Results A total of 120 patients met the inclusion criteria and 104 patients were included in the analysis. Postoperative serum melatonin levels were significantly lower than preoperative levels. Multivariate analyses showed that a longer duration of anesthesia (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.02–1.64), advanced age (OR = 3.36, 95% CI = 1.37–8.22), and lower postoperative levels of melatonin (OR = 0.50, 95% CI = 0.25–1.00) were associated with POD. Conclusions Serum melatonin levels significantly decline after surgery and anesthesia. Significantly decreased serum melatonin concentrations postoperatively may be a biomarker for predicting POD in older patients undergoing major abdominal surgery with general anesthesia.

Objectives. This study is aimed at gaining insights on the changing prevalence, economic burden, and catastrophic costs of diabetes in rural southwest China. Materials and Methods. Data were collected from two cross-sectional health interviews and examination surveys among individuals aged≥35 years in rural Yunnan Province. A prevalence-based cost-of-illness method was used to estimate the cost of diabetes. Information about the participants’ demographic characteristics and economic consequences of diabetes was obtained using a standard questionnaire. Fasting blood sugar levels were recorded for each study participant. Results. During the study period, the overall prevalence of diabetes increased from 7.7% to 9.5% (P0.05). Conclusions. The prevalence and economic burden of diabetes increased substantially from 2009 to 2016 in rural southwest China. The findings underscore an urgent need for the government to invest more financial resources in the prevention of diabetes and improvement of access to affordable medication in rural southwest China.

Calcineurin (Cn or CaN) is implicated in the control of skeletal muscle fiber phenotype and hypertrophy. However, little information is available concerning the expression of Cn in chickens. In the present study, the expression of two Cn subunit genes (CnAα and CnB1) was quantified by qPCR in the lateral gastrocnemius (LG, mainly composing of red fast-twitch myofibers), the soleus (mainly composing of red slow-twitch myofibers) and the extensor digitorum longus (EDL, mainly composing of white fast-twitch myofibers) from Qingyuan partridge chickens (QY, slow-growing chicken breed) and Recessive White chickens (RW, fast-growing chicken breed) on different days (1, 8, 22, 36, 50 and 64 days post-hatching). Although CnAα and CnB1 gene expressions were variable with different trends in different skeletal muscles in the two chicken breeds during postnatal growth, it is highly muscle phenotype and breed specific. In general, the levels of CnAα and CnB1 gene expressions of the soleus were lower than those of EDL and LG in both chicken breeds at the same stages. Compared between the two chicken breeds, the levels of CnAα gene expression of the three skeletal muscles in QY chickens were higher than those in RW chickens on days 1 and 22. However, on day 64, the levels of both CnAα and CnB1 gene expressions of the three skeletal muscles were lower in QY chickens than those in RW chickens. Correlation analysis of the levels of CnAα and CnB1 gene expressions of the same skeletal muscle showed that there were positive correlations for all three skeletal muscle tissues in two chicken breeds. These results provide some valuable clues to understand the role of Cn in the development of chicken skeletal muscles, with a function that may be related to meat quality.

Abstract: Little is known about the muscle developmental patterns during embryonic to neonatal development in ducks. We investigated the developmental patterns in the lateral gastrocnemius muscles of Gaoyou and Jinding ducks differing in their muscle growth rates during the final stages of egg incubation and the first week after hatching. Expression of the MyoD gene was quantified by quantitative real-time PCR (qRT-PCR). The average cross-sectional area and diameter of the fibers increased from embryonic day 21 (E21), peaking at E27, and then declining slightly 7 d after hatching. The density of the fibers decreased initially but increased after hatching in both breeds and sexes. The within-breed variation in muscle fiber-type composition was greater than the average variation between the breeds. Overall, the percentage of type I fibers increased and that of type IIb fibers decreased consistently. However, the percentage of type IIa fibers was almost constant as development proceeded in both duck breeds. The profiles of MyoD mRNA expression were similar in both breeds, and a significantly positive relationship was observed between the expression of MyoD and the percentage of type IIb fibers. This study firstly revealed the characteristics of duck muscle development and differences between the two breeds differing in growth rates. Moreover, type IIb fibers might convert to type I fibers in the lateral gastrocnemius, while MyoD may potentially function in controlling the muscle fiber phenotype during the secondary myogenesis of muscle development.

Golden cage-doped nanoclusters have attracted great attention in the past decade due to their remarkable electronic, optical and catalytic properties. However, the structures of large golden cage doped with Mo and Tc are still not well known because of the challenges in global structural searches. Here, we report anionic and neutral golden cage doped with a transition metal atom MAu16 (M = Mo and Tc) using Saunders ‘Kick' stochastic automation search method associated with density-functional theory (DFT) calculation (SK-DFT). The geometric structures and electronic properties of the doped clusters, MAu16q (M = Mo and Tc; q = 0 and −1), are investigated by means of DFT theoretical calculations. Our calculations confirm that the 4d transition metals Mo and Tc can be stably encapsulated in the Au16− cage, forming three different configurations, i.e. endohedral cages, planar structures and exohedral derivatives. The ground-state structures of endohedral cages C2v Mo@Au16−-(a) and C1 Tc@Au16−-(b) exhibit a marked stability, as judged by their high binding energy per atom (greater than 2.46 eV), doping energy (0.29 eV) as well as a large HOMO–LUMO gap (greater than 0.40 eV). The predicted photoelectron spectra should aid in future experimental characterization of MAu16− (M = Mo and Tc).

This study aimed to develop a scoring system to predict the survival time of patients with bone metastases after radiation therapy (RT). The scoring system can guide physicians to a better selection of appropriate treatment regimens.The medical records of 125 patients with bone metastases treated with RT between January 2007 and September 2010 were reviewed retrospectively. Fifteen potential prognostic factors were investigated: sex, age, Karnofsky performance score (KPS), type of primary tumor, resection of tumor before bone metastases, interval between primary tumor diagnosis and diagnosis of bone metastases, Carcinoembryonic Antigen(CEA), lung metastases before bone metastases, liver metastases before bone metastases, brain metastases before bone metastases, stage, T, N, M, and degree of cellular differentiation.In an univariate analysis, 10 factors were significantly associated with survival time after bone metastasis: sex, KPS, breast cancer, esophageal cancer, colorectal cancer, interval between tumor diagnosis and diagnosis of bone metastases, CEA, lung metastases before bone metastases, T-staging, and differentiation. In a multivariate analysis, 7 factors were found to be significant: sex, KPS, esophageal cancer, colorectal cancer, interval between tumor diagnosis and diagnosis of bone metastases, T-staging, and differentiation. The median survival of all patients with bone metastases after RT was 14.1 months. There were significant differences in the median survival of patients with bone metastases after RT of 4.9 months, 10.5 months, and 29.7 months in groups 1, 2, and 3, respectively (P

AIM: To explore the treatment of neonatal dacryocystitis of different ages and the relationship between caesarean section and neonatal dacryocystitis.METHODS: A total of 260 cases(260 eyes)of children with neonatal dacryocystitis were divided into 1-3 months group, 4-6 months group, 7-12 months group and 13-24 months group, Each group was respectively given the lacrimal sac massage, lacrimal passage irrigation and probing of lacrimal passage method. Curative effect of each method was observed in different groups. Analysis was made to determine whether caesarean section was the cause of neonatal dacryocystitis.RESULTS: The comparison between 1-3 months group and 4-6 months group showed significant difference(χ2=19.89, Pχ2=54.95, Pχ2=0.00003, P>0.05, lacrimal passage irrigation of these two groups showed no significant difference in efficacy. The comparison result between the other two groups showed no significant difference(Pχ2=10.29, PCONCLUSION:Lacrimal sac massage can exert very good therapeutic effects in infants less than 3 months. The curative effects of irrigation of lacrimal passage are quite good in babies under 12 months. Probing of lacrimal passage has a good curative effect in 7-12 months infants, but a poor curative effect in babies over 12 months. Caesarean section is an important cause for neonatal dacryocystitis.

Invertebrates rely on an innate immune system to combat invading pathogens. The system is initiated in the presence of cell wall components from microbes like lipopolysaccharide (LPS), β-1,3-glucan (βG) and peptidoglycan (PG), altogether known as pathogen-associated molecular patterns (PAMPs), via a recognition of pattern recognition protein (PRP) or receptor (PRR) through complicated reactions. We show herein that shrimp hemocytes incubated with LPS, βG, and PG caused necrosis and released endogenous molecules (EMs), namely EM-L, EM-β, and EM-P, and found that shrimp hemocytes incubated with EM-L, EM-β, and EM-P caused changes in cell viability, degranulation and necrosis of hemocytes, and increased phenoloxidase (PO) activity and respiratory burst (RB) indicating activation of immunity in vitro. We found that shrimp receiving EM-L, EM-β, and EM-P had increases in hemocyte count and other immune parameters as well as higher phagocytic activity toward a Vibrio pathogen, and found that shrimp receiving EM-L had increases in proliferation cell ratio and mitotic index of hematopoietic tissues (HPTs). We identified proteins of EMs deduced from SDS-PAGE and LC-ESI-MS/MS analyses. EM-L and EM-P contained damage-associated molecular patterns (DAMPs) including HMGBa, HMGBb, histone 2A (H2A), H2B, and H4, and other proteins including proPO, Rab 7 GPTase, and Rab 11 GPTase, which were not observed in controls (EM-C, hemocytes incubated in shrimp salt solution). We concluded that EMs induced by PAMPs contain DAMPs and other immune molecules, and they could elicit innate immunity in shrimp. Further research is needed to identify which individual molecule or combined molecules of EMs cause the results, and determine the mechanism of action in innate immunity.

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Methods: Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Results: Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intratumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. Conclusion: FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy. [ABSTRACT FROM AUTHOR]

Abstract Aberrant RNA editing has emerged as a pivotal factor in the pathogenesis of hepatocellular carcinoma (HCC), but the impact of RNA co-editing within HCC remains underexplored. We used a multi-step algorithm to construct an RNA co-editing network in HCC, and found that HCC-related RNA editings are predominantly centralized within the network. Furthermore, five pairs of risk RNA co-editing events were significantly correlated with the overall survival in HCC. Based on presence of risk RNA co-editings resulted in the categorization of HCC patients into high-risk and low-risk groups. Disparities in immune cell infiltrations were observed between the two groups, with the high-risk group exhibiting a greater abundance of exhausted T cells. Additionally, seven genes associated with risk RNA co-editing pairs were identified, whose expression effectively differentiates HCC tumor samples from normal ones. Our research offers an innovative perspective on the etiology and potential therapeutics for HCC.