Scutellarin-loaded pH/H2O2 dual-responsive polymer cyclodextrin mesoporous silicon framework nanocarriers for enhanced cancer therapy.

Stimulus-responsive nanomaterials, particularly with targeting capabilities, have garnered significant attention in the cancer therapy. However, the biological safety of these innovative materials in vivo remains unknown, posing a hurdle to their clinical application. Here, a pH/H2O2 dual-responsive and targeting nano carrier system (NCS) was developed using core shell structure of Fe3O4 mesoporous silicon (MSN@Fe3O4) as main body, scutellarin (SCU) as antitumor drug and polymer cyclodextrin (PCD) as molecular switch (denoted as PCD@SCU@MSN@Fe3O4, abbreviated as NCS). The NCS, with an average particle size of 100 nm, displayed exceptional SCU loading capacity, a result of its uniform radial channel structure. The in vitro investigation under condition of pH and H2O2 indicated that NCS performed excellent pH/H2O2-triggered SCU release behavior. The NCS displayed a higher cytotoxicity against tumor cells (Huh7 and HCT116) due to its pH/H2O2 dual-triggered responsiveness, while the PCD@MSN@Fe3O4 demonstrated lower cytotoxicity for both Huh7 and HCT116 cells. In vivo therapeutic evaluation of NCS indicates significant inhibition of tumor growth in mouse subcutaneous tumor models, with no apparent side-effects detected. The NCS not only enhances the bioavailability of SCU, but also utilizes magnetic targeting technology to deliver SCU accurately to tumor sites. These findings underscore the substantial clinical application potential of NCS.

Impact of preoperative transcatheter arterial chemoembolization (TACE) on postoperative long-term survival in patients with nonsmall hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: The purpose of this propensity score matching (PSM) analysis was to compare the effects of preoperative transcatheter arterial chemoembolization (TACE) and non-TACE on the long-term survival of patients who undergo radical hepatectomy. METHODS: PSM analysis was performed for 387 patients with hepatocellular carcinoma (HCC) (single > 3 cm or multiple) who underwent radical resection of HCC at our centre from January 2011 to June 2018. The patients were allocated to a preoperative TACE group (n = 77) and a non-TACE group (n = 310). The main outcome measures were progression-free survival (PFS) and overall survival (OS) since the treatment date. RESULTS: After PSM, 67 patients were included in each of the TACE and non-TACE groups. The median PFS times in the preoperative TACE and non-TACE groups were 24.0 and 11.3 months, respectively (p = 0.0117). The median OS times in the preoperative TACE and non-TACE groups were 41.5 and 29.0 months, respectively (p = 0.0114). Multivariate Cox proportional hazard regression analysis revealed that preoperative TACE (hazard ratio, 1.733; 95% CI, 1.168-2.570) and tumour thrombosis (hazard ratio, 0.323; 95% CI, 0.141-0.742) were independent risk factors significantly associated with OS. CONCLUSIONS: Preoperative TACE is related to improving PFS and OS after resection of HCC. Preoperative TACE and tumour thrombus volume were also found to be independent risk factors associated with OS.

Extended lymphadenectomy based on the TRIANGLE for pancreatic head cancer: a single-center experience.

BACKGROUND: This study was to compare the safety and efficacy of different lymphadenectomy methods in patients with pancreatic head cancer undergoing pancreaticoduodenectomy (PD). MATERIAL AND METHODS: A total of 150 patients were included in this study. Patients were divided into Group A (n = 79), Group B (n = 44), and Group C (n = 27) according to the different lymphadenectomy methods. The clinical endpoint was time to progression (TTP) and overall survival (OS). Postoperative complications of different lymphadenectomy methods were compared respectively. TTP and OS of the three groups were compared by Kaplan-Meier curves. RESULTS: There were no significant differences between the three groups in operative time (P = 0.300), death in the hospital (P = 0.253), postoperative hemorrhage (P = 0.863), postoperative pancreatic fistula (POPF) B/C (P = 0.306), bile leakage (P = 0.215), intestinal fistula (P = 0.177), lymphatic leakage (P = 0.267), delayed gastric emptying [(DGE) (P = 0.283)], ICU stay (P = 0.506), and postoperative hospital stay [(PHS) (P = 0.810)]. Median TTP in Groups B and C was significantly longer than in Group A (log-rank test, A vs B: P = 0.0005, A vs C: P = 0.0001). Median OS between the three groups has no statistical difference (P = 0.1546). CONCLUSIONS: Extended lymphadenectomy methods based on the TRIANGLE do not increase perioperative complications significantly and can effectively delay tumor progression in patients with pancreatic head cancer.

Analysis of clinical significance and molecular characteristics of methionine metabolism and macrophage-related patterns in hepatocellular carcinoma based on machine learning.

BACKGROUND: Increasing evidence has indicated that abnormal methionine metabolic activity and tumour-associated macrophage infiltration are correlated with hepatocarcinogenesis. However, the relationship between methionine metabolic activity and tumour-associated macrophage infiltration is unclear in hepatocellular carcinoma, and it contributes to the occurrence and clinical outcome of hepatocellular carcinoma (HCC). Thus, we systematically analysed the expression patterns of methionine metabolism and macrophage infiltration in hepatocellular carcinoma using bioinformatics and machine learning methods and constructed novel diagnostic and prognostic models of HCC. METHODS: In this study, we first mined the four largest HCC mRNA microarray datasets with patient clinical data in the GEO database, including 880 tissue mRNA expression datasets. Using GSVA analysis and the CIBERSORT and EPIC algorithms, we quantified the methionine metabolic activity and macrophage infiltration degree of each sample. WGCNA was used to identify the gene modules most related to methionine metabolism and tumour-associated macrophage infiltration in HCC. The KNN algorithm was used to cluster gene expression patterns in HCC. Random forest, logistic regression, Cox regression analysis and other algorithms were used to construct the diagnosis and prognosis model of HCC. The above bioinformatics analysis results were also verified by independent datasets (TCGA-LIHC, ICGC-JP and CPTAC datasets) and immunohistochemical fluorescence based on our external HCC panel. Furthermore, we carried out pancancer analysis to verify the specificity of the above model and screened a wide range of drug candidates. RESULTS: We identified two methionine metabolism and macrophage infiltration expression patterns, and their prognoses were different in hepatocellular carcinoma. We constructed novel diagnostic and prognostic models of hepatocellular carcinoma with good diagnostic efficacy and differentiation ability. CONCLUSIONS: Methionine metabolism is closely related to tumour-associated macrophage infiltration in hepatocellular carcinoma and can help in the clinical diagnosis and prognosis of HCC.

Wrapping pancreaticojejunostomy using the ligamentum teres hepatis during laparoscopic pancreaticoduodenectomy: a propensity score matching analysis.

BACKGROUND AND OBJECTIVE: It is controversial whether wrapping around the pancreaticojejunostomy (PJ) could reduce the rate of postoperative pancreatic fistula (POPF), especially in laparoscopic pancreaticoduodenectomy (LPD). This study aims to summarize our single-center initial experience in wrapping around PJ using the ligamentum teres hepatis (LTH) and demonstrate the feasibility and safety of this method. METHODS: Patients who underwent LPD applying the procedure of wrapping around the PJ were identified. The cohort was compared to the cohort with standard non-wrapping PJ. A 1:1 propensity score matching (PSM) was performed to compare the early postoperative outcomes of the two cohorts. Risk factors for POPF were determined by using univariate and multivariate logistic regression analysis. RESULTS: Overall, 143 patients were analyzed (LPD without wrapping (n = 91) and LPD with wrapping (n = 52)). After 1:1 PSM, 48 patients in each cohort were selected for further analysis. Bile leakage, DGE, intra-abdominal infection, postoperative hospital stays, harvested lymph nodes, and R0 resection were comparable between the two cohorts. However, the wrapping cohort was associated with significantly less POPF B (1 vs 18, P = 0.003), POPF C (0 vs 8, P = 0.043), and Clavien-Dindo classification level III-V (5 vs 26, P = 0.010). No patients died due to the clinically relevant POPF in the two cohorts. No patients who underwent the LTH wrapping procedure developed complications directly related to the wrapping procedure. After PSM, whether wrapping was an independent risk factor for POPF (OR = 0.202; 95%CI:0.080-0.513; P = 0.001). CONCLUSIONS: Wrapping the LTH around the PJ technique for LPD was safe, efficient, and reproducible with favorable perioperative outcomes in selected patients. However, further validations using high-quality RCTs are still required to confirm the findings of this study.

Laparoscopic left hemihepatectomy guided by real-time indocyanine green fluorescence imaging using the arantius-first approach.

BACKGROUND AND OBJECTIVE: Laparoscopic hepatectomy approaches, including major hepatectomy, were rapidly developed in the past decade. However, standard laparoscopic left hemihepatectomy (LLH) is still only performed in high-volume medical centres. In our series, we describe our technical details and surgical outcomes of LLH. METHODS: Thirty-nine patients who underwent LLH in our institute were enrolled in the study. Among these, 13 patients underwent LLH guided by real-time ICG fluorescence imaging using the Arantius-first approach (ICG-LLH group), and the other 26 underwent conventional LLH (conventional LLH group). Demographic characteristics and perioperative data were retrospectively collected and analysed. We compared the technical and postoperative short-term outcomes of the two groups. RESULTS: There were no significant differences in the demographic or clinicopathological characteristics of the patients in the two groups. ICG-LLH required significantly fewer pringle manoeuvres (1 vs. 3 times, p < 0.0001), had a shorter parenchyma dissection time (26 vs. 78 min, p < 0.001), and required fewer vessel clips (18 vs. 28, p < 0.001). Although there was no significant difference, the ICG-LLH group had less bile leakage (0 vs. 5, p = 0.09) and less blood loss (120 vs. 165, p = 0.119). There were no significant differences in the overall complication or R0 resection rates between the two groups. CONCLUSION: Our data demonstrate that laparoscopic left hemihepatectomy guided by real-time ICG fluorescence imaging using the Arantius-first approach is safe and feasible in selected patients, thus improving the fluency of the surgical procedure and postoperative short-term outcomes.

Prevalence and clinical significance of the Sg6/Sg7 intersegmental veins based on re-evaluation of the Couinaud classification for the right posterior portal vein.

Although Segment 6(Sg6) and Segment 7(Sg7) are two independent units, there are currently no clear anatomical boundary markers between Sg6 and Sg7. This study aimed to identify intersegmental veins (ISV) in the intersegmental plane of Sg6 and Sg7, and evaluate the prevalence of ISV, and its clinical significance in anatomical hepatectomy. We analyzed data from 180 patients undergoing abdominal computed tomography (CT) examination, and simultaneously performed 3D reconstruction models of the liver for each patient. The right posterior portal vein was analyzed and re-typed. Furthermore, the existence of ISV was defined, and prevalence and confluence patterns of ISV were analyzed. The author attempted to apply ISV to laparoscopic S6/S7 segmentectomy. We sorted data from the right posterior portal vein and divided it into six types. The ISV could be identified in 82.2% (148/180) of the patients, which were derived from the right hepatic vein (RHV) (91.9%) and right posterior inferior vein (IRHV) (8.1%). Ten ISV-guided laparoscopic Sg6/Sg7 segmentectomy were successfully carried out, seven patients underwent Sg6 segmentectomy, and three patients underwent Sg7 segmentectomy. There was no perioperative mortality. The median operative time was 223 min (range 181-260 min). The median blood loss was 200 ml (range 150-310 ml). The R0 resection rate was 100%. The ISV may be a candidate vessel to distinguish the boundary of the right posterior sector; it is expected to be a landmark in the liver parenchyma of anatomical hepatectomy.

A novel nomogram based on the hematological prognosis risk scoring system can predict the overall survival of patients with hepatocellular carcinoma.

BACKGROUND: This study aimed to establish and validate a nomogram based on a hematological prognostic risk scoring system to predict the overall survival in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Patients diagnosed with unresectable HCC undergoing transcatheter arterial chemoembolization (TACE) in 2012-2016 and 2017-2018 were included in the development set and validation set, respectively. The clinical outcome was overall survival (OS). The LASSO regression analysis was used to construct a hematological prognostic risk scoring system (HPR) by using the 18 hematological markers of patients in the development set. Combining the features of oncology on the basis of HPR to construct a nomogram for OS. In the development set and validation sets, the C-index, calibration curve, and decision curve analysis (DCA) were used to evaluate the prediction performance of the nomogram. RESULTS: Multiple markers of immunity, coagulation, liver function, and nutrition, including red blood cell distribution width-coefficient of variation (RDW-CV), platelet (PLT), aspartate transferase (AST), alkaline phosphatase (ALP), prognostic nutritional index (PNI), and fibrinogen (Fib), construct the HPR. HPR was an independent risk factor for OS in patients with HCC. The C-index of the nomogram was 0.731 (95% confidence interval (CI) 0.712-0.749) and 0.696 (95% CI 0.668-0.725) in the development set and the validation set, respectively. CONCLUSIONS: HPR was a complement to the clinical features of patients with unresectable HCC. The nomogram based on HPR proved to be a practical and effective method for prognosticating HCC patients who undergo TACE.

Prognostic value of preoperative prealbumin levels in patients with unresectable hepatocellular carcinoma undergoing transcatheter arterial chemoembolisation.

Background: This retrospective study analyzed the prognostic value of preoperative prealbumin (PAB) levels in patients with unresectable hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolisation (TACE). Methods: Four hundred and two patients diagnosed with unresectable HCC were included in this retrospective study. All patients underwent their first TACE procedure. Based on PAB levels before the first TACE, 402 patients were classified as having low PAB levels and high PAB levels. Potential confounding factors between the two groups were eliminated using. Propensity Score Matching (PSM) analysis. The time to progression (TTP) and overall survival (OS) of the two groups were compared using Kaplan-Meier curves before and after PSM. Risk factors for poor prognosis were determined using univariate and multivariate Cox proportional hazards models. Results: Before PSM, the high PAB level group had a significantly longer median TTP and OS than the low PAB level group (all P values < 0.0001). After PSM, the high PAB level group still had a significantly longer median TTP and OS than the low PAB level group (all P values < 0.05). After PSM, low PAB level was found to be an independent predictor of shorter OS (HR = 0.656; 95% CI:0.448-0.961; P = 0.03). The subgroup analysis before PSM showed that low PAB levels increased the risk of poor prognosis in most subgroups. Conclusions: Low preoperative PAB levels are associated with poor prognosis in patients with unresectable HCC after TACE.

Laparoscopic Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (L-ALPPS) After Conversion Therapy for BCLC-B Hepatocellular Carcinoma: A Video Article.

BACKGROUND: Despite the ALPPS technique remains a controversy, various ALPPS techniques have made many attempts.1-6 This video discusses the technical tips for L-ALPPS after conversion therapy. METHODS: A 56-year-old, HCC patient who performed the abdominal CT showed a 6.0*5.7-cm-sized mass with intrahepatic metastasis. After four cycles of conversion therapy, the patient achieved a radiologic complete response. However, the standardized, remnant liver volume ratio (SRLVR) was only 34%. Thus, L-ALPPS was contemplated. RESULTS: After full mobilization, intraoperative ultrasonography marked the main trunk of MHV. The concept of "Laennec membrane anatomy" was introduced.7 The anterior pedicle (AP) and the posterior pedicle (PP) were elastically suspended along the Laennec membrane. The conventional hilar dissection approach was used to isolate and suspend RHA and the right portal vein (RPV). Then, IRHV and short hepatic vein were clipped and cut. The Pringle maneuver was used intermittently during the parenchymal transection. Hepatic resection was performed from the caudal to the cranial side along MHV after RPV was ligated. The RHV was elastically suspended after hepatic resection. The omentum was used to cover the resection surface. Stage 2, preoperative SRLVR increased to 68.3%. The adhesion of the right hemiliver was bluntly separated. AP, PP, and RHV were divided by the stapler respectively. Operation time and bleeding volume for stage-1 surgery and stage-2 surgery were 240 min and 80 min, 200 ml and 250 ml, respectively. The postoperative recovery was uneventful. CONCLUSIONS: L-ALPPS as a surgical option seems to be feasible and safe for intermediate-advanced HCC after conversion therapy.

A single-center initial experience on laparoscopic pancreatic operation combined with hepatic arterial resection and reconstruction.

Objective: This study aims to summarize our single-center initial experience in laparoscopic pancreatic operation (LPO) combined with hepatic arterial resection and reconstruction, as well as to demonstrate the feasibility, safety, and key surgical procedure for LPO. Methods: We retrospectively analyzed 7 patients who had undergone LPO combined with hepatic arterial resection and reconstruction in our center from January 2021 to December 2022. The clinical data of these 7 patients were collected and analyzed. Results: In our case series, two patients underwent passive arterial resection and reconstruction due to iatrogenic arterial injury, and five patients underwent forward arterial resection and reconstruction due to arterial invasion. The arterial anastomosis was successful in 5 cases, including 2 cases of end-to-end in situ and 3 cases of arterial transposition, and the vascular reconstruction time was 38.28 ± 15.32 min. There were two conversions to laparotomy. The postoperative recovery of all patients was uneventful, with one liver abscess (Segment 4) and no Clavien III-IV complications. We also share valuable technical feedback and experience gained from the initial practice. Conclusions: Based on the surgeon's proficiency in open arterial resection and reconstruction and laparoscopic technique. This study demonstrated the feasibility of total laparoscopic hepatic arterial resection and reconstruction in properly selected cases of arterial involvement or iatrogenic arterial injury. Our initial experience provides valuable information for laparoscopic pancreas surgery with arterial resection and reconstruction.

Strategic Approach to Aberrant Hepatic Arterial Anatomy during Laparoscopic Pancreaticoduodenectomy: Technique with Video.

BACKGROUND: It is critical for every pancreatic surgeon to determine how to protect the aberrant hepatic artery intraoperatively in order to safely implement laparoscopic pancreatoduodenectomy (LPD). "Artery-first" approaches to LPD are ideal procedures in selected patients with pancreatic head tumors. Here, we described our surgical procedure and experience of aberrant hepatic arterial anatomy-LPD (AHAA-LPD) in a retrospective case series. In this study, we also sought to confirm the implications of the combined SMA-first approach on the perioperative and oncologic outcomes of AHAA-LPD. METHODS: From January 2021 to April 2022, the authors completed a total of 106 LPDs, of which 24 patients underwent AHAA-LPD. We evaluated the courses of the hepatic artery via preoperative multi-detector computed tomography (MDCT) and classified several meaningful AHAAs. The clinical data of 106 patients who underwent AHAA-LPD and standard LPD were retrospectively analyzed. We compared the technical and oncological outcomes of the combined SMA-first approach, AHAA-LPD, and the concurrent standard LPD. RESULTS: All the operations were successful. The combined SMA-first approaches were used by the authors to manage 24 resectable AHAA-LPD patients. The mean age of the patients was 58.1 ± 12.1 years; the mean operation time was 362 ± 60.43 min (325-510 min); blood loss was 256 ± 55.72 mL (210-350 mL); the postoperation ALT and AST were 235 ± 25.65 IU/L (184-276 IU/L) and 180 ± 34.43 IU/L (133-245 IU/L); the median postoperative length of stay was 17 days (13.0-26.0 days); the R0 resection rate was 100%. There were no cases of open conversion. The pathology showed free surgical margins. The mean number of dissected lymph nodes was 18 ± 3.5 (14-25); the number of tumor-free margins was 3.43 ± 0.78 mm (2.7-4.3 mm). There were no Clavien-Dindo III-IV classifications or C-grade pancreatic fistulas. The number of lymph node resections was greater in the AHAA-LPD group (18 vs. 15, p < 0.001). Surgical variables (OT) or postoperative complications (POPF, DGE, BL, and PH) showed no significant statistical differences in both groups. CONCLUSIONS: In performing AHAA-LPD, the combined SMA-first approach for the periadventitial dissection of the distinct aberrant hepatic artery to avoid hepatic artery injury is feasible and safe when performed by a team experienced in minimally invasive pancreatic surgery. The safety and efficacy of this technique need to be confirmed in large-scale-sized, multicenter, prospective randomized controlled studies in the future.

PNI-Based Nomograms to Predict Tumor Progression and Survival for Patients with Unresectable Hepatocellular Carcinoma Undergoing Transcatheter Arterial Chemoembolization.

BACKGROUND: The relationship between the prognostic nutritional index (PNI) and the prognosis of malignancy has been increasingly mentioned in recent research. This study aimed to construct nomograms based on the PNI to predict tumor progression and survival in patients with unresectable hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: The development set included 785 patients who underwent their first TACE between 2012 and 2016, and the validation set included 336 patients who underwent their first TACE between 2017 and 2018. The clinical outcomes included the time to progression (TTP) and overall survival (OS). Cox regression was applied to screen for independent risk factors of TTP and OS in the development set, and PNI-based nomograms were constructed for TTP and OS. The predictive performance of nomograms was conducted through the C-index, calibration curves, and decision analysis curves in the development set and validation set. RESULTS: After multivariate analysis, the prognostic predictors of both TTP and OS included portal vessel invasion, extrahepatic metastasis, tumor number, alpha-fetoprotein (AFP) level, longest tumor diameter, and PNI. Furthermore, the Child-Pugh classification and platelets (PLTs) were independent risk factors for OS only. Nomograms for predicting TTP and OS were constructed using TTP and OS prognostic factors. In the development set and the validation set, the C-index of the TTP nomograms was 0.699 (95% confidence interval (CI): 0.680-0.718) and 0.670 (95%CI: 0.638-0.702), and the C-index of the OS nomograms was 0.730 (95%CI: 0.712-0.748) and 0.700 (95%CI: 0.665-0.723), respectively. CONCLUSION: Nomograms based on the PNI can effectively predict tumor progression and survival in patients with unresectable HCC undergoing TACE.

Transradial versus transfemoral approach for TACE: a retrospective study.

OBJECTIVE: Transcatheter arterial chemoembolization (TACE) has been widely applied in the treatment of hepatocellular carcinoma (HCC). Our study aimed to investigate the feasibility and efficacy of transradial access as an alternative to transfemoral access for TACE. METHODS: Patients undergoing TACE were divided into the radial artery (RA) route group or the femoral artery (FA) route group according to the operation approach, namely, transradial or transfemoral access. We retrospectively analysed the clinical characteristics, technical outcomes, clinical efficacy and incidence of adverse events to compare the two technologies for intervention for HCC. RESULTS: Transradial access was found to achieve superior technical outcomes and clinical efficacy, as the patients in the RA group had a lower rate of hepatic arterial spasm, a higher partial response rate and a lower progression rate than the patients in the FA group according to the mRECIST evaluations. In contrast, the liver function indices and VAS (visual analogue scale) pain scores were consistent across the two groups. Moreover, patients in the RA group had a shorter length of stay than those in the FA group, despite similar hospitalization expenses. The total adverse events were significantly reduced by transradial access for TACE (72.5% vs. 84.1%, P = 0.027). CONCLUSION: Our study suggested that transradial access is an effective and feasible alternative to transfemoral access for TACE. Large-scale prospective randomized controlled studies are expected.

NAMPT inhibition reduces macrophage inflammation through the NAD+/PARP1 pathway to attenuate liver ischemia-reperfusion injury.

BACKGROUND: Liver ischemia-reperfusion injury (IRI) is a major complication in the perioperative period and often leads to liver failure and even systemic inflammation. Previous studies have suggested that the inflammatory response participated in the liver damage during liver IRI. Nicotinamide phosphoribosyl transferase (NAMPT) is required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD+) levels, catalyzing the rate-limiting step in the NAD + salvage pathway. NAMPT is strongly upregulated during inflammation and constitutes an important mechanistic link between inflammatory, metabolic, and transcriptional pathways. The aim of our study was to investigate the role of NAMPT in liver IRI. METHODS: We investigated the effect of pharmacological inhibition of NAMPT with FK866 in models of liver IRI. Liver damage was assessed by HE staining, serum ALT/AST, and TUNEL staining. To examine the mechanism, primary hepatocytes, liver macrophages and RAW264.7 cells were treated with or without NAMPT inhibitors before hypoxia-reoxygenation. Liver macrophages and RAW 264.7 cells activation in vitro was evaluated by western blotting, flow cytometry, and ELISA. RESULT: We found that NAMPT was upregulated in liver IRI. Treatment with the NAMPT inhibitor FK866 ameliorated liver IRI and suppressed inflammation in mice. Although NAMPT plays an important role both in hepatocytes and liver macrophages, we focused on the impact of NAMPT on liver macrophages. The mechanism revealed that FK866 potently inhibited NAMPT activity, as demonstrated by reduced liver NAD+ and intracellular NAD+, resulting in reduced abundance and activity of NAD + -dependent enzymes, including poly (ADP-ribose) polymerase 1 (PARP1), thus inhibiting macrophage M1 polarization by reducing CD86, iNOS, TNF-α, and interleukin (IL)-1ß. Taken together, our data suggested that NAMPT can regulate macrophage polarization through NAD+/PARP1 to ameliorate liver injury, and that FK866-mediated NAMPT blockade may be a therapeutic approach in liver IRI.

Risk of waning humoral responses after inactivated or subunit recombinant SARS-CoV-2 vaccination in patients with chronic diseases: Findings from a prospective observational study in China.

Heterogeneity of antibody responses has been reported in SARS-CoV-2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS-CoV-2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor-binding domain (RBD-IgG) were monitored following a full-course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS-CoV-2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD-IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46-0.93), cancer (OR: 0.65; 95% CI: 0.42-0.99), and diabetes (OR: 0.50; 95% CI: 0.28-0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11-0.76), cancer (OR: 0.38; 95% CI: 0.23-0.62), and diabetes (OR: 0.37; 95% CI: 0.20-0.69) were associated with lower seroconversion of RBD-IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD-IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS-CoV-2 vaccination are impaired in patients with certain chronic diseases.

ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression.

Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.