A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Predictors and risk factors of bile duct injury after transcatheter arterial chemoembolization for hepatocellular carcinoma.

PURPOSE: Bile duct injury is a serious complication after transcatheter arterial chemoembolization (TACE). If it is not detected early and treated actively, it will not only affect the subsequent tumor-related treatment of hepatocellular carcinoma (HCC) patients, but also may lead to serious consequences such as infection, liver failure and even death. To analyze the risk factors of bile duct injury after TACE in patients with HCC and explore the predictive indicators of bile duct injury after TACE, which is helpful for doctors to detect and intervene early and avoid the occurrence of serious complications. METHOD: We retrospectively analyzed the clinical data of 847 patients with primary hepatocellular carcinoma who underwent TACE for the first time in our interventional department. Patients were divided into two groups according to whether bile duct injury occurred after TACE: (1) bile duct injury group, N = 55; (2) no bile duct injury group, N = 792. The basic data, intraoperative conditions and the outcome of bile duct injury were analyzed. The chi-square test was used for comparison of enumeration data. The Mann-Whitney U test was used for comparison of measurement data. Risk factor analysis was performed using binary logistic regression analysis. RESULTS: Basic data and intraoperative conditions were compared between the bile duct injury group and the group without bile duct injury: preoperative alkaline phosphatase (ALP) (103.24 ± 32.77U/L vs. 89.17 ± 37.35U/L, P = 0.003); history of hepatobiliary surgery (36.4% vs. 20.8%, P = 0.011); intraoperative lipiodol volume (P = 0.007); combined use of gelatin sponge particles (65.5% vs. 35.0%, P < 0.001); hypovascularity (58.2% vs. 24.5%, P < 0.001); and embolization site (P < 0.001). Comparison of postoperative liver function between bile duct injury group and non-bile duct injury group: postoperative total bilirubin (43.34 ± 25.18umol/L vs. 21.94 ± 9.82umol/L, P < 0.001); postoperative γ-glutamyltransferase(GGT) (188.09 ± 55.62U/L vs. 84.04 ± 36.47U/L, P < 0.001); postoperative ALP(251.51 ± 61.51U/L vs. 99.92 ± 45.98U/L, P < 0.001). CONCLUSION: The dosage of lipiodol in TACE, supplementation of gelatin sponge particles, embolization site, and hypovascularity of the tumor are risk factors for biliary duct injury after TACE. After TACE, GGT and ALP increased ≥ 2 times compared with preoperative indicators as predictors of bile duct injury. Bile duct injury occurring after TACE can achieve good outcomes with aggressive management.

Efficacy and safety analysis of TACE + Donafenib + Toripalimab versus TACE + Sorafenib in the treatment of unresectable hepatocellular carcinoma: a retrospective study.

OBJECTIVE: To compare the efficacy and safety of TACE combined with Donafenib and Toripalimab versus TACE combined with Sorafenib in the treatment of unresectable hepatocellular carcinoma (HCC), aiming to guide personalized treatment strategies for HCC and improve patient prognosis. MATERIALS AND METHODS: A retrospective analysis was conducted on the clinical data of 169 patients with unresectable advanced-stage HCC who underwent treatment at the Interventional Department of Wuhan Union Hospital from January 2020 to December 2022. Based on the patients' treatment strategies, they were divided into two groups: TACE + Donafenib + Toripalimab group (N = 81) and TACE + Sorafenib group (N = 88). The primary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) of the two groups' tumors. The secondary endpoint was the occurrence of treatment-related adverse events in the two groups of patients. RESULTS: The TACE + Donafenib + Toripalimab group showed higher ORR and DCR compared to the TACE + Sorafenib group (66.7% vs. 38.6%, 82.6% vs. 68.2%, P < 0.05). The TACE + Donafenib + Toripalimab group also demonstrated longer median progression-free survival (mPFS) (10.9 months vs. 7.0 months, P < 0.001) and median overall survival (mOS) (19.6 months vs. 10.9 months, P < 0.001) compared to the TACE + Sorafenib group. When comparing the two groups, the TACE + Sorafenib group had a higher incidence of grade 3-4 hypertension (14.8% vs. 4.9%, P = 0.041), higher incidence of diarrhea (all grades) (18.2% vs. 7.4%, P = 0.042), and higher incidence of hand-foot syndrome (all grades) (26.1% vs. 12.3%, P = 0.032). CONCLUSION: TACE combined with Donafenib and Toripalimab demonstrates superior efficacy and safety in treating unresectable HCC patients. This combination therapy may serve as a feasible option to improve the prognosis of unresectable HCC patients.

TACE versus TACE + entecavir versus TACE + tenofovir in the treatment of HBV associated hepatocellular carcinoma.

BACKGROUND: At present, there are a variety of antiviral drugs for HBV in clinical practice, but there is no standard scheme for transcatheter arterial chemoembolization(TACE) combined with antiviral drugs. The aim of this study was to investigate whether TACE must be combined with antiviral therapy in patients of HBV-related hepatocellular carcinoma(HCC). Meanwhile, the efficacy and safety of TACE combined with entecavir and TACE combined with tenofovir in the treatment of HBV-related HCC were compared. METHOD: This study included 536 patients with HBV-related HCC who underwent TACE in Union Hospital from March 2017 to March 2020, and they met the criteria. They were divided into three groups: control group (N = 212): TACE alone; Entecavir group (N = 220): TACE combined with entecavir; and Tenofovir group (N = 228): TACE combined with tenofovir. We conducted a retrospective study to analyze the efficacy and safety of the three groups of patients. RESULTS: Objective response rate(ORR): 29.2% in control group, 54.1% in entecavir group, and 63.2% in tenofovir group (P < 0.05). Disease control rate(DCR): 63.7% in control group, 80.9% in entecavir group, and 88.1% in tenofovir group (P < 0.05). Median overall survival(mOS): control group, 12.2 months; entecavir group, 17.3 months; tenofovir group, 22.5 months (p < 0.05). Median progression-free survival (mPFS): control group, 9.3 months; entecavir group, 15.5 months; tenofovir group, 16.6 months (p < 0.05). At 6 months, there was an increase in creatinine(Cr) and a decrease in glomeruar filtration rate(GFR) in tenofovir group, which were statistically different from control and entecavir groups (p < 0.05). CONCLUSION: TACE combined with entecavir and TACE combined with tenofovir had higher ORR and DCR, longer OS and PFS than TACE alone. The OS of TACE combined with tenofovir was higher than that of TACE combined with entecavir. TACE combined with tenofovir is a safe strategy, but we cannot completely ignore the impact of tenofovir on renal function.

Efficacy and safety analysis of TACE + sunitinib vs. sunitinib in the treatment of unresectable advanced renal cell carcinoma: a retrospective study.

BACKGROUND: Since renal cell carcinoma(RCC) is insensitive to conventional chemoradiotherapy, molecularly targeted drugs are commonly used treatments for unresectable advanced RCC. The aim of this study was to explore the efficacy and safety of TACE + sunitinib vs. sunitinib in the treatment of unresectable advanced RCC. METHODS: This study included 98 patients with unresectable advanced RCC who were treated in Union Hospital from January 2015 to December 2018, and they met the criteria. They were divided into two groups: TACE + Sunitinib group (N = 47) and Sunitinib group (N = 51). We conducted a retrospective study to analyze the efficacy and safety of the two groups of patients. RESULTS: (1)TACE + Sunitinib group: 4 patients (8.5%) achieved CR, 27 patients (57.5%) achieved PR, 9 patients (19.1%) achieved SD, and 7 patients (14.9%) achieved PD. Sunitinib group, 0 patients (0%) achieved CR, 20 patients (39.2%) achieved PR, 14 patients (27.5%) achieved SD, and 17 patients (33.3%) achieved PD. (P = 0.017) (2)ORR: TACE + sunitinib group, 66.0%; sunitinib group, 39.2%. (P = 0.009) (3)DCR: TACE + sunitinib group, 85.1%; sunitinib group, 66.7%. (P = 0.038) (4) In the TACE + sunitinib group, mPFS was 15.6 months, mOS was 35.0 months; in the sunitinib group, the mPFS was 10.9 months, mOS was 25.7 months. (P < 0.001) (5) The incidence of abdominal pain, fever, and vomiting was higher in the TACE + sunitinib group than in the sunitinib group (abdominal pain: 55.3% vs. 13.7%; fever: 61.7% vs. 7.8%; vomiting: 40.4% vs. 19.6%; P < 0.05). The technical success rate of TACE in TACE + Sunitinib group is 100%. CONCLUSIONS: The TACE + sunitinib group had higher ORR and DCR, longer OS and PFS than the sunitinib alone group. TACE combined with sunitinib can play a complementary role and is a safe and effective treatment for advanced RCC.

Efficacy and safety of heparin plus dexamethasone after partial splenic embolization for liver cirrhosis with massive splenomegaly.

PURPOSE: The aim of this study was to investigate the efficacy and safety of the combination of low-molecular-weight heparin + dexamethasone after partial splenic embolization in cirrhotic patients with massive splenomegaly. METHODS: This study included 116 patients with liver cirrhosis complicated with massive splenomegaly who underwent PSE in Union Hospital from January 2016 to December 2019, and they met the criteria. They were divided into two groups: PSE + Hep + Dex group (N = 54) and PSE group (N = 62). We conducted a retrospective study to analyze the efficacy and safety of the two groups of patients. RESULTS: The volume of splenic embolization was 622.34 ± 157.06 cm3 in the PSE + Hep + DEX group and 587.62 ± 175.33 cm3 in the PSE group (P = 0.306). There was no statistically difference in the embolization rate of the spleen between the two groups (P = 0.573). WBC peaked 1 week after PSE and PLT peaked 1 month after PSE in both groups; it gradually decreased later, but was significantly higher than the preoperative level during the 12-month follow-up period. The incidences of abdominal pain (46.3% vs 66.1%, P = 0.039), fever (38.9% vs 75.8%, P < 0.001), PVT (1.9% vs 12.9%, P = 0.026), refractory ascites (5.6% vs 19.4%, P = 0.027) were lower in the PSE + Hep + DEX group than in the PSE group. The VAS score of abdominal pain in PSE group was higher than that in PSE + Hep + DEX group on postoperative days 2-8 (P < 0.05). Splenic abscess occurred in 1(1.6%) patient in the PSE group and none (0.0%) in the PSE + Hep + DEX group (P = 0.349). CONCLUSIONS: The combined use of dexamethasone and low-molecular-weight heparin after PSE is a safe and effective treatment strategy that can significantly reduce the incidence of complications after PSE (such as post-embolization syndrome, PVT, refractory ascites).

Analysis of long-term effect of ureteral balloon dilatation combined with internal and external drainage tube in the treatment of benign ureteral stricture.

PURPOSE: There are few reports about balloon dilatation combined with internal and external drainage tube in the treatment of ureteral stricture under interventional therapy. The aim of the study is to explore the safety, effectiveness and long-term efficacy of this treatment strategy. MATERIALS AND METHODS: It is a retrospective and observational study. From October 2013 to October 2016, 42 patients with benign lower ureteral stricture received interventional treatment. Balloon dilatation combined with internal and external drainage tube implantation were used. There were 25 male patients and 17 female patients. There were 7 cases (16.7%) with congenital ureteral stricture, 12 cases (28.6%) with inflammation, 15 cases (35.7%) with ureteral stricture after lithotomy or lithotripsy, and 8 cases (19.0%) with ureteral stricture after pelvic or abdominal surgery. After the drainage tube was removed, B ultrasound, enhanced CTU or IVP of urinary system were reexamined every six months. The follow-up time was 12-60 months. RESULTS: The age was 52.9 ± 11.6 years. The length of ureteral stricture was 1.1 ± 0.5 cm. 42 patients completed interventional treatment, the technical success rate was 100%, no ureteral perforation, rupture or other complications were identified. Preoperative urea nitrogen 9.2 ± 2.3 mmol/L and creatinine 175.8 ± 82.8umol/L. Urea nitrogen and creatinine were 3.8-9.1 mmol/L and 45.2-189.6 umol/L when removing the drainage tube. There were significant differences in the levels of urea nitrogen and creatinine before and after tube removal (P < 0.05). The ureteral patency rate was 100% at 6 months, 93% at 12 months, 83% at 18 months, 79% at 24 months, 76% at 30 months and 73% at 36-60 months. The overall success rate was 73%. Multivariate Cox regression analysis showed that stenosis length was a risk factor for postoperative patency (P < 0.05). CONCLUSION: Balloon dilatation combined with internal and external drainage tube implantation in the treatment of benign lower ureteral stricture is safe and effective.

Mechanism and risk factors of nausea and vomiting after TACE: a retrospective analysis.

PURPOSE: The mechanism of postoperative nausea and vomiting after TACE is not clear. This study retrospectively analyzed the patient data to explore the mechanism and risk factors of postoperative nausea and vomiting after TACE. MATERIALS AND METHODS: The data of 221 patients who underwent TACE in the interventional department from January 2019 to December 2020 were collected. Including: gender, age, liver function before TACE, etiology of liver cirrhosis, BCLC stage of hepatocellular carcinoma, preoperative use of analgesic drugs, preoperative limosis, previous history of vomiting, history of kinetosis, smoking history, history of drinking, chemotherapeutic drugs used during TACE, Dosage of lipiodol, and occurrence of postoperative nausea and vomiting. RESULTS: There were 116 cases of nausea after TACE, using binary logistic regression analysis, Sig: ALT0.003; ALP0.000; history of vomiting 0.043; kinetosis 0.006; history of alcohol consumption 0.011; preoperative limosis 0.006; dosage of lipiodol (5-10 mL) 0.029, dosage of lipiodol (> 10 mL) 0.001.There were 89 cases of vomiting after TACE, all accompanied by nausea, Sig: ALP0.000; BCLC stage (B) 0.007; kinetosis 0.034; chemotherapeutic drugs 0.015; dosage of lipiodol (5-10 ml) 0.015, dosage of lipiodol (> 10 ml) 0.000; patients used analgesics before TACE 0.034. CONCLUSIONS: Causes of post-TACE nausea and vomiting included operative trauma, aseptic inflammation caused by ischemia and hypoxia, chemotherapeutic drugs, ischemia of liver and bile duct, stress and pain during TACE, and patient factors. ALP, BCLC stage, kinetosis, chemotherapeutic drugs, dosage of lipiodol, and preoperative usage of analgesics were risk factors affecting nausea and vomiting after TACE.

Efficacy and safety analysis of dexamethasone-lipiodol emulsion in prevention of post-embolization syndrome after TACE: a retrospective analysis.

BACKGROUND: To investigate the efficacy and safety of dexamethasone-lipiodol emulsion in the prevention of post-embolization syndrome after TACE. METHOD: The data of 255 patients who underwent TACE in the interventional department from June 2017 to June 2020 were collected. This is a retrospective assessment of patients who were non-randomly treated with dexamethasone in TACE. The patients were divided into two groups: TACE using lipiodol + chemotherapeutic emulsion group (TACE group, N = 133); TACE using lipiodol + dexamethasone + chemotherapeutic emulsion group (TACE + dexamethasone group, N = 122). Primary study endpoint: incidence of abdominal pain, fever, nausea and vomiting 0-72 h after TACE in both groups. Secondary study endpoints: incidence of infection after TACE in both groups. RESULTS: Incidence of post-embolization syndrome after TACE (TACE group vs TACE + dexamethasone group): abdominal pain, 55.6% versus 36.1% (P value 0.002); fever, 37.6% versus 13.1% (P value 0.000); nausea, 60.9% versus 41.0% (P value 0.001); vomiting, 48.1% versus 21.3% (P value 0.000). Incidence of infection after TACE (TACE group vs TACE + dexamethasone group): 1.5% versus 2.5% (P value 0.583). CONCLUSION: The lipiodol + dexamethasone emulsion can significantly reduce the incidence rate of post-embolization syndrome after TACE, with exact effect and high safety.

Quantitative splenic embolization possible: application of 8Spheres conformal microspheres in partial splenic embolization (PSE).

BACKGROUND: To investigate the safety and efficacy of 8Spheres in partial splenic embolization. To explore the possibility of accurate control of splenic embolic volume by quantifying the number of microspheres used during PSE. METHOD: The data of 179 patients who underwent PSE were collected. The patients were divided into two groups: 300-500 um microsphere group (N = 83) and 500-700 um microsphere group (N = 96). The spleen volume before PSE, infarct volume and infarct rate of the spleen after PSE, changes in peripheral blood cells after PSE, postoperative adverse events and incidence of infection were compared between the two groups. RESULTS: 300-500 um group vs 500-700 um group: postoperative spleen volume (cm3): 753.82 ± 325.41 vs 568.65 ± 298.16 (P = 0.008); spleen embolization volume (cm3): 525.93 ± 118.29 vs 630.26 ± 109.71 (P = 0.014); spleen embolization rate: 41.1 ± 12.3% vs 52.4 ± 10.1% (P = 0.021). Leukocytes and platelets were significantly increased after PSE in both groups; leukocyte, 1 month: 4.13 ± 0.91 vs 5.08 ± 1.16 (P = 0.026); 3 months: 4.08 ± 1.25 vs 4.83 ± 0.98 (P = 0.022); platelet, 1 month: 125.6 ± 20.3 vs 138.7 ± 18.4 (P = 0.019); 3 months: 121.8 ± 16.9 vs 134.3 ± 20.1 (P = 0.017). Incidence of abdominal pain after PSE, 72 (86.7%) vs 69 (71.9%), P = 0.027. The incidence of other adverse events and infections after PSE was not statistically different. CONCLUSION: PSE with 8Spheres is safe and effective. The use of 500-700 um microsphere for PSE can make the increase of peripheral blood cells more stable. Each vial of 8Spheres corresponds to a certain volume of splenic embolization, so it is possible to achieve quantitative embolization in PSE.

Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer.

Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1+ ) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8+ T cells and induced CD8+ T-cells apoptosis. Biological and functional assays showed that TREM-1+ TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1+ TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1+ TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1+ TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1+ TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-κß pathway in response to hypoxia and tumor metabolites leading to CCR6+ Foxp3+ Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6+ Foxp3+ Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6+ Foxp3+ Treg recruitment was crucial for TREM-1+ TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1+ TAMs attracting CCR6+ Foxp3+ Tregs, and TREM-1+ TAMs endowed HCC with anti-PD-L1 therapy resistance.

Prospective Comparison of Conventional CTA With Angiography-CT for Identification of Culprit Systemic Arteries in Patients Undergoing Bronchial Artery Embolization for Hemoptysis.

In this prospective study of patients undergoing bronchial artery embolization for hemoptysis, preprocedural conventional CTA identified 86.3% of culprit systemic arteries confirmed by selective angiography, whereas intraprocedural angio-CT identified 97.1%. The findings indicate a role of angio-CT to help identify target vessels for embolization during such procedures.

Characterization and energy potential of food waste from catering service in Hangzhou, China.

Safe disposal of food waste is becoming an impending issue in China with the rapid increase of its production and the promotion of environmental awareness. Food waste from catering services in Hangzhou, China, was surveyed and characterized in this study. A questionnaire survey involving 632 units across the urban districts showed that 83.5% of the food waste was not properly treated. Daily food waste production from catering units was estimated to be 1184.5 tonnes. The ratio of volatile solid to total solid, easily biodegradable matter (including crude fat, crude protein and total starch) content in total solid and the ratio of total organic carbon to nitrogen varied in ranges of 90.1%-93.9%, 60.9%-72.1%, and 11.9-19.9, respectively. Based on the methane yield of 350 mL g VS(-1) in anaerobic batch tests, annual biogas energy of 1.0 × 10(9) MJ was estimated to be recovered from the food waste. Food waste from catering services was suggested to be an attractive clean energy source by anaerobic digestion.

Efficacy Analysis of PTCD + TACE vs PTCD + Apatinib in the Treatment of HCC with Obstructive Jaundice: A Retrospective Study.

PURPOSE: The aim was to evaluate the safety and effectiveness of PTCD combined with TACE in the treatment of hepatocellular carcinoma with obstructive jaundice and to compare the efficacy of TACE in patients with different levels of bilirubin after PTCD. METHODS: The clinical data of 141 patients with HCC complicated with obstructive jaundice were analyzed retrospectively. The patients underwent PTCD first. When the total bilirubin decreased, the patients received TACE or Apatinib treatment. They were divided into two groups: (1) PTCD+TACE group, N=68; (2) PTCD+Apatinib group, N=73. RESULTS: The PTCD+TACE group had higher ORR and DCR than the PTCD+Apatinib group (57.4% vs 12.3%, p < 0.001;80.9% vs 60.3%, p = 0.010). The mPFS of the PTCD+TACE group was longer than that of the PTCD+Apatinib group (7.1 months vs 3.8 months, p < 0.001). The mOS of the PTCD+TACE group was longer than that of the PTCD+Apatinib group(11.5 months vs 7.7 months, p < 0.001). In the subgroup analysis of the PTCD+TACE group, the results showed that the survival benefits of the groups with total bilirubin <2 times and 2-3 times were greater. CONCLUSION: In patients with HCC and obstructive jaundice, superselective TACE(lipiodol+epirubicin emulsion) significantly prolonged OS and PFS compared with Apatinib after using PTCD to reduce total bilirubin to <100umol/L. Patients whose total bilirubin dropped to ≤3 times of the upper limit of normal value after PTCD had longer OS and PFS than patients >3 times.

Transcriptomic Analysis of Cardiac Tissues in a Rodent Model of Coronary Microembolization.

Purpose: Coronary microembolization (CME) can result in cardiac dysfunction, severe arrhythmias, and a reduced coronary flow reserve. Impairment of mitochondrial energy metabolism has been implicated in the progression and pathogenesis of CME; however, its role remains largely undetermined. This study aimed to explore alterations in mitochondria-related genes in CME. Methods: A rat model of CME was successfully established by injecting plastic microspheres into the left ventricle. The cardiac tissues of the two groups were sequenced and mitochondrial functions were assessed. Results: Using RNA-Seq, together with GO and KEGG enrichment analyses, we identified 3822 differentially expressed genes (DEGs) in CME rats compared to control rats, and 101 DEGs were mitochondria-related genes. Notably, 36 DEGs were up-regulated and 65 DEGs were down-regulated (CME vs control). In particular, the oxidative phosphorylation (OXPHOS) and mitochondrial electron transport were obviously down-regulated in the CME group. Functional analysis revealed that CME mice exhibited marked reductions in ATP and mitochondrial membrane potential (MMP), by contrast, the production of reactive oxygen species (ROS) was much higher in CME mice than in controls. Protein-protein interaction (PPI) and quantitative PCR (qPCR) validation suggested that eight hub genes including Cmpk2, Isg15, Acsl1, Etfb, Ndufa8, Adhfe1, Gabarapl1 and Acot13 were down-regulated in CME, whereas Aldh18a1 and Hspa5 were up-regulated. Conclusion: Our findings suggest that dysfunctions in mitochondrial activity and metabolism are important mechanisms for CME, and mitochondria-related DEGs may be potential therapeutic targets for CME.

Efficacy and safety analysis of TACE + PEI + lenvatinib compared with TACE + lenvatinib for the treatment of hepatocellular carcinoma with PVTT: a retrospective study.

Objective: The aim of this study was to investigate the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with percutaneous ethanol injection (PEI) and lenvatinib in HCC patients with PVTT (Vp2-3), thus providing a safe and effective treatment strategy for advanced HCC patients. Materials and methods: Clinical data of 227 patients with unresectable HCC and PVTT treated at the Union Hospital from January 2018 to December 2021 were retrospectively analyzed. The patients were divided into two groups according to their treatment methods: TACE+PEI+lenvatinib group (N=103) and TACE+lenvatinib group (N=124). Results: The proportion of patients with disappearance, shrinkage, or no change of PVTT after treatment was significantly higher in the TACE+PEI+lenvatinib group compared to the TACE+lenvatinib group, with statistical significance (P<0.001). The TACE+PEI+lenvatinib group had higher objective response rate (ORR) (50.5% vs. 25.8%, P<0.001) and disease control rate (DCR) (87.4% vs. 74.2%, P=0.013) than the TACE+lenvatinib group. The median progression-free survival (mPFS) of the TACE+PEI+lenvatinib group was longer than that of the TACE+lenvatinib group (8.1 months vs. 6.5 months, P<0.001). Consistently, the median overall survival (mOS) of the TACE+PEI+lenvatinib group was longer than that of the TACE+lenvatinib group (17.1 months vs. 13.9 months, P<0.001). Conclusion: Among HCC patients with PVTT (Vp2-3), TACE+PEI+lenvatinib is more effective comparing to TACE+lenvatinib in prolonging PFS and OS. The control of PVTT in the TACE+PEI+lenvatinib group was significantly more satisfactory than that in the TACE+lenvatinib group. TACE+PEI+lenvatinib is a safe and effective treatment strategy for HCC patients with PVTT (Vp2-3).

[Effects of Long-term Biochar Addition on Denitrification N2O Emissions from Bacteria and Fungi in Paddy Soil].

Denitrification driven by bacteria and fungi is the main source of nitrous oxide （N2O） emissions from paddy soil. It is generally believed that biochar reduces N2O emissions by influencing the bacterial denitrification process, but the relevant mechanism of its impact on fungal denitrification is still unclear. In this study, the long-term straw carbonization returning experimental field in Changshu Agricultural Ecological Experimental Base of the Chinese Academy of Sciences was taken as the object. Through indoor anaerobic culture and molecular biology technology, the relative contributions of bacteria and fungi to denitrifying N2O production in paddy soil and the related microorganism mechanism were studied under different long-term biochar application amounts （blank, 2.25 t·hm-2, and 22.5 t·hm-2, respectively, expressed by BC0, BC1, and BC10）. The results showed that compared with that in BC0, biochar treatment significantly reduced N2O emission rate, denitrification potential, and cumulative N2O emissions, and the contribution of bacterial denitrification was greater than that of fungal denitrification in all three treatments. Among them, the relative contribution rate of bacterial denitrification in BC10 （62.9%） was significantly increased compared to BC0 （50.8%）, whereas the relative contribution rate of fungal denitrification in BC10 （37.1%） was significantly lower than that in BC0 （49.2%）. The application of biochar significantly increased the abundance of bacterial denitrification functional genes （nirK, nirS, and nosZ） but reduced the abundance of fungal nirK genes. The contribution rate of fungal denitrification was significantly positively correlated with the N2O emission rate and negatively correlated with soil pH, TN, SOM, and DOC. Biochar may have inhibited the growth of denitrifying fungi by increasing pH and carbon and nitrogen content, reducing the abundance of related functional genes, thereby weakening the reduction ability of NO to N2O during fungal denitrification process. This significantly reduces the contribution rate of N2O production during the fungal denitrification process and the denitrification N2O emissions from paddy soil. This study helps to broaden our understanding of the denitrification process in paddy soil and provides a theoretical basis for further regulating fungal denitrification N2O emissions.

Insight into the effects of biochar on manure composting: evidence supporting the relationship between N2O emission and denitrifying community.

Although nitrous oxide (N2O) emissions from composting contribute to the accelerated greenhouse effect, it is difficult to implement practical methods to mitigate these emissions. In this study, the effects of biochar amendment during pig manure composting were investigated to evaluate the inter-relationships between N2O emission and the abundance of denitrifying bacteria. Analytical results from two pilot composting treatments with (PWSB, pig manure + wood chips + sawdust + biochar) or without (PWS, pig manure + wood chips + sawdust) biochar (3% w/w) demonstrated that biochar amendment not only lowered NO2(-)-N concentrations but also lowered the total N2O emissions from pig manure composting, especially during the later stages. Quantification of functional genes involved in denitrification and Spearman rank correlations matrix revealed that the N2O emission rates correlated with the abundance of nosZ, nirK, and nirS genes. Biochar-amended pig manure had a higher pH and a lower moisture content. Biochar amendment altered the abundance of denitrifying bacteria significantly; less N2O-producing and more N2O-consuming bacteria were present in the PWSB, and this significantly lowered N2O emissions in the maturation phase. Together, the results demonstrate that biochar amendment could be a novel greenhouse gas mitigation strategy during pig manure composting.

Efficacy and safety of tyrosine kinase inhibitors plus PD-1 inhibitor in patients with transarterial chemoembolization- refractory hepatocellular carcinoma: a two-center retrospective study.

Object: To investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs: sorafenib and lenvatinib) plus PD-1 inhibitor (camrelizumab) versus TKIs alone in transarterial chemoembolization-refractory (TACE-refractory) hepatocellular carcinoma (HCC). Materials and methods: Data of TACE-refractory HCC patients treated with TACE+TKIs+PD-1 inhibitor (TACE+TKIs+PD-1group) (n=57) or TACE+TKIs (TACE+TKIs group) (n=50) from January 2019 to January 2022 were retrospectively collected and analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were evaluated by univariate and multivariate analyses. Results: Compared with the TKIs group, both PFS and OS were prolonged in the TACE+TKIs+PD-1 group (median PFS: 7 months vs. 5 months, P=0.007; median OS: 17 months vs. 11 months, P=0.002). In multivariate analysis, tumor size and treatment were independent prognostic factors for PFS and OS. The incidence and severity of AEs related to the treatment between the two groups showed no significant difference. Conclusion: The treatment of TACE combined with TKIs plus camrelizumab demonstrated promising efficacy and safety in TACE-refractory HCC.