Clinical utility of two-dimensional shear-wave elastography in monitoring disease course in autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

BACKGROUND: Autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome has a worse prognosis than AIH or PBC alone. Therefore, accurately staging liver fibrosis and dynamically monitoring disease progression are essential. AIM: To investigate the performance of two-dimensional shear-wave elastography (2D-SWE) for noninvasively staging liver fibrosis and assessing the clinical utility of repeated 2D-SWE for monitoring treatment response in AIH-PBC overlap syndrome. METHODS: A total of 148 patients diagnosed with AIH-PBC overlap syndrome were retrospectively enrolled. Among them, 82 patients had a 2D-SWE follow-up time of more than 1 year. The Scheuer scoring system was used to evaluate stages of hepatic inflammation and liver fibrosis. The performance of 2D-SWE for staging liver fibrosis was evaluated with the liver biopsy. Changes in liver stiffness (LS) measured by 2D-SWE in patients with or without complete biochemical remission were evaluated. RESULTS: LS value was strongly correlated with liver fibrosis stage (Spearman r = 0.84, P < 0.0001). The areas under the receiver operating characteristic curves of LS for diagnosing significant fibrosis (≥ S2), severe fibrosis (≥ S3), and cirrhosis (S4) were 0.91, 0.97, and 0.96, respectively. Patients with complete biochemical remission had a considerable decrease in LS values (P < 0.0001). More importantly, the declined LS in patients with S0-S2 was significantly lower than that in patients with S3-S4 (P = 0.0002). In contrast, patients who failed to achieve biochemical remission had a slight but not significant decrease in LS (P = 0.37). CONCLUSION: LS measured by 2D-SWE is an accurate and reliable method in assessing liver fibrosis, especially for diagnosing severe fibrosis (≥ 3) and monitoring treatment response in patients with AIH-PBC overlap syndrome.

[Efficacy Analysis of Transcatheter Arterial Embolization in Acute Non-Variceal Upper Gastrointestinal Bleeding].

Objective: To evaluate the safety and effectiveness of transcatheter arterial embolization (TAE) in the treatment of acute non-variceal upper gastrointestinal bleeding (ANVUGIB), and to guide clinical practice and continue to optimize diagnosis and treatment strategies. Methods: This retrospective study included 266 patients who underwent angiography due to ANVUGIB between March 2016 and March 2021. Data on the positive rate of angiography, the technical success rate and clinical success rate of TAE, and the rebleeding rate and the all-cause mortality within 30 days after TAE treatment were collected, and the influencing factors relevant to the above events were analyzed accordingly. Results: All 266 patients completed angiography--the positive rate of angiography was 54.1% (144/266), the total technical success rate was 97.3% (217/223), the clinical success rate was 73.1% (155/212), and the rebleeding rate and all-cause mortality within 30 days were 26.9% (57/212) and 16.1% (35/217), respectively. This study found that shock index>1 ( OR=5.950; 95% CI: 1.481-23.895; P=0.012), computed tomography angiography (CTA) positive result ( OR=6.813; 95% CI: 1.643-28.252; P=0.008) and interval<24 h ( OR=10.530; 95% CI: 2.845-38.976; P<0.001) were independent predictors of positive angiography. Shock index>1 ( OR=2.544; 95% CI: 1.301-4.972; P=0.006) and INR>1.5 ( OR=3.207; 95% CI: 1.381-7.451; P=0.007) were independent risk factors for rebleeding. Patients with postoperative bleeding ( OR=3.174; 95% CI: 1.164-8.654; P=0.024) and patients with rebleeding after embolization ( OR=34.665; 95% CI: 11.471-104.758; P<0.001) had a higher risk of death within 30 days. Conclusion: TAE is safe and effective in the treatment of ANVUGIB. Patients with shock index>1 and positive CTA are more likely to be angiographic positive, and should undergo angiography as early as possible after bleeding. In addition, rebleeding after embolization deserves high attention.

Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint.

BACKGROUND: The CD47-SIRPα pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRPα axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expression of CD47, the antigen sink and hematologic toxicity, such as anemia and thrombocytopenia, are main problems for developing CD47-targeting therapies. Considering the limited expression of SIRPα, targeting SIRPα is an alternative approach to block the CD47-SIRPα pathway, which may result in differential efficacy and safety profiles. METHODS: SIRPα-targeting antibody BR105 was generated by hybridoma fusion and following humanization. BR105 was characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. The functional activity was determined in in vitro phagocytosis assays by using human macrophages. The effect of BR105 on human T cell activation was studied using an OKT3-induced T-cell proliferation assay and an allogeneic mixed lymphocyte reaction. Human SIRPα-humanized immunodeficient mice were used in cancer models for evaluating the in vivo antitumor efficacy of BR105. Safety was addressed in a repeat-dose toxicity study in cynomolgus monkeys, and toxicokinetic analysis was further evaluated. RESULTS: BR105 shows broad binding activity across various SIRPα variants, and potently blocks the interaction of SIRPα and CD47. In vitro functional assays demonstrated that BR105 synergizes with therapeutic antibodies to promote phagocytosis of tumor cells. Moreover, the combination of BR105 and therapeutic antibody significantly inhibits tumor growth in a xenograft tumor model. Although BR105 may slightly bind to SIRPγ, it does not inhibit T cell activation, unlike other non-selective SIRPα-targeting antibody and CD47-targeting agents. Toxicity studies in non-human primates show that BR105 is well tolerated with no treatment-related adverse effects noted. CONCLUSIONS: The novel and differentiated SIRPα-targeting antibody, BR105, was discovered and displays promising antitumor efficacy in vitro and in vivo. BR105 has a favorable safety profile and shows no adverse effects on T cell functionality. These data support further clinical development of BR105, especially as a therapeutic agent to enhance efficacy when used in combination with tumor-targeting antibodies or antibodies that target other immune checkpoints.

Simultaneous embolization of a spontaneous porto-systemic shunt and intrahepatic arterioportal fistula: A case report.

BACKGROUND: Hepatic encephalopathy (HE) is a frequent and debilitating complication of chronic liver disease. Recurrent HE is strongly linked with spontaneous portosystemic shunts (SPSSs). Intrahepatic arterioportal fistulas (IAPFs) occur rarely but pose a major clinical challenge and may lead to or worsen portal hypertension. Herein, we present a rare case of recurrent HE secondary to a SPSS combined with an IAPF. CASE SUMMARY: A 63-year-old female with primary biliary cirrhosis presented with recurrent disturbance of consciousness for 4 mo. SPSS communicating the superior mesenteric vein with the inferior vena cava and IAPF linking the intrahepatic artery with the portal vein were found on contrast-enhanced abdominal computed tomography. The patient did not respond well to medical treatment. Therefore, simultaneous embolization of SPSS and IAPF was scheduled. After embolization, the symptoms of HE showed obvious resolution. CONCLUSION: The presence of liver vascular disorders should not be neglected in patients with chronic liver disease, and interventional therapy is a reasonable choice in such patients.

[Role of Hemostatic Clips as Guidance during Transcatheter Arterial Embolization in Patients with Peptic Ulcer Bleeding after Endoscopic Treatment Failure].

OBJECTIVE: To investigate the feasibility and clinical efficacy of transcatheter arterial embolization using hemostatic clips as the guidance in the patients with peptic ulcer bleeding after endoscopic treatment failure. METHODS: From February 2009 to October 2018, 33 patients with peptic ulcer bleeding who were treated with transcatheter arterial embolization after endoscopic treatment failure were included in the study. Clinical success rate, 30-d mortality rate and complication rate were observed. RESULTS: According to Forrest grading of ulcer bleeding on endoscopy, 8 patients (24.2%) were defined as Ⅰa, 14 patients (42.5%) Ⅰb, 4 patients (12.1%) Ⅱa, and 7 patients (21.2%) Ⅱb. There were 8 patients not given endoscopic treatment due to poor vision. In 25 patients who received endoscopic treatment, 7 patients did not achieve primary endoscopic hemostasis and 18 patients had re-bleeding despite successful primary hemostasis. The mean interval time from endoscopic treatment failure to transcatheter arterial embolization was (35.42±67.54) h. All patients underwent arterial angiography, and 18 patients with positive angiographic findings were treated with embolization. Among the 15 patients with negative angiographic findings, hemostatic clip could be observed fluoroscopically in 8 patients and used as guidance for embolization. Prophylactic embolization was performed in 4 out of 7 patients without visualization of clip fluoroscopically. The clinical success rates in negative angiographic findings patients with and without clip guidance were 75.0% and 28.6% respectively. The clinical success rate with positive angiographic findings was 66.7%. The overall clinical success rate and 30-d mortality rate were 60.0% and 20.0% respectively. No complication related to embolization was observed. CONCLUSION: The preliminary clinical study demonstrates that transcatheter arterial embolization with the guidance of clips is effective and safe for patients with peptic ulcer bleeding after endoscopic treatment failure.

Chronic aerobic exercise training alleviates myocardial fibrosis in aged rats through restoring bioavailability of hydrogen sulfide.

Age-related fibrosis is attenuated by aerobic exercise; however, little is known concerning the underlying molecular mechanism. To address this question, aged rats were given moderate-intensity exercise for 12 weeks. After exercise in aged rats, hydrogen sulfide levels in plasma and heart increased 39.8% and 90.9%, respectively. Exercise upregulated expression of cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase in heart of aged rats. Furthermore, aged rats were given moderate-intensity exercise for 12 weeks or treated with NaHS (intraperitoneal injection of 0.1 mL/kg per day of 0.28 mol/L NaHS). After exercise in aged rats, Masson-trichrome staining area decreased 34.8% and myocardial hydroxyproline levels decreased 29.6%. Exercise downregulated expression of collagen-I and α- smooth muscle actin in heart of aged rats. Exercise in aged rats reduced malondialdehyde levels in plasma and heart and 3-nitrotyrosine in heart. Exercise in aged rats reduced mRNA and protein expression of C/EBP homologous protein, glucose regulated protein 78, and X-box protein 1. Exercise also reduced mRNA and protein expression of interleukin 6 and monocyte chemotactic protein 1and suppressed activation of c-Jun N-terminal kinase in aging heart. Similar effects were demonstrated in aged rats treated with NaHS. Collectively, exercise restored bioavailability of hydrogen sulfide in the heart of aged rats, which partly explained the benefits of exercise against myocardial fibrosis of aged population.

Contribution of receptor for advanced glycation end products to vasculature-protecting effects of exercise training in aged rats.

The aim of present work was to investigate the underlying mechanism of vasculature-protecting effects of exercise training in aged rats. Experiment 1: aged rats were given moderate-intensity exercise for 12 weeks. Exercise training suppressed advanced glycation evidenced by reduced activity of aldose reductase, increased activity of glyoxalase 1, reduced levels of methylglyoxal and N(ε)-(carboxymethyl) lysine, and decreased expression of receptor for advanced glycation end products (RAGE) in aged aortas. Experiment 2: aged rats were given moderate-intensity exercise for 12 weeks or treated with FPS-ZM1, an inhibitor of RAGE. Exercise training attenuated aortic stiffening with age marked by reduced collagen levels, increased elastin levels and reduced pulse wave velocity (PWV), and prevented aging-related endothelial dysfunction marked by restored endothelium-mediated vascular relaxation of aortas in response to acetylcholine. Exercise training in aging aortas reduced formation of malondialdehyde, 3-nitrotyrosin and reactive oxygen species, increased GSH/GSSG ratio, suppressed activation of NFκB, and reduced levels of IL-6 and chemokine (C-C motif) ligand 2. Similar effects were demonstrated in aged rats treated with FPS-ZM1. Collectively, exercise suppressed advanced glycation in the aortas of aged rats, which, at least in part, explained the vasculature-protecting effects of exercise training in aged population.

Contribution of renin-angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats.

INTRODUCTION: It is well known that exercise alleviates aortic remodeling and preserves endothelial function in spontaneously hypertensive rats (SHRs). However, the underlying molecular mechanism remains unclear. This study aimed to investigate the role of renin-angiotensin system (RAS) components in exercise-induced attenuation of aortic remodeling and improvement of endothelial function in an animal model of human essential hypertension. METHODS: The 10-week-old male SHR and age-matched normotensive Wistar-Kyoto rats were given moderate-intensity exercise for 12weeks (four groups, n=80-86 in each group). RESULTS: In this work, exercise training reduced blood pressure and effectively attenuated aortic remodeling, marked by a reduction in aortic weight/length, wall thickness, and aortic levels of elastin and hydroxyproline, and improved endothelium-mediated vascular relaxations of aortas in response to acetylcholine. Exercise training in SHR reduced angiotensin II (AngII) levels and enhanced Ang-(1-7) levels in aortas. Exercise training in SHR suppressed aortic angiotensin-converting enzyme (ACE) and AngII type 1 receptor (AT1R) messenger RNA (mRNA) levels and protein expression and up-regulated ACE2, AngII type 2 receptor, and Mas mRNA levels and protein expression. In addition, exercise training in SHR increased levels of microRNA-27a (targeting ACE) and microRNA-155 (targeting AT1R) and decreased levels of microRNA-143 (targeting ACE2) in the aortas. CONCLUSION: Chronic aerobic exercise training improved RAS balance in the aortas, which may in part explain the protective effect of exercise on aortic function and structure. SUMMARY: Chronic aerobic exercise training improved RAS balance in the aortas, which may explain the protective effect of exercise on aortic function and structure, at least in part.

Chronic aerobic exercise training attenuates aortic stiffening and endothelial dysfunction through preserving aortic mitochondrial function in aged rats.

Aging leads to large vessel arterial stiffening and endothelial dysfunction, which are important determinants of cardiovascular risk. The aim of present work was to assess the effects of chronic aerobic exercise training on aortic stiffening and endothelial dysfunction in aged rats and investigate the underlying mechanism about mitochondrial function. Chronic aerobic exercise training attenuated aortic stiffening with age marked by reduced collagen concentration, increased elastin concentration and reduced pulse wave velocity (PWV), and prevented aging-related endothelial dysfunction marked by improved endothelium-mediated vascular relaxation of aortas in response to acetylcholine. Chronic aerobic exercise training abated oxidative stress and nitrosative stress in aortas of aged rats. More importantly, we found that chronic aerobic exercise training in old rats preserved aortic mitochondrial function marked by reduced reactive oxygen species (ROS) formation and mitochondrial swelling, increased ATP formation and mitochondrial DNA content, and restored activities of complexes I and III and electron-coupling capacity between complexes I and III and between complexes II and III. In addition, it was found that chronic aerobic exercise training in old rats enhanced protein expression of uncoupling protein 2 (UCP-2), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), manganese superoxide dismutase (Mn-SOD), aldehyde dehydrogenase 2 (ALDH-2), prohibitin (PHB) and AMP-activated kinase (AMPK) phosphorylation in aortas. In conclusion, chronic aerobic exercise training preserved mitochondrial function in aortas, which, at least in part, explained the aorta-protecting effects of exercise training in aging.

Contribution of hydrogen sulfide and nitric oxide to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats.

It is well known that exercise training attenuates aortic remodeling and improves endothelial function in spontaneously hypertensive rats (SHR). However, the underlying molecular mechanism remains unclear. Hydrogen sulfide (H(2)S) and nitric oxide (NO), as two established physiologic messenger molecules, have important roles in the development of aortic remodeling and endothelial dysfunction in hypertensive animals and patients. In this work, it was found that exercise training had no significant effect on blood pressure, but effectively attenuated baroreflex dysfunction in SHR. Exercise training in SHR attenuated aortic remodeling and improved endothelium-mediated vascular relaxations of aortas in response to acetylcholine. Interestingly, exercise training in SHR restored plasma H(2)S levels and aortic H(2)S formation and enhanced levels of mRNA for cystathionine γ-lyase in aortas. Furthermore, exercise training in SHR resulted in augmentation of nitrite and nitrate (NOx) contents and reduction of asymmetric dimethylarginine contents of aortas, upregulation of dimethylarginine dimethylaminohydrolase 2, and phosphorylation of nitric oxide synthase 3, but had no significant effect on protein levels of NOS3. In addition, exercise training could effectively reduce malondialdehyde production and suppressed formation of O(2) (-), and OONO(-) in aortas of SHR through enhancing activities of superoxide dismutase and catalase, and suppressing NADPH oxidase activity. In conclusion, exercise training ameliorates aortic hypertrophy and endothelial dysfunction, possibly via restoring bioavailabilities of hydrogen sulfide and nitric oxide in SHR.

Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature.

PURPOSE: Tumor associated macrophages (TAMs) are considered with the capacity to have both negative and positive effects on tumor growth. The prognostic value of TAM for survival in patients with solid tumor remains controversial. EXPERIMENTAL DESIGN: We conducted a meta-analysis of 55 studies (n = 8,692 patients) that evaluated the correlation between TAM (detected by immunohistochemistry) and clinical staging, overall survival (OS) and disease free survival (DFS). The impact of M1 and M2 type TAM (n = 5) on survival was also examined. RESULTS: High density of TAM was significantly associated with late clinical staging in patients with breast cancer [risk ratio (RR)  = 1.20 (95% confidence interval (CI), 1.14-1.28)] and bladder cancer [RR = 3.30 (95%CI, 1.56-6.96)] and with early clinical staging in patients with ovarian cancer [RR = 0.52 (95%CI, 0.35-0.77)]. Negative effects of TAM on OS was shown in patients with gastric cancer [RR = 1.64 (95%CI, 1.24-2.16)], breast cancer [RR = 8.62 (95%CI, 3.10-23.95)], bladder cancer [RR = 5.00 (95%CI, 1.98-12.63)], ovarian cancer [RR = 2.55 (95%CI, 1.60-4.06)], oral cancer [RR = 2.03 (95%CI, 1.47-2.80)] and thyroid cancer [RR = 2.72 (95%CI, 1.26-5.86)],and positive effects was displayed in patients with colorectal cancer [RR = 0.64 (95%CI, 0.43-0.96)]. No significant effect was showed between TAM and DFS. There was also no significant effect of two phenotypes of TAM on survival. CONCLUSIONS: Although some modest bias cannot be excluded, high density of TAM seems to be associated with worse OS in patients with gastric cancer, urogenital cancer and head and neck cancer, with better OS in patients with colorectal cancer.