Mesenchymal stem cells transplantation combined with IronQ attenuates ICH-induced inflammation response via Mincle/syk signaling pathway.

BACKGROUND: Intracerebral hemorrhage (ICH) is a severe brain-injured disease accompanied by cerebral edema, inflammation, and subsequent neurological deficits. Mesenchymal stem cells (MSCs) transplantation has been used as a neuroprotective therapy in nervous system diseases because of its anti-inflammatory effect. Nevertheless, the biological characteristics of transplanted MSCs, including the survival rate, viability, and effectiveness, are restricted because of the severe inflammatory response after ICH. Therefore, improving the survival and viability of MSCs will provide a hopeful therapeutic efficacy for ICH. Notably, the biomedical applications of coordination chemistry-mediated metal-quercetin complex have been verified positively and studied extensively, including growth-promoting and imaging probes. Previous studies have shown that the iron-quercetin complex (IronQ) possesses extraordinary dual capabilities with a stimulating agent for cell growth and an imaging probe by magnetic resonance imaging (MRI). Therefore, we hypothesized that IronQ could improve the survival and viability of MSCs, displaying the anti-inflammation function in the treatment of ICH while also labeling MSCs for their tracking by MRI. This study aimed to explore the effects of MSCs with IronQ in regulating inflammation and further clarify their potential mechanisms. METHODS: C57BL/6 male mice were utilized in this research. A collagenase I-induced ICH mice model was established and randomly separated into the model group (Model), quercetin gavage group (Quercetin), MSCs transplantation group (MSCs), and MSCs transplantation combined with IronQ group (MSCs + IronQ) after 24 h. Then, the neurological deficits score, brain water content (BWC), and protein expression, such as TNF-α, IL-6, NeuN, MBP, as well as GFAP, were investigated. We further measured the protein expression of Mincle and its downstream targets. Furthermore, the lipopolysaccharide (LPS)-induced BV2 cells were utilized to investigate the neuroprotection of conditioned medium of MSCs co-cultured with IronQ in vitro. RESULTS: We found that the combined treatment of MSCs with IronQ improved the inflammation-induced neurological deficits and BWC in vivo by inhibiting the Mincle/syk signaling pathway. Conditioned medium derived from MSCs co-cultured with IronQ decreased inflammation, Mincle, and its downstream targets in the LPS-induced BV2 cell line. CONCLUSIONS: These data suggested that the combined treatment exerts a collaborative effect in alleviating ICH-induced inflammatory response through the downregulation of the Mincle/syk signaling pathway following ICH, further improving the neurologic deficits and brain edema.

Adjuvant therapy with gemcitabine and stereotactic body radiation therapy versus gemcitabine alone for resected stage II pancreatic cancer: a prospective, randomized, open-label, single center trial.

BACKGROUND: The role of adjuvant radiation in pancreatic adenocarcinoma (PDAC) remains unclear. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II PDAC. METHODS: In this single-center randomized controlled trial, patients with stage II PDAC that underwent margin-negative resection were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. RESULTS: Forty patients were randomly assigned to treatment between Sep 1, 2015 and Mar 31, 2018. Of these, 38 were included in the intention-to-treat analysis (20 in gemcitabine arm and 18 in gemcitabine plus SBRT arm). The median RFS and OS were 9.70, 28.0 months in the gemcitabine arm and 5.30, 15.0 months in the gemcitabine plus SBRT arm (RFS, P = 0.53; OS, P = 0.20), respectively. The median LRFS in both arms was unreached (P = 0.81). Grade 3 or 4 adverse events were all comparable between the two arms. Evaluation of data from the enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence-free survival. CONCLUSIONS: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II PDAC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02461836 . Registered 03/06/2015.

Comprehensive Clinical Analysis of Gallbladder Neuroendocrine Neoplasms: A Large-Volume Multicenter Study During One Decade.

BACKGROUND: This study aimed to comprehensively investigate the clinicopathologic characteristics and therapeutic situations of gallbladder neuroendocrine neoplasms (GB-NENs) in the real world via a multicenter, large-scale cohort study. METHODS: The study searched for patients in 143 hospitals in China and enrolled 154 patients with GB-NENs diagnosed in 40 hospitals between 2004 and 2021. Clinicopathologic characteristics and therapeutic approaches were analyzed retrospectively. RESULTS: The median age at the initial diagnosis of the patients with GB-NENs was 63 years (range 33-83 years), and 61.7% of the patients were women. Tumor-node-metastasis staging classified 92 patients as stage 3 or above. Based on the 2019 World Health Organization classification, 96 cases (62.3%) were confirmed pathologically as poorly differentiated neuroendocrine carcinomas, 13 cases (8.4%) as well-differentiated neuroendocrine tumors, and 45 cases as mixed neuroendocrine-non-neuroendocrine neoplasms. The liver was the most frequent metastatic site. Immunohistochemistry showed that synaptophysin was most frequently positive (80.4%), followed by chromogranin A (61.7%), and CD56 (58.4%). Computed tomography and magnetic resonance imaging showed more common clear boundaries (25/39 cases) and invasive growth features (27 cases). None of these cases had an accurate diagnosis before surgery, with a misdiagnosis rate of 100%. Surgical resection is the main treatment, and platinum-based chemotherapeutic regimens were preferred as adjuvant therapies for patients with GB-NENs. The available survival data for 74 patients showed an overall survival rate of 59% at 1 year, 33% at 3 years, and 29% at 5 years. No significant difference was found between the patients treated with and those treated without adjuvant chemotherapy. CONCLUSIONS: Gallbladder neuroendocrine neoplasms have high malignancy and a poor prognosis. Importantly, this large-scale cohort study significantly improves our understanding of GB-NENs and will benefit the exploration of its mechanism and treatment modes. Further investigation is necessary to explore the management of this disease.

Alkaloids with acetylcholinesterase inhibitory activity from Corydalis racemosa (Thunb.) Pers.

Two new isoquinoline alkaloids (1 and 2) along with fourteen known alkaloids (3-16) were isolated from Corydalis racemosa (Thunb.) Pers. Their structures were elucidated by analyzing spectroscopic and spectrometric data (NMR, UV, IR, and MS) and comparing their spectroscopic, spectrometric and physicochemical data with the values archived in the literature. The absolute configurations of new compounds were determined via X-ray crystallographic assay and electronic circular dichroism calculations. Acetylcholinesterase (AChE) inhibitory activity of all compounds was evaluated. Compounds 5, 6, 9, 11, and 12 exhibited inhibitory activity against AChE with IC50 values ranged from 10.2 to 63.4 µM.

Liver Transplantation from Voluntary Organ Donor System in China: A Comparison between DBD and DCD Liver Transplants.

BACKGROUND: In China, the cases of liver transplantation (LT) from donation after citizens' death have rose year by year since the citizen-based voluntary organ donor system was initiated in 2010. The objective of our research was to investigate the early postoperative and late long-term outcomes of LT from donation after brain death (DBD) and donation after circulatory death (DCD) according to the current organ donation system in China. METHODS: Sixty-two consecutive cases of LT from donation after citizens' death performed in our hospital between February 2012 and June 2017 were examined retrospectively for short- and long-term outcomes. These included 35 DCD LT and 27 DBD LT. RESULT: Subsequent median follow-up time of 19 months and 1- and 3-year graft survival rates were comparative between the DBD group and the DCD group (81.5% and 66.7% versus 67.1% and 59.7%; P = 0.550), as were patient survival rates (85.2% and 68.7% versus 72.2% and 63.9%; P = 0.358). The duration of ICU stay of recipients was significantly shorter in the DBD group, in comparison with that of the DCD group (1 versus 3 days, P = 0.001). Severe complication incidence (≥grade III) after transplantation was identical among the DBD and DCD groups (48.1% versus 60%, P = 0.352). There was no significant difference in postoperative mortality between the DBD and DCD groups (3 of 27 cases versus 5 of 35 cases). Twenty-one grafts (33.8%) were lost and 18 recipients (29.0%) were dead till the time of follow-up. Malignancy recurrence was the most prevalent reason for patient death (38.8%). There was no significant difference in incidence of biliary stenosis between the DBD and DCD groups (5 of 27 cases versus 6 of 35 cases, P = 0.846). CONCLUSION: Although the sample size was small to some extent, this single-center study first reported that LT from DCD donors showed similar short- and long-term outcomes with DBD donors and justified the widespread implementation of voluntary citizen-based deceased organ donation in China. However, the results should be verified with a multicenter larger study.

Gemcitabine enhances OSI-027 cytotoxicity by upregulation of miR-663a in pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is well-known to be the most deadly malignancy with the worst survival rate of all cancers. Gemcitabine-based chemotherapy is the most common treatment option for pancreatic ductal adenocarcinoma. However, it offers little therapeutic value in many cases due to the rapid development of chemoresistance. MicroRNAs (miRNAs) have been found to play pivotal roles in the chemotherapeutic resistance of PDAC. In the present study, we examined the molecular basis for the effective combination of OSI-027 and gemcitabine (GEM). Firstly, we identified a specific miRNA expression profile in PDAC cells after treatment with either of these drugs. We found that miR-663a was significantly upregulated after treatment with GEM and downregulated after OSI-027 treatment. With combination of the two drugs, miR-663a level was lower than the GEM group, but higher than the OSI-027 group. Real-time quantitative PCR confirmed these observations. To further establish the role of miR-663a in OSI-027 and GEM resistance in pancreatic cancer, we transfected PDAC cells with miR-663a mimic or miR-663a inhibitor. Cell viability and proliferation assays showed that miR-663a mimic enhanced drug sensitivity, while inhibitor promoted drug resistance. Moreover, we found that the combined effect of OSI-027 and GEM disappeared after inhibiting miR-663a. Our study clearly demonstrates that GEM upregulates miR-663a, thereby promoting the sensitivity of pancreatic cancer cells to OSI-027. Our study suggests that miR-663a expression may be a useful indicator of the potential for chemoresistance and provides a potential new therapeutic target to avert chemoresistance in PDAC.

Esophageal neuroendocrine carcinoma complicated with unexpected hyperprocalcitonin: Case report and literature review.

RATIONALE: Neuroendocrine tumors (NETs) with hyperprocalcitonin are relatively rare with a low incidence rate. PATIENT CONCERNS: An afebrile 63-year-old male with persistent low back pain unexpectedly presented with an extreme hyperprocalcitonin. Radiological assessment revealed thickening of the esophageal wall with vertebral bone destruction and liver lesions. Endoscopy showed an irregular-shaped esophageal lesion which turned out to be poorly-differentiated NETs. DIAGNOSIS: Esophageal NETs with multiple metastases. INTERVENTIONS: The patient was treated with chemotherapies, and was evaluated by procalcitonin level and radiology within follow-up. OUTCOME: The procalcitonin levels were altered in line with the therapeutic response and disease progression during the treatment course. LESSONS: Increased procalcitonin occurs in several malignancies with neuroendocrine components, such as NETs of the digestive system.

Combination of transarterial chemoembolization and sorafenib improves outcomes of unresectable hepatocellular carcinoma: an updated systematic review and meta-analysis.

BACKGROUND: The effectiveness of combination therapy of transarterial chemoembolization and sorafenib for unresectable hepatocellular carcinoma are controversial in some studies. This meta-analysis aims to compare efficacy and safety, as well as regional disparities, between transarterial chemoembolization plus sorafenib and transarterial chemotherapy alone for hepatocellular carcinoma. METHODS: We systematically searched multiple databases to select eligible studies. Studies comparing transarterial chemoembolization plus sorafenib and transarterial chemoembolization alone for unresectable hepatocellular carcinoma were included. RESULTS: Thirteen studies including five randomized clinical trials with 2538 patients (1121 in combination therapy group and 1417 in monotherapy group) were selected. The combination therapy significantly improved time to progression (hazard ratio 0.66; 95% confidence interval 0.48-0.89; P = 0.006) and overall survival (hazard ratio 0.57; 95% confidence interval 0.45-0.72; P < 0.001) in Asian region but not in non-Asian countries (overall survival: hazard ratio 0.96, 95% confidence interval 0.73-1.20; time to progression: hazard ratio 1.08, 95% confidence interval 0.73-1.60). Additionally, disease control rate also favored combination therapy (hazard ratio 1.30; 95% confidence interval 1.00-1.69; P = 0.05), which simultaneously caused higher incidences of adverse events, including hand-foot skin reaction (relative ratio 7.03; 95% confidence interval 4.77-10.37), hematological events (relative ratio 3.14; 95% confidence interval 0.99-10.01), diarrhea (relative ratio 2.75; 95% confidence interval 1.74-4.35), hypertension (relative ratio 2.58; 95% confidence interval 1.33-4.99), rash (relative ratio 2.87; 95% confidence interval 1.86-4.43) and alopecia (relative ratio 4.88; 95% confidence interval 1.67-14.13). CONCLUSIONS: The combination of transarterial chemoembolizaiton and sorafenib significantly improves outcomes of unresectable hepatocellular carcinoma compared with transarterial chemoembolization monotherapy, especially in Asian region.

Complete Chloroplast Genome Sequence and Phylogenetic Analysis of Aster tataricus.

We sequenced and analyzed the complete chloroplast genome of Aster tataricus (family Asteraceae), a Chinese herb used medicinally to relieve coughs and reduce sputum. The A. tataricus chloroplast genome was 152,992 bp in size, and harbored a pair of inverted repeat regions (IRa and IRb, each 24,850 bp) divided into a large single-copy (LSC, 84,698 bp) and a small single-copy (SSC, 18,250 bp) region. Our annotation revealed that the A. tataricus chloroplast genome contained 115 genes, including 81 protein-coding genes, 4 ribosomal RNA genes, and 30 transfer RNA genes. In addition, 70 simple sequence repeats (SSRs) were detected in the A. tataricus chloroplast genome, including mononucleotides (36), dinucleotides (1), trinucleotides (23), tetranucleotides (1), pentanucleotides (8), and hexanucleotides (1). Comparative chloroplast genome analysis of three Aster species indicated that a higher similarity was preserved in the IR regions than in the LSC and SSC regions, and that the differences in the degree of preservation were slighter between A. tataricus and A. altaicus than between A. tataricus and A. spathulifolius. Phylogenetic analysis revealed that A. tataricus was more closely related to A. altaicus than to A. spathulifolius. Our findings offer valuable information for future research on Aster species identification and selective breeding.

Salvage Liver Transplant versus Primary Liver Transplant for Patients with Hepatocellular Carcinoma.

The strategy of salvage liver transplantation (SLT) originated for initially resectable and transplantable hepatocellular carcinoma (HCC) to preclude upfront transplantation, with SLT in the case of recurrence. However, SLT remains a controversial approach in comparison to primary liver transplant (PLT). The aim of our study was to conduct a systemic review and meta-analysis to assess the short-term outcomes, overall survival (OS), and disease-free survival (DFS) between SLT and PLT for patients with HCC, stratifying results according to the Milan criteria and donor types. A search of PubMed, EMBASE, and the Cochrane Library was conducted to identify studies comparing SLT and PLT. A fixed effects model and a random effects model meta-analysis were conducted to assess the short-term outcomes, OS, and DFS based on the evaluation of heterogeneity. SLT had superior 1-year, 3-year, and 5-year OS and DFS compared with that of PLT. After classifying data according to donor type and Milan criteria, our meta-analysis revealed: that for deceased-donor liver transplantation (DDLT) recipients, there were no significant differences in 1-year and 3-year OS rate between the SLT group and the PLT group. However, the 5-year OS rate was superior in the SLT group compared to the PLT group. Similarly, SLT had superior 1-year, 3-year, and 5-year OS rate compared to PLT in living-donor liver transplantation (LDLT) recipients. Moreover, 1-year, 3-year, and 5-year DFS were also superior in SLT compared to PLT in both the DDLT and LDLT recipients. In patients within Milan criteria there were no statistically significant differences in 1-year, 3-year, and 5-year OS and DFS between the SLT group and the PLT group. Similarly, in patients beyond Milan criteria, both SLT and PLT showed no significant difference for 1-year, 3-year, and 5-year OS rate. Our meta-analysis included the largest number of studies comparing SLT and PLT, and SLT was found to have significantly better OS and DFS. Moreover, this meta-analysis suggests that SLT has comparable postoperative complications to that of PLT, and thus, SLT may be a better treatment strategy for recurrent HCC patients and patients with compensated liver, whenever feasible, considering the severe organ limitation and the safety of SLT. However, PLT can be referred as a treatment strategy for HCC patients with cirrhotic and decompensated liver.

The implementation of an enhanced recovery after surgery (ERAS) program following pancreatic surgery in an academic medical center of China.

INTRODUCTION: The experience of implementing enhanced recovery after surgery (ERAS) programs in pancreatic surgery is limited. The aim of this study was to evaluate the feasibility of ERAS program in pancreatic surgery in an academic medical center of China. METHODS: Between May 2014 and August 2015, 124 patients managed with an ERAS program following pancreatic surgery (ERAS group), were compared to a historical cohort of 63 patients, treated with traditional perioperative care between August 2013 and April 2014 (no-ERAS group). Postoperative hospital stay (POPH), unplanned reoperation, unplanned readmissions, mortality and complications were compared between the two groups. RESULTS: Mean POPH of all patients was significantly reduced (p = 0.007) from 17.1 days (no-ERAS group) to 11.7 days (ERAS group). Especially, mean POPH was reduced significantly in ERAS group of patient with no (7.0 vs. 8.7, p = 0.020) or grade I-II (10.6 vs. 14.4, p = 0.001) complications. There was no difference of complication grades and types between two groups, as well as the rate of mortality, unplanned reoperation and readmission. CONCLUSION: The ERAS program is safe and feasible for patients undergoing pancreatic surgery, and it can decrease the postoperative hospital stay.

Establishment of an experimental mouse model of trauma-hemorrhagic shock.

This study established an experimental mouse model of trauma-hemorrhagic shock (THS). THS-induced mice (C57BL/6J, n=33) were subjected to femoral fracture, ischemia for 90 min, and resuscitation for 15 min. The sham-operated mice (C57BL/6J, n=33) underwent the same anesthetic and surgical procedures, but neither trauma-hemorrhage nor fluid resuscitation were performed. Mean arterial pressure (MAP) and microvascular tissue perfusion over the small intestine, liver, and left kidney were longitudinally measured in all mice. Blood was collected for analysis at baseline and 3, 6, 12, and 24 h post resuscitation, and the small intestine, liver, and left kidney were resected for hematoxylin and eosin staining 24 h post resuscitation. Compared with the sham group, MAP and microvascular tissue perfusion over the small intestine, liver, and left kidney were all significantly reduced in the THS group at the end of hemorrhage. Following resuscitation, no significant differences were observed between the groups. THS induction was associated with significantly increased plasma concentrations of Cr, AST, CPK, IL-6, IL-10, and TNF-α from the baseline values by two- to three-fold after the hemorrhage phase, and THS-induced mice demonstrated significantly increased histological injury scores. The rapid drop in MAP and microvascular tissue perfusion observed following THS induction, and the gradual recovery post resuscitation, reflects the successful establishment of a THS experimental mouse model.

A novel recirculating flow-perfusion bioreactor for periosteal chondrogenesis.

PURPOSE: Previous research indicated that engineered cartilage was soft and fragile due to less extracellular matrix than native articular cartilage. Consequently, the focus of this study was mostly confined to application in vitro function. In order to generate 3D engineered cartilage resembling native articular cartilage, we developed a recirculating flow-perfusion bioreactor to simulate the motion of a native diarthrodial joint by offering shear stress and hydrodynamic pressure simultaneously. MATERIALS: The bioreactor we developed offers steady oscillating laminar flow (maximum shear stress of 250 dyne/cm(2)) and hydrodynamic pressure (increased from 0 to 15 psi) simultaneously. The periosteal explants were harvested from the proximal medial tibiae of rabbits and fixed onto PCL scaffold with four corner sutures and cambium layer facing upward, then these periosteal composites (periosteum/ PCL) were placed into the culture chamber of our bioreactor for six weeks in vitro culture. RESULTS: The cartilage yield in our recirculating bioreactor was 75-85%. The outcome was better than the 65-75% in the spinner flask bioreactor (shear stress only) and 17% in static culture. In addition, there was a significant difference in the cell morphology and zonal organisation among the three methods of culture; the engineered cartilage in the recirculating bioreactor presented many more characteristics of native articular cartilage. CONCLUSIONS: If the environment of culture provides the shear stress and hydrodynamic pressure simultaneously, the composition of the engineered cartilage resembles native articular cartilage, including their ECM composition, cell distribution, zonal organisation and mechanical properties.