Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways.

This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe2+, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.

Photodynamic therapy improves the outcome of immune checkpoint inhibitors via remodelling anti-tumour immunity in patients with gastric cancer.

BACKGROUND: Photodynamic therapy (PDT) plays an immunoregulatory role in tumours. Here, we conducted a retrospective patient analysis to evaluate the effectiveness of PDT plus immune checkpoint inhibitors (ICIs) in gastric cancer. Further, we performed a dynamic analysis of gastric cancer patients receiving PDT to clarify its effects on anti-tumour immunity. METHODS: Forty ICI-treated patients that received PDT or not were retrospectively analysed. Five patients with gastric adenocarcinoma were enrolled for sample collection before and after PDT. Single-cell RNA/T cell receptor (TCR) sequencing, flow cytometry and histological exanimation were used to analyse the collected specimens. RESULTS: Patients in PDT group had a significantly better OS after ICI treatment than those in No PDT group. Single-cell analysis identified ten cell types in gastric cancer tissues and four sub-populations of T cells. Immune cell infiltration increased in the tumours after PDT and the circular immune cells showed consistent alterations. TCR analysis revealed a specific clonal expansion after PDT in cytotoxic T lymphocytes (CTL), but a constriction in Tregs. The B2M gene is upregulated in tumour cells after PDT and is associated with immune cell infiltration. Several pathways involving the positive regulation of immunity were enriched in tumour cells in the post-PDT group. The interactions following PDT were increased between tumour cells and effector cells but decreased between Tregs and other immune cells. Some co-stimulatory signaling emerged, whereas co-inhibitory signaling disappeared in intercellular communication after PDT. CONCLUSIONS: PDT elicits an anti-tumour response through various mechanisms and is promising as an adjuvant to enhance ICI benefit.

Predictive Roles of ADAM17 in Patient Survival and Immune Cell Infiltration in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the deadliest malignant tumour worldwide. The metalloproteinase ADAM17 is associated with tumour formation and development; however, its significance in HCC is unclear. This study aimed to investigate the role of ADAM17 in HCC and the correlation between its expression and immune cell infiltration. ADAM17 expression was analysed in pan-cancer and HCC tissues using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Kaplan-Meier survival analysis displayed a negative association between ADAM17 expression and the overall survival of patients with HCC. High ADAM17 expression was linked to poor tumour/node (T/N) stage and alpha fetoprotein (AFP) levels. Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopaedia of Genes and Genomes analyses revealed the enrichment of several pathways, including epithelial-mesenchymal transition, inflammatory response, Hedgehog, and KRAS signalling, in patients with upregulated ADAM17. ADAM17 was shown to be positively correlated with immune cell infiltration and immune checkpoint expression via the Tumour Immune Estimation Resource (TIMER) database and immunohistochemistry analyses. Protein-protein interaction (PPI) network analysis revealed that ADAM17 plays a core role in cancer development and immune evasion. In vitro and in vivo experiments demonstrated that ADAM17 influences HCC growth and metastasis. In conclusion, ADAM17 is upregulated in most cancers, particularly HCC, and is critical in the development and immune evasion of HCC.

Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice.

Hepatic ischemia/reperfusion (I/R) injury may arise after partial hepatectomy and liver transplantation. Neutrophil extracellular traps (NETs) were involved in hepatic I/R injury. This study tested the hypothesis that blocking NETs formation could be a potential therapeutic target against hepatic I/R injury. NETs were excessively formed within liver and in serum of I/R mice models and were testified to be an independent contributor to hepatic I/R injury. Hydroxychloroquine (HCQ) alleviated hepatic I/R injury by inhibiting NETs formation in SCID and c57BL/6 mice models. In vitro, HCQ inhibited neutrophils to form NETs at a concentration of 100 µg/ml. CpG-ODN reversed the effect of HCQ inhibiting NETs formation. HCQ inhibited PAD4 and Rac2 expressions by blocking TLR9. NETs are essential contributors to hepatic I/R injury. HCQ blocking TLR9 protects against hepatic I/R injury by inhibiting NETs formation, which may suggest utility of HCQ or other TLR9 agonists for preventing hepatic I/R injury in clinical practices.

Assessment of the quality of systematic reviews on COVID-19: A comparative study of previous coronavirus outbreaks.

Several systematic reviews (SRs) have been conducted on the COVID-19 outbreak, which together with the SRs on previous coronavirus outbreaks, form important sources of evidence for clinical decision and policy making. Here, we investigated the methodological quality of SRs on COVID-19, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Online searches were performed to obtain SRs on COVID-19, SARS, and MERS. The methodological quality of the included SRs was assessed using the AMSTAR-2 tool. Descriptive statistics were used to present the data. In total, of 49 SRs that were finally included in our study, 17, 16, and 16 SRs were specifically on COVID-19, MERS, and SARS, respectively. The growth rate of SRs on COVID-19 was the highest (4.54/month) presently. Of the included SRs, 6, 12, and 31 SRs were of moderate, low, and critically low quality, respectively. SRs on SARS showed the optimum quality among the SRs on the three diseases. Subgroup analyses showed that the SR topic (P < .001), the involvement of a methodologist (P < .001), and funding support (P = .046) were significantly associated with the methodological quality of the SR. According to the adherence scores, adherence to AMSTAR-2 items sequentially decreased in SRs on SARS, MERS, and COVID-19. The methodological quality of most SRs on coronavirus outbreaks is unsatisfactory, and those on COVID-19 have higher risks of poor quality, despite the rapid actions taken to conduct SRs. The quality of SRs should be improved in the future. Readers must exercise caution in accepting and using the results of these SRs.

Approaching treatment for immunological rejection of living-donor liver transplantation in rats.

BACKGROUND: The anti-immunological rejection therapy for small-for-size syndrome (SFSS) after live donor liver transplantation (LDLT) play a central role in keeping graft survival. The hepatocyte number and grafts function has undergone real-time changes with the proliferation and apoptosis of the grafts after reperfusion. Lacking an accurate and effective treatment regiments or indicators to guide the use of immunosuppressive drugs in SFS liver transplantation has made immunotherapy after SFS liver transplantation an urgent problem to be solved. Herein, we established small-for-size (SFS) and normal size liver transplantation model in rats to explore the effective indicators in guiding immunotherapy, to find an effective way for overcoming SFSS. METHODS: Lewis rats (donors) and BN rats (recipients) were used to mimic allograft liver transplantation and treated with tacrolimus. Local graft immune response was analyzed through haematoxylin and eosin and immunohistochemistry. Flow cytometry was used to assess the overall immune status of recipient. The pharmacokinetics mechanism of immunosuppressive drugs was explored through detecting CYP3A2 expression at mRNA level and protein levels. RESULTS: The results showed the local immune reaction of SFS grafts and systemic immune responses of recipient were significantly increased compared with those in normal size grafts and their recipient at four days after liver transplantation. Regression equation was used to regulate the tacrolimus dose which not only controlled tacrolimus serum concentration effectively but alleviated liver damage and improved survival rate. CONCLUSIONS: This study showed that AST level and tacrolimus serum concentrations are effective indicators in guiding immunotherapy. Regression equation (TD = - 0.494TC-0.0035AST + 260.487) based on AST and tacrolimus serum concentration can be used as a reference for adjustment of immunotherapy after SFS liver transplantation, which is applicable in clinical practice.

Prediction of progression of chronic atrophic gastritis with Helicobacter pylori and poor prognosis of gastric cancer by CYP3A4.

BACKGROUND AND AIM: It has been well documented that Helicobacter pylori (H. pylori) infection is a risk factor for aggravating gastric mucosal atrophy. However, the exact molecular mechanism mediating this process is not fully elucidated. The purpose of this study was to identify biomarkers, which may predict the risk for progression of chronic atrophic gastritis (CAG) with H. pylori. METHODS: GSE27411 was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) between H. pylori-infected samples without CAG and H. pylori-infected CAG samples were analyzed. Gene Ontology and pathway enrichment analyses were performed, followed by protein-protein interaction network construction. We used immunohistochemistry analysis to identify DEGs in 20 chronic gastritis, 20 CAG, and 22 gastric cancer (GC) specimens. RESULTS: A total of 303 upregulated and 26 downregulated DEGs were identified. The pathways enriched by upregulated DEGs were mainly related to fat digestion and absorption, peroxisome proliferator-activated receptor signaling pathway, and chemical carcinogenesis. Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) had the highest degrees in protein-protein interaction network. Moreover, the positive rates of CYP3A4 protein expression in chronic gastritis, CAG, and GC were 10% (2/20), 55% (11/20), and 77.3% (17/22), respectively (P < 0.001). The Kaplan-Meier analysis revealed that elevated expression of CYP3A4 was significantly associated with worse overall survival and first progression, respectively (P < 0.0001). CONCLUSION: According to the findings of this study, the expression of CYP3A4 might be related to the potential carcinogenic transformation of CAG to GC. Therefore, CYP3A4 may be biomarkers to predict progression of CAG and poor prognosis of gastric cancer.

A Novel Method for the Prevention and Treatment of Small-for-Size Syndrome in Liver Transplantation.

BACKGROUND: Currently there is no consensus on the optimal management of small-for-size syndrome following liver transplantation. Here we describe a technique to alleviate portal hypertension and improve the hepatocyte reperfusion in small-for-size liver transplantation in a Lewis rat model. METHODS: The rats underwent trans-portal vein intra-hepatic portosystemic shunt using a self-developed porous conical tube (TPIPSS: Fig. 1) on small-for-size liver transplants (SFS) with right lobe graft. The treatment effect was evaluated by comparing hemodynamic parameters, morphological changes, serum parameters, ET-1 and eNOS expression, hepatocyte proliferation and apoptosis, CYP3A2 levels, postoperative complications, and survival between the two groups with SFS liver transplants. RESULTS: Porous conical prosthesis prolonged the filling time of small-for-size grafts. Moreover, grafts with TPIPSS showed a lower portal vein pressure, improved microcirculatory flow, alleviated histological changes, decreased ET-1 and increased eNOS expressions, and significantly less damage to liver function comparing to grafts without TPIPSS. Mean survival and overall 30-day survival were significantly higher in the TPIPSS group. CONCLUSIONS: These results demonstrate that porous conical tube as trans-portal vein intra-hepatic portosystemic shunt device is an effective way to alleviate portal vein hypertension and improve hepatocyte reperfusion after small-for-size liver transplantation.

[Preventive strategy for post-ERCP pancreatitis].

Endoscopic retrograde cholangiopancreatography (ERCP) is an irreplaceable measure with minimally invasive diagnosis and treatment of endoscopy for biliary and pancreatic diseases, but the related complications associated with ERCP are the highest among the endoscopic procedures. Post-ERCP pancreatitis (PEP) is one of the most common complications with life-threatening in severe cases. Early active prevention can effectively reduce the incidence of post-ERCP pancreatitis. At present, measures including preoperative rectal non-steroidal anti-inflammatory drugs and prophylactic pancreatic stent placement, have definite effective strategy in clinic. Aggressive hydration with lactated Ringer's solution is also a safe and effective way to prevent PEP.

Exploring the therapeutic potential of diterpenes in gastric cancer: Mechanisms, efficacy, and clinical prospects.

Gastric cancer (GC) remains a significant global health challenge, particularly prevalent in East Asia. Despite advancements in various treatment modalities, the prognosis for patients, especially those in advanced stages, remains poor, highlighting the need for innovative therapeutic approaches. This review explores the promising potential of diterpenes, naturally occurring compounds with robust anticancer properties, derived from diverse sources such as plants, marine organisms, and fungi. Diterpenes have shown the ability to influence reactive oxygen species (ROS) generation, ferroptosis, and autophagy, positioning them as attractive candidates for novel cancer therapies. This review explores the mechanisms of action of diterpenes and their clinical implications for the treatment of GC. Additionally, it addresses the challenges in translating these compounds from preclinical studies to clinical applications, emphasizing the need for further research to enhance their therapeutic profiles and minimize potential side effects. The discussion underscores the importance of diterpenes in future anticancer strategies, particularly in the fight against gastric cancer.

FXa-mediated PAR-2 promotes the efficacy of immunotherapy for hepatocellular carcinoma through immune escape and anoikis resistance by inducing PD-L1 transcription.

BACKGROUND: The high metastasis rate is one of the main reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC). Coagulation factor Xa (FXa) and its receptor proteinase-activated receptor-2 (PAR-2) proven to promote tumor metastasis in other forms of cancer. Here, we explore the role and mechanism of FXa in the regulation of resistance of anoikis and immune escape of HCC. METHODS: In vitro and in vivo experiments were conducted to explore the role of FXa in HCC metastasis and its potential mechanism. The effects of FXa inhibitor rivaroxaban on HCC immunotherapy were evaluated using intrahepatic metastasis animal models and clinical trial (No. ChiCTR20000040540). We investigated the potential of FXa inhibition as a treatment for HCC. RESULTS: FXa was highly expressed in HCC and promoted metastasis by activating PAR-2. Mechanistically, FXa-activated PAR-2 endows HCC cells with the ability of anoikis resistance to survive in the circulating blood by inhibiting the extrinsic apoptosis pathway. Furthermore, suspension stimulation-induced phosphorylation of STAT2, which promotes programmed death-ligand 1 (PD-L1) transcription and inhibits the antitumor effects of immune cells by inhibiting the infiltration of CD8+T cells in tumors and the levels of secreted cytokines. In vivo inhibition of FXa with rivaroxaban reduced HCC metastasis by decreasing PD-L1 expression and exhausting tumor-infiltrating lymphocytes. Notably, the combination of rivaroxaban and anti-programmed death-1 monoclonal antibody (anti-PD-1) programmed Death-1 monoclonal antibody (anti-PD-1) induced synergistic antitumor effects in animal models. Most importantly, rivaroxaban improved the objective response rate of patients with HCC to immune checkpoint inhibitors and prolonged overall survival time. CONCLUSIONS: FXa-activated PAR-2 promotes anoikis resistance and immune escape in HCC, suggesting the potential for combining coagulation inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance the therapeutic efficacy of HCC.

Preliminary study of donor volume changes after dual-graft liver transplantation in rats.

Dual-graft liver transplantation (DGLT) expands the pool of donors, ensures the safety of the donors, and treats a potential small for size syndrome (SFSS). However, some of the recipient graft showed atrophy. The cause and mechanism of the unbalanced proliferation and atrophy of dual grafts after clinical DGLT have not been clarified. We established and optimized the rat model of DGLT to explore the causes of growth unbalance. Continuously and dynamically observed bilateral graft volume and portal vein blood flow change by magnetic resonance imaging (MRI) and ultrasound (US). We detected liver function indexes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL). Liver samples from receptors were obtained for morphology, and apoptosis was measured by RT-PCR and western blot. Optimization of the model improved the 7-day survival rate from former 58.3% to 87.5%, and the 30-day survival rate was 68.8%. The volume of the right graft gradually increased, and the left graft atrophied during the 30-day observation period. The portal blood flow of the left graft gradually decreased until the 30th day (0.13 ± 0.01 ml/s) compared with the sham group (0.63 ± 0.05 ml/s), and the right graft significantly increased on the 30th day (0.75 ± 0.11ml/s). The liver function initially increased and then recovered. The total volume (12.52 ± 1.60 ml vs 4.47 ± 0.08 ml) and weight (12.09 ± 1 g vs 4.91 ± 0.18 g) of the graft increased significantly compared to pre-transplantation and reached the level of the sham operation group on the 30th day. The volume and weight of the right graft increased more than those of the left graft (P < 0.05). There was more inflammatory cell infiltration in the left graft, and the right graft had obvious proliferation of hepatocytes and mature bile duct cells. Left grafts were more prone to apoptosis than right grafts (P < 0.05). In conclusion, growth of the right graft is superior to the left; after double liver transplantation, perfusion blood flow and apoptosis may be the reason contributing to the volume differences in dual grafts.

Molecular mechanism underlying epithelial-mesenchymal transformation and cisplatin resistance in esophageal squamous cell carcinoma.

Esophageal cancer (EC) occupies the seventh spot of the most prevalent malignancy cancer ailments worldwide and the sixth leading cause of cancer-related death. Esophageal squamous cell carcinoma (ESCC) is also the most predominant histological subtype of EC, and cisplatin (DDP) is commonly used as a first-line chemotherapeutic drug for the late advanced stages of the disease. However, the emergence of drug resistance during clinical treatment possesses a significant challenge to the therapeutic success and patient outcomes. Collectively, the epithelial-mesenchymal transformation (EMT) is a process in which transcription factors are induced to regulate the expression of epithelial and stromal markers to promote the differentiation of epithelial cells into stromal cells. Recent studies have demonstrated a close association between EMT and chemotherapy resistance in tumor cells, with concrete evidence of reciprocal reinforcement. Therefore, in this review, we elucidate the molecular mechanism underlying ESCC, shed light on the mechanisms driving DDP resistance, and provide insights into the intricate interplay between EMT and ESCC. We have aimed to provide some new hypotheses and perspectives that may address-inform future therapeutic strategies for ESCC treatment.

Photodynamic therapy combined with systemic chemotherapy for unresectable extrahepatic cholangiocarcinoma: A systematic review and meta-analysis.

BACKGROUND: Extrahepatic cholangiocarcinoma (ECC) is a tumor with high invasiveness and poor outcome. The current treatments for unresected ECC are not ideal. Novel strategies are needed to improve the outcomes of patients with unresected ECC. Photodynamic therapy (PDT) plus chemotherapy is one of the promising interventions for ECC patients. We conducted this systematic review to determine the efficacy and safety of PDT plus chemotherapy in unresected ECC patients. METHODS: Databases of PubMed, Cochrane Library, Embase, and Web of science were searched from inception to July 2022. Studies that compared PDT plus chemotherapy to PDT alone or chemotherapy alone in patients with unresected ECC were included. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled for overall survival (OS) and adverse events, respectively. RESULTS: Seven eligible studies were finally included. There are four studies on PDT plus chemotherapy vs. chemotherapy alone and three studies on PDT plus chemotherapy vs. PDT alone. The meta-analysis showed that PDT plus chemotherapy had a significantly better OS than chemotherapy or PDT alone (PDT+chemotherapy vs. chemotherapy alone, HR: 0.69, p = 0.02; PDT+chemotherapy vs. PDT alone, HR:0.36, p<0.01). The occurrence of cholangitis, abscess, and photosensitivity reaction in PDT plus chemotherapy were comparable to either chemotherapy alone or PDT alone (p>0.05). CONCLUSION: The combination of PDT and chemotherapy can improve patient survival for unresected ECC without increased adverse events. It may be a potential standard therapy in the future management of ECC.

Utility of near-infrared fluorescence imaging with indocyanine green in resection of oesophageal squamous cell carcinoma: A literature review and a case report.

BACKGROUND: Surgery remains the main primary treatment for non-advanced oesophageal cancer. Conventional thoracotomy and laparotomy can result in severe trauma, slow recovery, more complications, low quality of life, and reduced survival outcomes. Laparoscopic surgery has reduced the above-mentioned problems. However, some challenges remain associated with this approach, such as lymphadenectomy, anastomotic leakage, and inadequate surgical margins. Near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) in combination with laparoscopic surgery, provides real-time navigation throughout the entire surgical procedure. CASE PRESENTATION: A middle-aged male patient presented to our health centre with progressive dysphagia for > 2 months. Endoscopy and biopsy revealed oesophageal squamous cell carcinoma 34 cm from the incisors (tumour node metastasis classification (TNM) T3N1M0 IIIB). ICG imaging fluorescence laparoscopic surgery was successfully performed to complete the oesophagectomy and oesophageal and tubular stomach anastomosis by accurately locating the lesion, retaining adequate upper and lower margins, visually dissecting the lymph nodes, and testing the anastomotic blood supply. The postoperative TNM stage was T2N0M0 ⅡA. The patient recovered quickly without complications. Postoperative chemotherapy was administered. After three years of follow-up, the patient had no recurrence or complications. CONCLUSIONS: Fluorescence laparoscopy provides an excellent surgical treatment modality for patients with oesophageal cancer.

Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors.

The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.