US-guided high-intensity focused ultrasound in pancreatic cancer treatment: a consensus initiative between Chinese and European HIFU centers.

Purpose: Ultrasound-guided high-intensity focused ultrasound (USgHIFU) represents a safe and effective non-invasive thermoablative technique for managing inoperable pancreatic cancer. This treatment method significantly alleviates disease-related symptoms and reduces pancreatic tumor volume. However, the current body of evidence is constrained by a lack of randomized controlled trials. The utilization of USgHIFU is primarily indicated for patients with unresectable, locally advanced, or metastatic pancreatic cancer, particularly those experiencing symptoms due to a locally advanced primary tumor.Methods: This collaborative consensus paper, involving European and Chinese HIFU centers treating pancreatic cancer, delineates criteria for patient selection, focusing on those most likely to benefit from USgHIFU treatment. Consideration is given to endpoints encompassing symptom alleviation, local response rates, other oncological outcomes, as well as overall and progression-free survival. Additionally, this paper defines relevant contraindications, side effects, and complications associated with USgHIFU. The publication also explores the feasibility and role of USgHIFU within the context of palliative care, including standard systemic chemotherapy.Results: The non-invasive local treatment of advanced pancreatic cancer using HIFU should be regarded as an adjunctive option alongside systemic chemotherapy or best supportive care for managing this aggressive disease. Based on the ability of USgHIFU therapy to mitigate pain and reduce primary tumor volume, it should be considered as a complementary therapy for symptomatic patients with inoperable pancreatic cancer and as a potential means of tumor debulking. The underutilized yet promising USgHIFU exhibits the potential to enhance patients' quality of life by alleviating cancer-related pain. Experts in the field should evaluate this treatment option be evaluated by experts in this field, with this consensus paper potentially serving as a guiding resource for the medical community.Conclusions: US-guided HIFU for advanced pancreatic cancer addresses treatment goals, available options, success rates, and limitations. As a non-invasive, effective local therapy, complementary to chemotherapy and best supportive care, it plays a pivotal role in pain relief, reducing of tumor volume, and potentially improving survival rates.

Establishment of a lipopolysaccharide-induced inflammation model of human fetal colon cells.

BACKGROUND: Inflammatory bowel disease (IBD) is a global health problem and there are few cell models for IBD at present. To culture a human fetal colon (FHC) cell line in vitro and establish an FHC cell inflammation model that meets the requirements for high expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). METHODS AND RESULTS: FHC cells were cultured with various concentrations of Escherichia coli lipopolysaccharide (LPS) in appropriate media for 0.5, 1, 2, 4, 8, 16 and 24 h to stimulate an inflammatory reaction. The viability of FHC cells was detected by a Cell Counting Kit-8 (CCK-8) assay. The transcriptional levels and protein expression changes of IL-6 and TNF-α in FHC cells were detected by Quantitative Real­Time Polymerase Chain Reaction (qRT-PCR) and Enzyme­Linked Immunosorbent Assay (ELISA), respectively. Appropriate stimulation conditions were selected (i.e., LPS concentration and treatment time), based on changes in cell survival rate, and IL-6 and TNF-α expression levels. An LPS concentration higher than 100 µg/mL or a treatment time longer than 24 h resulted in morphological changes and decreased cell survival. By contrast, expression levels of IL-6 and TNF-α significantly increased within 24 h when LPS concentration lower than 100 µg/mL and peaked at 2 h, whilst maintaining cell morphology and viability in FHC cells. CONCLUSION: The treatment of FHC cells with 100 µg/mL LPS within 24 h was optimal in terms of stimulating IL-6 and TNF-α expression.

Intestinal Immune Imbalance is an Alarm in the Development of IBD.

Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.

Aquaporins in Digestive System.

In this chapter, we mainly discuss the expression and function of aquaporins (AQPs) expressed in digestive system. AQPs are highly conserved transmembrane protein responsible for water transport across cell membranes. AQPs in gastrointestinal tract include four members of aquaporin subfamily: AQP1, AQP4, AQP5, and AQP8, and three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP10. In the digestive glands, especially the liver, we discuss four members of aquaporin subfamily: AQP1, AQP4, AQP5, and AQP8, three members of aquaglyceroporin subfamily: AQP7, AQP9, and AQP12. In digestive system, the abnormal expression of AQPs is closely related to the occurrence and development of a variety of diseases. AQP1 is involved in saliva secretion and fat digestion and is closely related to gastric cancer and chronic liver disease; AQP3 is involved in the diarrhea and inflammatory bowel disease; AQP4 regulates gastric acid secretion and is associated with the development of gastric cancer; AQP5 is relevant to gastric carcinoma cell proliferation and migration; AQP7 is the major aquaglyceroporin in pancreatic ß cells; AQP8 plays a role in pancreatic juice secretion and may be a potential target for the treatment of diarrhea; AQP9 plays considerable role in glycerol metabolism and hepatocellular carcinoma; Studies on the function of AQP10 and AQP12 are still limited. Further studies are necessary for specific locations and functions of AQPs in digestive system.

AQP9 suppresses hepatocellular carcinoma cell invasion through inhibition of hypoxia-inducible factor 1α expression under hypoxia.

BACKGROUND AND AIM: Intratumor hypoxia is a hallmark of hepatocellular carcinoma (HCC) and is associated with an aggressive tumor phenotype. Although it has been shown that AQP9 plays an important role in HCC, the relevance between hypoxia and AQP9 is still unknown. METHODS: We established in vitro normoxic or hypoxic models to investigate the role of AQP9 in the regulation of hypoxia-inducible factor 1α (HIF-1α) and hypoxia-enhanced invasion of hepatoma cells. Molecular expression was detected using western blot or quantitative polymerase chain reaction. Cell invasion ability was determined using Transwell invasion assay. In vivo xenograft experiment was used to detect the role of AQP9 on tumor growth. RESULTS: Our present study revealed a decrease in the expression levels of AQP9 in hypoxic microenvironments. Overexpression of AQP9 led to a decreased expression of HIF-1α; conversely, suppression of AQP9 in HCC cells had an opposite effect. Furthermore, up-regulated AQP9 blocked the hypoxic-enhanced invasion of HCC cells. The overexpression of AQP9 inhibited the growth of tumors and HIF-1α expression in vivo. CONCLUSIONS: These data suggest that AQP9 acts as a tumor suppressor in HCC invasion via the regulation of HIF-1α expression in the tumor hypoxic microenvironment.

Potential Benefits of Multimedia-Based Home Catheter Management Education in Patients With Peripherally Inserted Central Catheters: Systematic Review.

BACKGROUND: In recent years, there have been many suggestions to use multimedia as a strategy to fully meet the educational needs of patients with peripherally inserted central catheters. However, the potential benefits remain unreliable in the literature. OBJECTIVE: In this study, we identified the potential benefits of multimedia-based home catheter management education in patients with peripherally inserted central catheters and discussed the clinical implications. METHODS: We performed systematic searches of the PubMed, Cochrane Library, Embase Ovid, Medline, BioMed Central-cancer (BMC-cancer), ScienceDirect, and Google Scholar databases without date constraints until November 30, 2019. The methodological quality of the eligible studies was appraised using the Cochrane risk of bias tool. Narrative synthesis of the study findings was conducted. RESULTS: A total of 6 intervention studies met the inclusion criteria, including 3 randomized controlled trials and 3 case-control studies/quasi-experimental studies. The studies included a total of 355 subjects, including a total of 175 in the multimedia groups and 180 in the control groups. We identified 4 potential benefits to patients: (1) improved knowledge, (2) increased satisfaction, (3) reduced incidence of catheter-related complications, and (4) reduced number of cases of delayed care after complications. CONCLUSIONS: The current systematic review highlights the potential benefits of multimedia-based home catheter management education for patients with peripherally inserted central catheters.

Budesonide foam for mild to moderate distal ulcerative colitis: A systematic review and meta-analysis.

BACKGROUND AND AIM: Budesonide is a second-generation steroid with prominent topical effects and minimal systemic activity for patients with ulcerative colitis (UC). We perform a systematic review and meta-analysis of randomized placebo-controlled trials to assess the efficacy and safety of budesonide foam in mild-to-moderate distal UC. METHODS: Comprehensive searches were performed to identify all eligible studies. Outcome measures were clinical remission, endoscopic improvement, elimination of rectal bleeding, and adverse events. The risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. All statistical analyses were performed in STATA 12.0. RESULTS: Three randomized placebo-controlled trials recruiting 711 patients with mild-to-moderate distal UC were included in this study. No significant bias and heterogeneity was identified. Pooled analyses showed that budesonide foam was significantly superior to placebo for induction of clinical remission (RR = 1.83, 95%CI: 1.41, 2.37; P < 0.001) and endoscopic improvement (RR = 1.44, 95%CI: 1.23, 1.68; P < 0.001), and eliminating rectal bleeding at week 2 (RR = 2.00, 95%CI: 1.50, 2.66; P < 0.001), week 4 (RR = 1.73, 95%CI: 1.42, 2.12; P < 0.001), and week 6 (RR = 1.76, 95%CI: 1.45, 2.14; P < 0.001). No statistically significant difference was observed in the incidence of treatment-related adverse events and therapeutic discontinuation because of adverse events between budesonide foam and placebo. CONCLUSIONS: Budesonide foam is well tolerated and superior to placebo in inducing clinical remission and endoscopic improvement, and eliminating rectal bleeding for mild-to-moderate distal UC.

Aquaporins in Digestive System.

In this chapter, we mainly discuss the expression and function of aquaporins (AQPs ) expressed in digestive system . AQPs in gastrointestinal tract include four members of aquaporin subfamily: AQP1, AQP4, AQP5 and AQP8, and a member of aquaglyceroporin subfamily: AQP3. In the digestive glands, especially the liver, we discuss three members of aquaporin subfamily: AQP1, AQP5 and AQP8, a member of aquaglyceroporin subfamily: AQP9. AQP3 is involved in the diarrhea and inflammatory bowel disease; AQP5 is relevant to gastric carcinoma cell proliferation and migration; AQP9 plays considerable role in glycerol metabolism , urea transport and hepatocellular carcinoma. Further investigation is necessary for specific locations and functions of AQPs in digestive system.

[Effect of aquaporin 9 on proliferation, apoptosis, invasiveness and migration of HepG2 cells].

OBJECTIVE: To investigate the impact of aquaporin 9 (AQP9) on the proliferation,apoptosis,invasiveness and migration of hepatocellular carcinoma cells using the HepG2 cell line. METHODS: A lentiviral vector targeting the coding region of human AQP9 was constructed. The recombinant lentiviral vector was harvested from the 293T cell line and transfected into the HepG2 cell line; resistant cell clones were selected with puromycin. Three groups of cells were established, including the CC group (control without lentiviral vector), the PWPI group (control with empty carrier virus), and the AQP9 overexpression group (experimental with the AQP9 recombinant virus). Transfection efficiency was validated by laser confocal microscopy.Expression of AQP9 was detected in the transfected HepG2 cells by westem blotting (protein) and real-time qPCR (mRNA). AQP9 effects on proliferation, migration, invasion and apoptosis of the HepG2 cell line were assessed by plate colony formation assay, woumd healing assay, transwell assay and flow cytometry. RESULTS: The green fluorescent protein of the recombinant lentiviral vector was appropriately distributed in the cell membrane. The AQP9 overexpression group showed significantly higher AQP9 mRNA and protein levels than the PWPI group and the CC group (both P < 0.01). Cells with AQP9 overexpression showed a lower colony formation rate (16.93±3.19% vs. CC group: 23.53±2.10% and PWPI group: 23.00±2.02%; F=6.46, P=0.032) and a lower overall apoptosis rate (44.96±3.53% vs. CC group:19.7±2.49% and PWPI group: 24.37±2.38%; F=66.88, P < 0.01). The AQP9 overexpression group also showed significantly higher number of cells in the G1 stage and significantly lower number of cells in the S stage (G1: 66.58±0.99% and S:15.25±1.81%), significantly smaller cell migration distance (P=0.01 < 0.05), and significantly suppressed invasiveness (17±8 vs. CC group:109+/-9 and PWPI group: 95±11; P=0.01 < 0.05). CONCLUSION: In HepG2 cells, AQP9 significantly reduces the migrative and invasive capabilities, induces cell apoptosis, and inhibits cell proliferation via cell cycle arrest at the G1/S phases.

Ligustilide Inhibits the PI3K/AKT Signalling Pathway and Suppresses Cholangiocarcinoma Cell Proliferation, Migration, and Invasion.

BACKGROUND: Angelica sinensis (Oliv.) Diels, a renowned traditional Chinese medicine, has gained widespread recognition for its antitumor properties. Further investigation is warranted to determine whether ligustilide (LIG), which is extracted from this plant, can effectively inhibit tumors. OBJECTIVE: We delved into the impact of LIG on cholangiocarcinoma cells, aiming to unravel the mechanisms underlying its effects. MATERIALS AND METHODS: Cholangiocarcinoma cells (HuccT1 and RBE) were exposed to varying concentrations of LIG (2, 5, 10, 15, 20 µg/mL) for 24, 48, and 72 h. After identifying differentially expressed genes, stable transcription strains were utilized to explore LIG's antitumor mechanism. The inhibitory effects of LIG (5 µg/mL, 48 h) were assessed by CCK-8, colony formation, wound healing, transwell migration, western blotting, and immunofluorescence. In vivo, experiments in NOG mice (Ac, Ac+LIG; five per group) evaluated LIG's antiproliferative efficacy (5 mg/kg, intraperitoneal injection, 18-day period). RESULTS: LIG significantly inhibited cell proliferation and migration with IC50 5.08 and 5.77 µg/mL in HuccT1 and RBE cell lines at 48h, increased the expression of E-cadherin while decreased N-cadherin and the protein of PI3K/AKT pathway. Silenced NDRG1 (N-Myc downstream- regulated gene 1) attenuated these effects. In vivo, the AC+LIG group (LIG, 5 mg/kg, qd, 18 d) exhibited smaller tumor volumes compared to the Ac group. The expression of Ki-67 was significantly downregulated in the AC+LIG group. CONCLUSION: For the first time, our study has revealed that LIG holds therapeutic potential for treating cholangiocarcinoma. These findings hold promise for advancing innovative therapeutic approaches in the treatment of cholangiocarcinoma. LIG may serve as a useful patent for treating CCA.

FEN1 upregulation mediated by SUMO2 via antagonizing proteasomal degradation promotes hepatocellular carcinoma stemness.

PURPOSE: Metastasis of hepatocellular carcinoma (HCC) critically impacts the survival prognosis of patients, with the pivotal role of hepatocellular carcinoma stem cells in initiating invasive metastatic behaviors. The Flap Endonuclease 1 (FEN1) is delineated as a metallonuclease, quintessential for myriad cellular processes including DNA replication, DNA synthesis, DNA damage rectification, Okazaki fragment maturation, baseexcision repair, and the preservation of genomic stability. Furthermore, it has been recognized as an oncogene in a diverse range of malignancies. Our antecedent research has highlighted a pronounced overexpression of protein FEN1 in hepatocellular carcinoma, where it amplifies the invasiveness and metastatic potential of liver cancer cells. However, its precise role in liver cancer stem cells (LCSCs) remains an enigma and requires further investigation. METHODS: To rigorously evaluate the stemness attributes of LCSCs, we employed sphere formation assays and flow cytometric evaluations. Both CD133+ and CD133- cell populations were discerningly isolated utilizing immunomagnetic bead separation techniques. The expression levels of pertinent genes were assayed via real-time quantitative PCR (RT-qPCR) and western blot analyses, while the expression profiles in hepatocellular carcinoma tissues were gauged using immunohistochemistry. Subsequent immunoprecipitation, in conjunction with mass spectrometry, ascertained the concurrent binding of proteins FEN1 and Small ubiquitin-related modifier 2 (SUMO2) in HCC cells. Lastly, the impact of SUMO2 on proteasomal degradation pathway of FEN1 was validated by supplementing MG132. RESULTS: Our empirical findings substantiate that protein FEN1 is profusely expressed in spheroids and CD133+ cells. In vitro investigations demonstrate that the upregulation of protein FEN1 unequivocally augments the stemness of LCSCs. In a congruent in vivo context, elevation of FEN1 noticeably enhances the tumorigenic potential of LCSCs. Conversely, inhibiting protein FEN1 resulted in a marked reduction in LCSC stemness. From a mechanistic perspective, there exists a salient positive correlation between the protein expression of FEN1 and SUMO2 in liver cancer tissues. Furthermore, the level of SUMO2-mediated modification of FEN1 is pronouncedly elevated in LCSCs. Interestingly, SUMO2 has the ability to bind to FEN1, leading to a inhibition in the proteasomal degradation pathway of FEN1 and an enhancement in its protein expression. However, it is noteworthy that this interaction does not affect the mRNA level of FEN1. CONCLUSION: In summation, our research elucidates that protein FEN1 is an effector in augmenting the stemness of LCSCs. Consequently, strategic attenuation of protein FEN1 might proffer a pioneering approach for the efficacious elimination of LCSCs.