NAT10-mediated ac4C modification promotes stemness and chemoresistance of colon cancer by stabilizing NANOGP8.

Background: Colon cancer (CC) stem cells can self-renew as well as expand, thereby promoting tumor progression and conferring resistance to chemotherapeutic agents. The acetyltransferase NAT10 mediates N4-acetylcytidine (ac4C) modification, which in turn drives tumorigenesis, metastasis, stemness properties maintenance, and cell fate decisions. Nonetheless, the specific involvement of ac4C modification mediated by NAT10 in regulating stemness and chemosensitivity in CC remains undetermined. Methods: The levels of NAT10 in normal colon and chemoresistant CC tissues were determined utilizing quantitative real-time polymerase chain reaction alongside immunohistochemistry. Assessing cancer cell stemness and chemosensitivity was conducted by various methods including spheroid and colony formation, western blotting, and flow cytometry. RNA-Seq was used to identify target genes, and RNA immunoprecipitation analysis was used to explore the potential mechanisms. Results: We observed NAT10 overexpression and increased ac4C modification levels in chemoresistant CC tissues. The in vivo and in vitro analysis findings suggested that NAT10 promoted CC cell stemness while suppressing their chemosensitivity. Conversely, Remodelin, a NAT10-specific inhibitor, enhanced CC cell chemosensitivity. Mechanistically, NAT10 increased the level of NANOGP8 ac4C modification and promoted NANOGP8 mRNA stability. Conclusions: NAT10 promotes the maintenance of stemness and chemoresistance in CC cells by augmenting the mRNA stability of NANOGP8. The inhibition of NAT10 via Remodelin improves chemotherapeutic efficacy and impedes CC progression.

Post-translational protein lactylation modification in health and diseases: a double-edged sword.

As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

Insight into increased risk of portal vein thrombosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the leading chronic liver diseases with increased morbidity and mortality rates for extrahepatic diseases (including cardiovascular disease, portal vein thrombosis, etc.). There is an increased risk of thrombosis in both the portal and systemic circulation in patients with NAFLD, independent of traditional liver cirrhosis. However, increased portal pressure, the most critical factor, is frequently observed in NAFLD patients, predisposing them to portal vein thrombosis (PVT). It has been reported that there is an 8.5% incidence of PVT among patients with non-cirrhotic NAFLD in a prospective cohort study. Based on the prothrombotic status of NAFLD itself, patients combined with cirrhosis may accelerate the development of PVT and lead to a poor prognosis. Moreover, PVT has been shown to complicate the procedure and adversely affect the outcome during liver transplantation surgery. NAFLD is in a prothrombotic state, and its underlying mechanisms have not been fully understood so far. Particularly noteworthy is that gastroenterologists currently overlook the higher risk of PVT in NAFLD. We investigate the pathogenesis of NAFLD complicated with PVT from the perspective of primary, secondary, and tertiary hemostasis, and also summarize relevant studies in humans. Some treatment options that may affect NAFLD and its PVT are also explored to improve patient-oriented outcomes.

Eradication rates of Helicobacter pylori in treatment-naive patients following 14-day vonoprazan-amoxicillin dual therapy: A multicenter randomized controlled trial in China.

BACKGROUND: Potassium-competitive acid blockers (P-CAB) are recommended for the treatment of Helicobacter pylori infections, but dual therapy of P-CAB with amoxicillin has been poorly studied. The current study compared the efficacy, adverse reactions, compliance, and effects on gut microbiota of 14-day vonoprazan-amoxicillin (VA) dual therapy with esomeprazole, bismuth potassium citrate, amoxicillin, and metronidazole (EBAM) quadruple therapy in treatment-naive patients with H. pylori. MATERIALS AND METHODS: This was a multicenter, open-label, randomized, and controlled, non-inferiority study. Patients (n = 194) enrolled from six centers were randomly divided into either the VA or EBAM group. H. pylori eradication was determined using 13 C urea breath tests (UBT) 4-6 weeks post-treatment. Fecal samples were collected, and gut microbial populations were analyzed by 16S rDNA and metagenomic sequencing technology. RESULTS: Eradication rates of H. pylori in the VA and EBAM groups were 88.7% and 91.8%, respectively, according to intention-to-treat (ITT) analysis; 95.6% and 96.7% with per-protocol (PP) analysis; and 94.5% and 96.7% with modified ITT (mITT) analysis (all p > 0.05). The incidence of adverse reactions in the VA group was significantly lower compared to the EBAM group, and compliance within both groups was good. There was no difference in α-diversity or microbial composition in the VA and EBAM groups at one-month post-treatment compared to baseline, except for a markedly reduced abundance of Bacteroides in the EBAM group. CONCLUSION: VA therapy achieved excellent eradication rates with low adverse reactions, good compliance, and little impact on gut microbiota. VA therapy should be recommended as a first-line treatment against H. pylori.

Focusing on discoidin domain receptors in premalignant and malignant liver diseases.

Discoidin domain receptors (DDRs) are receptor tyrosine kinases on the membrane surface that bind to extracellular collagens, but they are rarely expressed in normal liver tissues. Recent studies have demonstrated that DDRs participate in and influence the processes underlying premalignant and malignant liver diseases. A brief overview of the potential roles of DDR1 and DDR2 in premalignant and malignant liver diseases is presented. DDR1 has proinflammatory and profibrotic benefits and promotes the invasion, migration and liver metastasis of tumour cells. However, DDR2 may play a pathogenic role in early-stage liver injury (prefibrotic stage) and a different role in chronic liver fibrosis and in metastatic liver cancer. These views are critically significant and first described in detail in this review. The main purpose of this review was to describe how DDRs act in premalignant and malignant liver diseases and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for cancer treatment and accelerate translation from bench to bedside.

Colloidal bismuth pectin-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection: A multicenter, randomized, double-blind, non-inferiority clinical trial.

BACKGROUND: Bismuth-containing quadruple therapy is an effective regimen for Helicobacter pylori (H. pylori) treatment. No head-to-head comparison trials have been conducted to evaluate the efficacy of colloidal bismuth pectin (CBP) in quadruple therapy for eradicating H. pylori. We aimed to compare the efficacy and safety of CBP quadruple therapy and bismuth potassium citrate (BPC) quadruple therapy for 14 days in the first-line treatment of H. pylori. METHODS: In this multicenter, randomized, double-blind, non-inferiority clinical trial, H. pylori-infected subjects without eradication history were randomized to receive amoxicillin 1 g twice daily, tetracycline 500 mg three time daily, esomeprazole 20 mg twice daily in combination with CBP 200 mg three time daily or BPC 240 mg twice daily for 14 days. 13 C-urea breath tests were used to access the eradication rate at least 4 weeks after treatment. RESULTS: Between April 2021 and July 2022, 406 patients were assessed for eligibility and 339 subjects were randomized. The cure rates (primary outcome) of CBP and BPC quadruple therapy were 90.5% and 92.3% (p = 0.56) by intention-to-treat analysis, respectively, and 96.1% and 96.2% (p = 1.00) by per-protocol analysis, respectively. CBP quadruple therapy was non-inferior to BPC quadruple therapy in the intention-to-treat and per-protocol analysis (p < 0.025). The frequency of adverse events and compliance were not different among the two groups (p > 0.05). CONCLUSIONS: Both CBP and BPC quadruple therapy for 14 days provide high efficacy, good compliance, and safety in the first-line treatment of H. pylori in China.

Focusing on Helicobacter pylori infection in the elderly.

As a confirmed carcinogen, Helicobacter pylori (H. pylori) is the main cause of inflammatory diseases of the upper digestive tract and even gastric cancer. There is a high prevalence of H. pylori infection among the elderly population, which may cause adverse clinical outcomes. Particularly noteworthy is that guidelines or expert consensus presently available on H. pylori infection overlook the management of the elderly population as a special group. A brief overview of H. pylori in the elderly is as follows. The detection of H. pylori infection can be divided into invasive and non-invasive techniques, and each technique has its advantages and shortcomings. There may be more side effects associated with eradication treatment in elderly individuals, especially for the frail population. Physical conditions and risk-benefit assessments of the elderly should be considered when selecting therapeutic strategies for H. pylori eradication. Unless there are competing factors, elderly patients should receive H. pylori eradication regimens to finally reduce the formation of gastric cancer. In this review, we summarize the latest understanding of H. pylori in the elderly population to provide effective managements and treatment measures.

High-dose amoxicillin-proton pump inhibitor dual therapy as first-line treatment for Helicobacter pylori infection in Northwest China: A prospective, randomised controlled trial.

AIMS: We aimed to assess the eradication efficacy and factors that influencing it of high-dose dual therapy (HDDT) in Gansu region, Northwest China. METHODS: A total of 216 treatment-naive patients with Helicobacter pylori infection were randomly assigned to two groups for the 14-day eradication treatment: the HDDT group (amoxicillin 750 mg q.i.d. and esomeprazole 40 mg t.i.d.) and the amoxicillin and clarithromycin-containing bismuth quadruple therapy group (ACBQT: esomeprazole 20 mg, bismuth potassium citrate 2 g, amoxicillin 1 g, and clarithromycin 500 mg; b.i.d.). The eradication rates, adverse effects and patient compliance of these two groups were compared. Eradication efficacy was determined by 13 C urea breath test (13 C UBT) 4-8 weeks after finishing treatment. Antibiotic resistance was determined by the Epsilometer testing (E-test) method. RESULTS: The eradication rates for the HDDT and ACBQT groups were 71.0% and 74.7% (P = .552) by per-protocol analysis, and 65.7% and 68.5% (P = .664) by intention-to-treat analysis. The overall adverse event rates in the HDDT and ACBQT groups were 2.0% and 43.4% (P < .001), respectively. The resistance rates to amoxicillin, clarithromycin, tetracycline, levofloxacin and metronidazole were 15.2%, 42.0%, 5.4%, 35.7% and 83.0%, respectively. Amoxicillin resistance and delta over baseline (DOB) of 13 C UBT ≥ 20 before treatment significantly reduced the eradication rate in 112 participants with H. pylori cultured. CONCLUSION: The HDDT as first-line treatment for H. pylori was unsatisfactory in Gansu. Amoxicillin resistance and DOB of 13 C UBT ≥ 20 before treatment were significantly correlated with H. pylori eradication failure.

[A Prognostic Nomogram Based on Response to Bortezomib and BTK Expression for Treatment-Experienced Multiple Myeloma Patients].

OBJECTIVE: To establish a prognostic nomogram based on response to bortezomib and BTK expression for treatment-experienced multiple myeloma patients. METHODS: The Oncomine database was utilized to determine BTK expression, sex, age, albumin, Mayo index, response to bortezomib treatment, follow-up time and survival status in multiple myeloma(MM) patients. Cut-off point for BTK expression was calculated using R software. Univariate and multivariate analyses by Cox proportional hazards regression were then performed. Significant prognostic factors were combined to build a nomogram. The discrimination ability and predictive accuracy of the nomogram were evaluated using the index of concordance (C-index) and calibration curves. RESULTS: Multivariate analysis showed that response to bortezomib, BTK expression and sex were independent risk factors for prognosis. The C-index value of the nomogram made according to the independent risk factors was 0.729 (95%CI, 0.642-0.8164). The calibration curves showed good consistency between predicted and actual survivals for 1-year and 2-year overall survival. CONCLUSION: The proposed nomogram is accurate in predicting the prognosis of patients with MM.

Discoidin domain receptor 1a (DDR1a) confers 5-fluorouracil cytotoxicity in LoVo cell via PI3K/AKT/Bcl-2 pathway.

5-Fluorouracil (5-FU) is a common chemotherapy drug for patients with advanced colorectal cancer; however, many patients develop resistance to 5-FU and suffer from treatment failure. Discoidin domain receptor 1 (DDR1) is upregulated in multiple cancers and positively associated with chemoresistance. We explored the effect of DDR1a on the cytotoxicity induced by 5-FU in LoVo cells and the underlying mechanism. Therefore, DDR1a overexpression (DDR1ahigh) and knockdown in LoVo cell lines (shDDR1a) were constructed to detect cell viability and cytotoxicity induced by 5-FU. The results showed that cell viability of DDR1ahigh cells was higher in comparison with that of the control group. When 5-FU (5 µM) was administered, the percentage of apoptotic cells, cytochrome C release and caspase-3 activity was found to be higher in the shDDR1a group than that in the control group. Both of PI3K and MDM2 proteins level decreased in DDR1ahigh and shDDR1a, but the BAX/Bcl-2 level in the shDDR1a group increased compared to that in the control. Therefore, DDR1a might be a potential therapeutic target for 5-FU chemoresistance in colorectal cancer.

Efficacy and safety of high-dose esomeprazole and amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori infection: a multicenter, randomized controlled clinical trial.

Background: A high-dose proton pump inhibitor (PPI)-amoxicillin dual therapy has been investigated for treatment of patients with Helicobacter pylori (H. pylori) infection. Currently, the efficacy of this dual therapy remains inconclusive, with controversial findings from various single-center clinical trials. Objectives: To assess the efficacy and safety of high-dose dual therapy (HDDT) compared with the bismuth-containing quadruple therapy (BQT) in treatment-naive patients with H. pylori infection. Design: A multicenter, open-label, randomized controlled clinical trial. Methods: Three hundred and forty treatment-naïve patients with H. pylori infection were prospectively recruited from seven participating hospitals. The enrolled patients were randomized into one of two treatment groups: the HDDT group (esomeprazole, 20 mg four times daily; amoxicillin, 750 mg four times daily) and the BQT group (esomeprazole, 20 mg, twice daily; bismuth potassium citrate, 600 mg, twice daily; amoxicillin, 1 g, twice daily; metronidazole, 400 mg, four times daily). The primary outcome was eradication rate, and secondary outcomes were safety and patient compliance. Results: The eradication rates in the HDDT group versus the BQT group were 86.47% versus 87.06% on intention-to-treat (ITT) analysis, 91.88% versus 92.50% on modified ITT (MITT) analysis, and 91.77% versus 93.04% on per-protocol (PP) analysis, with no significant differences between the two groups. The patient compliance rates in the HDDT group versus the BQT group were 97.02% versus 95.86%, and no significant difference was found between the two groups. Notably, the HDDT group exhibited significantly lower incidence in the drug-induced adverse events (AEs) compared to the BQT group (16.67% versus 47.94%). Conclusion: HDDT is equally efficacious in eradicating H. pylori infection and resulted in good patient compliance and safety compared with BQT. These findings provide evidence in support of HDDT as a first-line treatment for H. pylori infection. Registration: This clinical trial was registered at The Chinese Clinical Trial Registry (trial registration number: ChiCTR2000039096).

Thoracoscopic resection of a large lower esophageal schwannoma: A case report and review of the literature.

BACKGROUND: Esophageal schwannomas originating from Schwann cells are extremely rare esophageal tumors. They commonly occur in the upper and middle esophagus but less frequently in the lower esophagus. Herein, we report a rare case of a large lower esophageal schwannoma misdiagnosed as a leiomyoma. We also present a brief literature review on lower esophageal schwannomas. CASE SUMMARY: A 62-year-old man presented with severe dysphagia lasting 6 mo. A barium esophagogram showed that the lower esophagus was compressed within approximately 5.5 cm. Endoscopy revealed the presence of a large submucosal protuberant lesion in the esophagus at a distance of 32-38 cm from the incisors. Endoscopic ultrasound findings demonstrated a 4.5 cm × 5.0 cm hypoechoic lesion. Chest computed tomography revealed a mass of size approximately 53 mm × 39 mm × 50 mm. Initial tests revealed features indicative of leiomyoma. After multidisciplinary discussions, the patient underwent a video-assisted thoracoscopic partial esophagectomy. Further investigation involving immunohistochemical examination confirming palisading spindle cells as positive for S100 and Sox10 led to the final diagnosis of a lower esophageal schwannoma. There was no tumor recurrence or metastasis during follow-up. CONCLUSION: The final diagnosis of esophageal schwannoma requires histopathological and immunohistochemical examination. The early appropriate surgery favors a remarkable prognosis.

microRNA-592 blockade inhibits oxidative stress injury in Alzheimer's disease astrocytes via the KIAA0319-mediated Keap1/Nrf2/ARE signaling pathway.

MicroRNA-592 (miR-592) has been reported to play a significant role in mediating neuronal activity, but its possible link with Alzheimer's disease (AD) remains unclear. We aimed to explore the mechanism of miR-592 in oxidative stress (OS) injury of astrocytes (ASTs) from AD rat models induced by D-galactose or Aß25-35 injection. Bioinformatics website and dual-luciferase reporter gene assay clarified the binding affinity between miR-592 and KIAA0319. KIAA0319 was identified as a target gene of miR-592. The mechanism of miR-592, KIAA0319 and the Keap1/Nrf2/ARE signaling pathway in AD was examined after transducing miR-592 mimic, miR-592 inhibitor and siRNA-KIAA0319 into ASTs to query cell viability, OS injury and reactive oxygen species (ROS). The rat models of AD Exhibited highly expressed miR-592 and poorly expressed KIAA0319. Furthermore, inhibition of miR-592 diminished C-Keap1 expression and enhanced N-Nrf2 and NQO1 expression, thus promoting cell viability and reducing OS injury of ASTs. Taken together, these findings suggested that the downregulation of miR-592 inhibited OS injury of ASTs in rat models of AD by up-regulating KIAA0319 through the activation of the Keap1/Nrf2/ARE signaling pathway.

[Application of Digestive Endoscopy in Diagnosis of Helicobacter Pylori Infection].

Helicobacter pylori (Hp),a proven pathogen of digestive disease,is closely associated with gastrointestinal diseases including peptic ulcer,chronic active gastritis,stomach cancer,and stomach-associated lymphoid tissue lymphoma. Thus,precise and timely diagnosis of Hp is of great significance. In addition to 13C or 14C breath test,rapid urease test,and other commonly used Hp diagnosis methods,some new endoscopic techniques such as magnifying endoscopy,narrow-band imaging,confocal laser endomicroscopy,Fuji intelligent chromoendoscopy,and I scanning have been used for the direct observation of the fine-structure of stomach with Hp infection or for the identification of living Hp. This article reviews the application of digestive endoscopy in the diagnosis of Hp infection.

A Picrorhiza kurroa derivative, picroliv, attenuates the development of dextran-sulfate-sodium-induced colitis in mice.

BACKGROUND: Free radicals and proinflammatory cytokines have been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). Picroliv, a Picrorhiza kurroa derivative, has been demonstrated to have antioxidant and anti-inflammatory effect. The purpose of the study was to investigate the effects of picroliv on experimental model of UC in mice. MATERIALS AND METHODS: Picroliv was administrated orally by gavage to mice with colitis induced by dextran sulfate sodium (DSS). Disease activity index (DAI), colon length, and histology score were observed. Myeloperoxidase (MPO) activity, and SOD, MDA concentrations were measured by enzyme-linked immunosorbent assay (ELISA) while the expression of cytokine mRNAs was studied by real-time-quantitative polymerase chain reaction and also ELISA. The expression of NF-κB p65 was observed by immunohistochemistry staining and western blotting. RESULTS: A significant improvement was observed in DAI and histological score in mice treated with picroliv, and incerased MPO activity, MDA concentrations, and the expression of IL-1ß, TNF-α, and NF-κB p65 in mice with DSS-induced colitis were significantly reduced while decreased SOD level increased following administration of picroliv. CONCLUSION: The administration of picroliv leads to an amelioration of DSS-induced colitis, suggesting administration of picroliv may provide a therapeutic approach for UC.

[Change from inflammation to carcinoma in ulcerative colitis: the role of PTEN/PI3K/AKT].

OBJECTIVE: To detect the changes of expression of PTEN protein and AKT protein in patients with Ulcerative Colitis (UC) in the pathway from inflammation to carcinoma. METHODS: A total of 110 paraffin colorectal sections were examined, which included 65 cases with UC, 25 cases with colorectal cancer and 25 cases with normal tissues. The expression of PTEN protein and AKT protein was detected with immunohistochemistry. RESULTS: (1) The patients with UC had lower expression of PTEN protein and higher expression of AKT than those with normal tissues (P < 0.01). (2) The patients with UC had higher expression of PTEN protein and lower expression of AKT protein than those with colorectal cancer (P < 0.01). (3) With the progress of UC, the expression of PTEN protein decreased while the expression of AKT protein increased (P < 0.01). (4) The expression of PTEN protein was negatively correlated with the expression with AKT protein in patients with UC and colorectal cancer (r = -0. 542 and -0. 674, respectively P < 0.01). CONCLUSION: The change of expressions of PTEN protein and AKT protein might play an important role in the development of UC and colorectal cancer. Decreased PTEN protein and increased AKT protein might be a marker for the early detection of the occurrence of colorectal cancer in patients with UC.

NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with ulcerative colitis.

BACKGROUND: Activation of nuclear factor-kappa B (NF-kappaB), which controls transcription of various proinflammatory cytokine genes, has been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). The aim of this study was to investigate if NF-kappaB p65 antisense oligonucleotides may affect the expression of NF-kappaB p65 and cytokines in lamina propria mononuclear cells (LPMCs) from patients with UC. METHODS: LPMCs, which were isolated from intestinal mucosal biopsy specimens from patients with UC, were cultured with or without NF-kappaB p65 antisense oligonucleotides, missense oligonucleotides and dexamethasone. NF-kappaB p65 expression was determined by Western blot analysis. The expression of cytokine mRNA was studied by reverse transcription-polymerase chain reaction (RT-PCR). Cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS: NF-kappaB p65 antisense oligonucleotides resulted in downregulation of NF-kappaB p65 expression, blocked the expression of IL-1beta mRNA and IL-8 mRNA, and strikingly reduced the production of IL-1beta and IL-8. These effects were greater than those of dexamethasone in cultured LPMCs from patients with UC (p <0.05). CONCLUSIONS: Application of NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with UC.