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Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.
Subject(s)
Adrenal Gland Neoplasms , Cysteine , Methionine , Pheochromocytoma , Pyrimidines , Tyrosine , Pheochromocytoma/metabolism , Pheochromocytoma/blood , Humans , Adrenal Gland Neoplasms/metabolism , Adrenal Gland Neoplasms/blood , Pyrimidines/metabolism , Methionine/metabolism , Tyrosine/metabolism , Tyrosine/blood , Cysteine/metabolism , Male , Metabolomics/methods , Female , Middle Aged , Adult , Metabolic Networks and PathwaysABSTRACT
Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.
ABSTRACT
In the original publication [...].
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BACKGROUND: The chronic infection with Helicobacter pylori (H. pylori), especially cytotoxin-associated gene A-positive (CagA+) strains, has been associated with various extragastric disorders. Evaluating the potential impacts of virulence factor CagA on intestine may provide a better understanding of H. pylori pathogenesis such as colitis. The intestinal mucosal barrier is essential for maintaining its integrity and functions. However, how persistent CagA+ H. pylori colonization influences barrier disruption and thereby affects chronic colitis is not fully understood. RESULTS: Chronic colitis models of CagA+ H. pylori-colonized mice treated with 2% Dextran sulphate sodium (DSS) were established to assess the disease activity and pertinent expression of tight junction proteins closely related to mucosal integrity. The aggravating effect of CagA+ H. pylori infection on DSS-induced chronic colitis was confirmed in mouse models. In addition, augmented Claudin-2 expression was detected in CagA+ H. pylori infection conditions and selected for mechanistic analysis. Next, GES-1 human gastric epithelial cells were cultured with CagA+ H. pylori or a recombinant CagA protein, and exosomes isolated from conditioned media were then identified. We assessed the Claudin-2 levels after exposure to CagA+ exosomes, CagA- exosomes, and IFN-γ incubation, revealing that CagA+ H. pylori compromised the colonic mucosal barrier and facilitated IFN-γ-induced intestinal epithelial destruction through CagA-containing exosome-mediated mechanisms. Specifically, CagA upregulated Claudin-2 expression at the transcriptional level via a CDX2-dependent mechanism to slow the restoration of wounded mucosa in colitis in vitro. CONCLUSIONS: These data suggest that exosomes containing CagA facilitate CDX2-dependent Claudin-2 maintenance. The exosome-dependent mechanisms of CagA+ H. pylori infection are indispensable for damaging the mucosal barrier integrity in chronic colitis, which may provide a new idea for inflammatory bowel disease (IBD) treatment.
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OBJECTIVE: To explore the effects of low-dose dexmedetomidine (DM) combined with hydromorphone (HM) in postoperative analgesia and on levels of serum interleukin-6 (IL-6) and C-reactive protein (CRP) in PCa patients. METHODS: Using the random number table, we divided 102 PCa patients undergoing radical prostatectomy from January 2019 to November 2020 into a trial group (n = 51) and a control group (n = 51), the former given HM and the latter low-dose DM + HM for postoperative analgesia. We recorded the postoperative resuscitation time, extubation time and pain, perioperative cognitive function, IL-6 and CRP levels, and drug-related adverse reactions of the patients, and compared them between the two groups. RESULTS: There was no statistically significant difference in postoperative resuscitation time and extubation time between the two groups of patients (P > 0.05). The frequency of patient-controlled epidural analgesia (PCEA) compressions was lower in the trial than in the control group within 24 hours after surgery (P < 0.05). The Visual Analogue Scale (VAS) scores were higher in both of the groups at 24 hours than at 4, 12, and 48 hours after surgery (P < 0.05), at 12 hours than at 4 and 48 hours (P < 0.05) and at 4 hours than at 48 hours (P < 0.05), but lower in the trial than in the control group at 4, 12 and 24 hours postoperatively (P < 0.05). No statistically significant difference was observed in the scores of the Mini Mental State Evaluation Scale between the two groups of patients (P > 0.05). The levels of IL-6 and CRP were higher in both of the groups at 24 hours after than before and at 4, 12 and 48 hours after surgery (P < 0.05), at 48 hours after than before and at 4 and 12 hours after surgery (P < 0.05), at 12 hours after than before and at 4 hours after surgery (P <0.05), and at 4 hours after than before surgery (P < 0.05), but lower in the trial than in the control group at 4, 12, 24 and 48 hours postoperatively (P < 0.05). There was no statistically significant difference in the total incidence rate of adverse reactions between the two groups (P > 0.05). CONCLUSIONS: Low-dose dexmedetomidine combined with hydromorphone is a safe and effective option for postoperative analgesia in PCa patients, and it can inhibit the expression of inflammatory factors.
Subject(s)
Analgesia , Dexmedetomidine , Prostatic Neoplasms , Humans , Hydromorphone , Interleukin-6 , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/surgeryABSTRACT
O-GlcNAcylation is an important post-translational modification (PTM) jointly controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Aberrant hyper-O-GlcNAcylation is reported to yield hepatocellular carcinoma (HCC) malignancy, but the underlying mechanisms of the OGT/OGA imbalance responsible for HCC tumorigenesis remain largely unknown. Here, we report that RAN-binding protein 2 (RANBP2), one of the small ubiquitin-like modifier (SUMO) E3 ligases, contributed to malignant phenotypes in HCC. RANBP2 was found to facilitate CCAAT/enhancer-binding protein alpha (CEBPα) SUMOylation and degradation by direct interplay with CEBPα. As a transcriptional factor, CEBPα was verified to augment OGA transcription, and further experiments demonstrated that RANBP2 enhanced the O-GlcNAc level by downregulating OGA transcription while not affecting OGT expression. Importantly, we provided in vitro and in vivo evidence of HCC malignant phenotypes that RANBP2 triggered through an imbalance of OGT/OGA and subsequent higher O-GlcNAcylation events for oncogenic proteins such as peroxisome proliferative-activated receptor gamma coactivator 1 alpha (PGC1α) in a CEBPα-dependent manner. Altogether, our results show a novel molecular mechanism whereby RANBP2 regulates its function through CEBPα-dependent OGA downregulation to induce a global change in the hyper-O-GlcNAcylation of genes, such as PGC1α, encouraging the further study of promising implications for HCC therapy.
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BACKGROUND: Helicobacter pylori (H. pylori) infection is closely associated with the etiology of a variety of gastric diseases. The effective eradication of H. pylori infection has been shown to reduce the incidence of gastric carcinoma. However, the rate of H. pylori eradication has significantly declined due to its increasing resistance to antibiotics, especially to clarithromycin. Therefore, the detection of clarithromycin resistance is necessary prior to the treatment of H. pylori. Although many studies have been conducted on the use of polymerase chain reaction (PCR)-based tests to detect clarithromycin resistance in stool samples, no accurate data on the feasibility of these tests are available. Here, we performed a meta-analysis to assess the feasibility of these noninvasive tests. AIM: To evaluate the reliability of PCR-based tests for detecting H. pylori clarithromycin resistance in stool samples. METHODS: We searched PubMed, Medline, Embase, and other databases for articles that evaluated the value of the PCR analysis of stool samples for detecting the resistance of H. pylori to clarithromycin. We collected cross-sectional studies that met the inclusion criteria. Diagnostic accuracy measures were pooled using a random-effects model. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Subgroup analysis was also conducted according to PCR type, purification technique, reference standard, mutation site, sample weight, number of patients, and age group, and the clinical utility of diagnostic tests was evaluated using the Likelihood Ratio Scatter Graph. RESULTS: Out of the 1818 identified studies, only 11 met the eligibility criteria, with a total of 592 patients assessed. A meta-analysis of the random-effect model showed that PCR-based analysis of stool samples had high diagnostic accuracy for detecting clarithromycin resistance in patients infected with H. pylori. The combined sensitivity was 0.91 [95% confidence interval (CI): 0.83-0.95], Q = 30.34, and I 2 = 67.04, and the combined specificity was 0.97 (95%CI: 0.62-1.00), Q = 279.54, and I 2 = 96.42. The likelihood ratio for a positive test was 33.25 (95%CI: 1.69-652.77), and that for a negative test was 0.10 (95%CI: 0.05-0.18), with an area under the curve of 0.94. The diagnostic odds ratio was 347.68 (95%CI: 17.29-6991.26). There was significant statistical heterogeneity, and the sub-analyses showed significant differences in the number of patients, sample weight, purification methods, PCR types, mutation points, and reference standards. The included studies showed no risk of publication bias. CONCLUSION: PCR-based tests on stool samples have high diagnostic accuracy for detecting H. pylori clarithromycin resistance.
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BACKGROUND: Bismuth has antimicrobial activity and can improve the efficacy of triple Helicobacter pylori (H. pylori) therapy. Allicin added to conventional therapy for H. pylori infection also improves H. pylori eradication rates. Thus, this study aims to evaluate and compare the efficacy, safety and tolerability of allicin-containing quadruple therapy and bismuth-containing quadruple therapy and to investigate the factors that affect the eradication rates. METHODS: Two hundred twenty H. pylori-infected patients were included and randomly (1:1) assigned to 14-day quadruple therapy: ilaprazole (5 mg bid), doxycycline (100 mg bid), and furazolidone (100 mg bid) with an allicin soft capsule (40 mg of DATS tid) (IDFA) or colloidal bismuth tartrate (220 mg of elemental bismuth bid) (IDFB). Eradication was confirmed by urea breath tests. Symptom improvement, adverse events, and adherence were assessed by a questionnaire. RESULTS: In the intention-to-treat and per-protocol analysis, the eradication rates for IDFA and IDFB groups were 87.5% (70/80) vs. 86.3% (69/80, P = 0.815) and 91.9% (68/74) vs. 91.8% (67/73, P = 0.980) as first-line therapies; 83.3% (25/30) vs. 83.3% (25/30, P = 1) and 89.3% (25/28) vs. 88.9% (24/27, P = 1) as second-line therapies. Symptom improvement rates were 96.1% and 97.0% for IDFA and IDFB (P = 1). The adverse event rates were 10.9% in IDFA and 14.5% in IDFB groups (P = 0.418). Nausea occurred frequently in IDFB than IDFA (1.8% vs. 8.2%, P = 0.030). Smoking and sharing utensils significantly affected the efficacy. CONCLUSION: Allicin-containing quadruple therapy might be regarded as a promising alternative to bismuth-containing quadruple therapy in H. pylori eradication.
Subject(s)
Helicobacter Infections , Helicobacter pylori , Amoxicillin/therapeutic use , Anti-Bacterial Agents/adverse effects , Bismuth/adverse effects , Disulfides , Drug Therapy, Combination , Helicobacter Infections/diagnosis , Helicobacter Infections/drug therapy , Humans , Prospective Studies , Proton Pump Inhibitors/adverse effects , Sulfinic Acids , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate viral loads at different stages of disease progression in patients infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first four months of the epidemic in Zhejiang province, China. DESIGN: Retrospective cohort study. SETTING: A designated hospital for patients with covid-19 in Zhejiang province, China. PARTICIPANTS: 96 consecutively admitted patients with laboratory confirmed SARS-CoV-2 infection: 22 with mild disease and 74 with severe disease. Data were collected from 19 January 2020 to 20 March 2020. MAIN OUTCOME MEASURES: Ribonucleic acid (RNA) viral load measured in respiratory, stool, serum, and urine samples. Cycle threshold values, a measure of nucleic acid concentration, were plotted onto the standard curve constructed on the basis of the standard product. Epidemiological, clinical, and laboratory characteristics and treatment and outcomes data were obtained through data collection forms from electronic medical records, and the relation between clinical data and disease severity was analysed. RESULTS: 3497 respiratory, stool, serum, and urine samples were collected from patients after admission and evaluated for SARS-CoV-2 RNA viral load. Infection was confirmed in all patients by testing sputum and saliva samples. RNA was detected in the stool of 55 (59%) patients and in the serum of 39 (41%) patients. The urine sample from one patient was positive for SARS-CoV-2. The median duration of virus in stool (22 days, interquartile range 17-31 days) was significantly longer than in respiratory (18 days, 13-29 days; P=0.02) and serum samples (16 days, 11-21 days; P<0.001). The median duration of virus in the respiratory samples of patients with severe disease (21 days, 14-30 days) was significantly longer than in patients with mild disease (14 days, 10-21 days; P=0.04). In the mild group, the viral loads peaked in respiratory samples in the second week from disease onset, whereas viral load continued to be high during the third week in the severe group. Virus duration was longer in patients older than 60 years and in male patients. CONCLUSION: The duration of SARS-CoV-2 is significantly longer in stool samples than in respiratory and serum samples, highlighting the need to strengthen the management of stool samples in the prevention and control of the epidemic, and the virus persists longer with higher load and peaks later in the respiratory tissue of patients with severe disease.
Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Adult , COVID-19 , China , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Viral LoadABSTRACT
Helicobacter pylori (H. pylori) is a Gram-negative bacterium with a number of virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin A, its pathogenicity island, and lipopolysaccharide, which cause gastrointestinal diseases. Connexins function in gap junctional homeostasis, and their downregulation is closely related to gastric carcinogenesis. Investigations into H. pylori infection and the fine-tuning of connexins in cells or tissues have been reported in previous studies. Therefore, in this review, the potential mechanisms of H. pylori-induced gastric cancer through connexins are summarized in detail.
Subject(s)
Carcinogenesis/pathology , Connexins/metabolism , Helicobacter Infections/pathology , Helicobacter pylori/pathogenicity , Stomach Neoplasms/pathology , Down-Regulation , Gastric Mucosa/pathology , Gene Expression Regulation, Neoplastic , Genomic Islands , Helicobacter Infections/microbiology , Helicobacter pylori/genetics , Helicobacter pylori/metabolism , Host-Pathogen Interactions , Humans , Stomach Neoplasms/microbiology , Virulence Factors/genetics , Virulence Factors/metabolismABSTRACT
Preanalytical quality control of blood samples is critical for tests of coagulation function and coagulation factor activity. Preanalytical storage time and temperature are the main variables. We investigated the effects of preanalytical frozen storage time and temperature on activated partial thromboplastin time (APTT), fibrinogen (Fbg), prothrombin time (PT)/international normalized ratio (INR), thrombin time (TT), factor VIII activity (FVIII:C), and factor IX activity (FIX:C) in frozen plasma. Samples (n = 144) were randomly and equally divided into four groups (storage at -80 °C or -20 °C) and analysed by CS5100 or CA7000 coagulation analysers. Baseline values and results after storage for 15 days, 1 month, 3 months, 6 months, and 1 year were measured after thawing. Mean percent changes and scatter plots were used to determine clinically relevant differences. The stabilities of coagulation tests and coagulation factor activities measured by the CS5100 system were consistent with those measured by the CA7000 system. At -80 °C, assessment samples of PT/INR, Fbg, and TT can be safely stored for 1 year, APTT for 6 months, and FVIII:C and FIX:C for 1 month. At -20 °C, samples of Fbg and TT can be stored for 1 year, PT/INR and FIX:C for 1 month, and APTT and FVIII:C for 15 days.
