CircUGGT2 downregulation by METTL14-dependent m6A modification suppresses gastric cancer progression and cisplatin resistance through interaction with miR-186-3p/MAP3K9 axis.

Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N6-methyladenosine (m6A) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which m6A modification of circRNAs contributes to GC and chemoresistance remain unknown. We found that hsa_circ_0030632 (circUGGT2) was a predominant m6A target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 m6A levels but increased its mRNA levels. The expression of circUGGT2 was markedly increased in cisplatin (DDP)-resistant GC cells. CircUGGT2 KD impaired cell growth, metastasis and DDP-resistance in vitro and in vivo, but circUGGT2 overexpression prompted these effects. Furthermore, circUGGT2 was validated to sponge miR-186-3p and upregulate MAP3K9 and could abolish METTL14-caused miR-186-3p upregulation and MAP3K9 downregulation in GC cells. circUGGT2 negatively correlated with miR-186-3p expression and harbored a poor prognosis in patients with GC. Our findings unveil that METTL14-dependent m6A modification of circUGGT2 inhibits GC progression and DDP resistance by regulating miR-186-3p/MAP3K9 axis.

Superoxide dismutases: marker in predicting reduced left ventricular ejection fraction in patients with type 2 diabetes and acute coronary syndrome.

AIM: To examine the prognostic value of superoxide dismutase (SOD) activity for monitoring reduced left ventricular ejection fraction(LVEF)in the patients with type 2 diabetes and acute coronary syndrome (ACS). METHODS: The population of this cross-sectional study included 2377 inpatients with type 2 diabetes who had an ACS admitted to the Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2016 to January 2021. RESULTS: Diabetic patients with ACS were divided into 2 subgroups based on LVEF. The mean SOD activity was significantly lower in patients with an LVEF ≤ 45% than in those with an LVEF > 45% (149.1 (146.4, 151.9) versus 161.9 (160.8, 163.0)). Using ROC statistic, a cut-off value of 148.8 U/ml indicated an LVEF ≤ 45% with a sensitivity of 51.6% and a specificity of 73.7%. SODs activity were found to be correlated with the levels of NT-proBNP, hs-cTnT, the inflammatory marker CRP and fibrinogen. Despite taking the lowest quartile as a reference (OR 0.368, 95% CI 0.493-0.825, P = 0.001) or examining 1 normalized unit increase (OR 0.651, 95% CI 0.482-0.880, P = 0.005), SOD activity was found to be a stronger predictor of reduced LVEF than CRP and fibrinogen, independent of confounding factors. CONCLUSIONS: Our cross-sectional study suggests that SOD activity might be a valuable and easily accessible tool for assessing and monitoring reduced LVEF in the diabetic patients with ACS.

[Research Progress in the Role of Advanced Glycation End Products in the Pathogenesis of Sarcopenia].

Sarcopenia is an age-related condition characterized by a decrease in muscle mass and a decline in muscle strength.Sarcopenia increases the risk of falls,severely affecting the quality of life of patients,and it may be associated with various age-related chronic diseases.Advanced glycation end products(AGEs)are a class of stable glycation products produced by condensation,rearrangement,cleavage,and oxidative modification between the free amino groups of proteins,lipids or nucleic acids and the free carbonyl groups of reducing sugars.Studies have revealed associations of AGEs with muscle mass,muscle strength,and sarcopenia.AGEs can lead to hardening of the extracellular matrix of skeletal muscle through glycation cross-linking.The binding of AGEs to receptors induces inflammation and oxidative stress,consequently resulting in decreases in muscle mass and muscle strength.Therefore,AGEs may play a role in the occurrence and development of sarcopenia.This review summarizes the role of AGEs in the pathogenesis of sarcopenia,offering theoretical support for probing into the mechanisms underlying sarcopenia.

[Effects of Personalized Exercise Prescriptions on Sarcopenia in Patients Undergoing Hemodialysis].

Sarcopenia is a major factor affecting the health and quality of life of the patients undergoing hemodialysis.Exercise can effectively ameliorate sarcopenia in these patients.However,the type,intensity,time,and frequency of exercise influence the effect of exercise.This review describes the effects of different exercise prescriptions on sarcopenia in the patients undergoing hemodialysis.It aims to assist medical staff in developing personalized exercise prescriptions,guiding patients to engage in exercise,and provide effective strategies for the prevention and treatment of sarcopenia in the patients undergoing hemodialysis.

[Research Progress in Pathogenesis,Nutrition and Exercise Intervention of Patients With Protein Energy Wasting].

Protein energy wasting(PEW)is common in maintenance hemodialysis(MHD)patients,and it is associated with a variety of adverse clinical outcomes,including weight loss and increased protein catabolism.There are many studies on health interventions for MHD patients through nutrition strategies,exercise patterns and the combination of both.This article reviews the pathogenesis,diagnostic criteria and intervention measures of PEW,aiming to provide a reference for early clinical diagnosis,identification and intervention of PEW.

Characterization of a New Laccase from Vibrio sp. with pH-stability, Salt-tolerance, and Decolorization Ability.

Laccases have been widely used for fruit juice clarification, food modification, and paper pulp delignification. In addition, laccases exhibit remarkable performance in the degradation of toxic substances, including pesticides, organic synthetic dyes, antibiotics, and organic pollutants. Thus, the screening and development of robust laccases has attracted significant attention. In this study, Vibrio sp. LA is a strain capable of producing cold-adapted laccases. The laccase coding gene L01 was cloned from this strain and expressed in Yarrowia lipolytica, a host with good secretion ability. The secreted L01 (approximate MW of 56,000 Da) had the activity and specific activity of 18.6 U/mL and 98.6 U/mg toward ABTS, respectively. The highest activity occurred at 35 °C. At 20 °C, L01 activity was over 70% of the maximum activity in pH conditions ranging from 4.5-10.0. Several synthetic dyes were efficiently degraded by L01. Owing to its robustness, salt tolerance, and pH stability, L01 is a promising catalytic tool for potential industrial applications.

METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m6A modification of circRNAs contributes to GC progression. METHODS: The association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m6A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m6A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses. RESULTS: We found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo, whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m6A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m6A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC. CONCLUSION: Our findings demonstrate that METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

A new phenotype of syndromic retinitis pigmentosa with myopathy is caused by mutations in retinol dehydrogenase 11.

Retinol dehydrogenase 11 (RDH11) is an 11-cis-retinol dehydrogenase that has a well-characterized, albeit auxiliary role in the retinoid cycle. Diseases caused by mutations in the RDH11 gene are very rare, and only one affected family with eye and intelligence involvement has been reported. In the present study, we describe the clinical and genetic findings in a Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. Trio-based whole-exome sequencing and whole genomic copy number variation detection were performed in this family, and compound heterozygous mutations were identified in RDH11 of the patient: c.938T>C (p.Leu313Pro) derived from the father and c.75-3C>A derived from the mother. Variant c.75-3C>A was confirmed to be a splice-site mutation by cDNA sequencing. It caused exon 2 skipping, resulting in a frameshift mutation and premature translation termination (p.Lys26Serfs*38). Moreover, we found mislocalization of RDH11 protein in muscle cells of the patient by using immunofluorescence staining. This is the first case reported in the Chinese population harboring mutations in RDH11 and revealing a new phenotype of syndromic RP with myopathy.

Alterations in the saliva microbiome in patients with gastritis and small bowel inflammation.

The oral microbiome is an important part of the human microbiome. Accumulating data have shown that oral microbiome alterations are closely related to multiple human diseases. However, salivary microbiota distributions remain unclear in patients with gastritis and small bowel inflammation. Magnetically guided capsule endoscopy (MGCE) is a noninvasive diagnostic tool for patients with gastritis and small bowel inflammation. Herein, we analysed the alterations in saliva microbiota in the normal, small intestinal inflammation and chronic gastritis groups through 16S rRNA gene amplicon sequencing. We found that the abundance of Lactobacillaceae was dramatically higher in chronic gastritis group than healthy individuals (p = 0.001). The levels of Porphyromonas and Faecalibaculum in gastritis samples were increased (p = 0.028; p = 0.006), and the enrichments of Faecalibaculum and Kosakonia in small intestine inflammation samples were elevated (p < 0.001; p = 0.002) compared to those in normal individuals. Our findings clarify the saliva microbiota components and their importance of specific bacteria in gastritis and small bowel inflammation.

Predicting first session working alliances using deep learning algorithms: A proof-of-concept study for personalized psychotherapy.

OBJECTIVE: The aim of this proof-of-concept study is to develop a predictive model based on deep learning algorithms to predict working alliances after the first therapeutic session and to provide a basis for clinical decisions. METHODS: Using a sample of 325 patients and 32 psychotherapists from three university counseling centers, a deep learning algorithm known as fully connected neural networks (FCNNs) was adopted to construct data-driven predictive models. The performance differences between the model including only patient indicators and the model including both patient and therapist indicators were compared. The optimal model was further tested in a general hospital sample of 85 patients and 8 therapists. RESULTS: The model incorporating both patient indicators and therapist-level indicators (R²: 0.30 ± 0.02) performed better than the model incorporating only patient indicators (R²: 0.11 ± 0.02). The performance of this model decreased when being transferred to the independent general hospital sample, but still retained some predictive value (R² = 0.11). CONCLUSION: This study showed that the inclusion of therapist-level indicators can improve the performance of a predictive model in predicting working alliances. This model could assist clinical decisions on choosing psychotherapists for patients and may also initiate new possibilities for future research.

Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor.

Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5' region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5' region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.

Sonographic and pathological features of metaplastic squamous cell carcinoma of the breast: a case series.

OBJECTIVE: The aim of this study was to evaluate the sonographic features and to compare the sonographic findings with the pathologic features. METHODS: The sonographic and pathological features of all patients were retrospectively reviewed. RESULTS: All these 9 patients presented with a palpable breast mass first found by the patient before presentation. The median diameters were 3.67 cm. On two-dimensional imaging, 8 masses showed mixed echogenicity with both solid and cystic components, and only 1 mass showed hypoechoic. All the masses had irregular shapes. 1 mass had indistinct margin and 8 masses had microlobulated margins. Calcifications was seen in 1 mass. On color Doppler flow imaging, 8 masses had high vascularity with high resistance index; 5 masses had grade III blood flow signal; 3 masses had grade II blood flow signal. On histopathological examination, 5 masses were adenocarcinoma with squamous metaplasia, and 4 masses were pure SCC. On immunohistochemical staining, estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor (HER2) were negative in 5 masses. There were 2 patients with lymph node metastasis. CONCLUSIONS: Most of the sonographic features of MSCC were mixed echogenicity with central cystic components, posterior echo enhancement, abundant vascularity with high resistance.

Novel insights into the interplay between m6A modification and noncoding RNAs in cancer.

N6-methyladenosine (m6A) is one of the most common RNA modifications in eukaryotes, mainly in messenger RNA (mRNA). Increasing evidence shows that m6A methylation modification acts an essential role in various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs and circRNAs, are known to participate in regulating cell differentiation, angiogenesis, immune response, inflammatory response and carcinogenesis. m6A regulators, such as METTL3, ALKBH5 and IGF2BP1 have been reported to execute a m6A-dependent modification of ncRNAs involved in carcinogenesis. Meanwhile, ncRNAs can target or modulate m6A regulators to influence cancer development. In this review, we provide an insight into the interplay between m6A modification and ncRNAs in cancer.

Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis.

Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96 years [range, 0.101 to 14.4]; mean body weight, 15.8 kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2 µg/ml were 87.5% and 68.6% following administration of 40 mg/kg/dose (every 8 h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8 µg/ml following administration of 110 mg/kg/day as a continuous infusion in critically ill infants and children under 70% fT>MIC (the free time during which the plasma concentration of meropenem exceeds the MIC), respectively. The standard dosage regimens for meropenem did not meet an appropriate PD target, and an optimal dosing regimen was established in critically ill infants and children. (This study has been registered at ClinicalTrials.gov under identifier NCT03643497.).

The role of m6A RNA methylation in human cancer.

N6-methyladenosine (m6A) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). M6A modification is installed by the m6A methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as "writers"), reverted by the demethylases (FTO and ALKBH5, termed as "erasers") and recognized by m6A binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as "readers"). Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying m6A RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.

Microscopic features of small bowel mucosa of patients with Crohn's disease.

BACKGROUND: Double-balloon enteroscopy enables performing numerous small bowel biopsies for pathologic analysis. However, most histopathological characteristics of Crohn's disease are non-specific characteristics. We aimed to explore the small bowel mucosal histopathologic characters of Crohn's disease and identify some disease-specific changes. METHODS: We included 253 patients without tumors and grouped them into Crohn's disease, suspected Crohn's disease, and non-Crohn's disease groups. These patients underwent double-balloon endoscopy examination and small bowel biopsy at Renji Hospital, Shanghai. All histopathological sections were reviewed, and > 20 histopathological parameters were assessed. Immunohistochemistry was conducted when necessary. RESULTS: There were different forms of granulomatous lymphangitis on the small bowel mucosa in Crohn's disease. They showed as various macrophages or epithelioid cells in the lumina of lymphatics or in the center of the villi with or without evident obstruction. These features were only observed in Crohn's disease patients. Furthermore, they were correlated with granuloma and lymphangiectasia. Additionally, 15 other features showed significant differences among the three groups, and Crohn's disease patients showed an average of almost seven histopathological characteristics. CONCLUSIONS: We described the detailed morphologies of granulomatous lymphangitis on the small bowel mucosa and recommend it as a useful histopathological feature for the diagnosis of Crohn's disease. In terms of specificity and sensitivity, it was superior to non-caseating epithelioid granuloma.

Doppler ultrasonographic and clinical features of middle aortic syndrome.

OBJECTIVES: To discuss Doppler ultrasonographic and clinical features of middle aortic syndrome (MAS). MATERIALS AND METHODS: Doppler ultrasonographic images and clinical dates of 11 patients with MAS confirmed by angiography were retrospectively analyzed from January 2004 to September 2016. RESULTS: The median age of 11 patients was 10 years (1-39 years). Ten patients presented with hypertension, only 2 cases presented with symptomatic intermittent claudication, and 1 case presented with abdominal pain. The ultrasonographic features of 11 patients with MAS included: (a) Gray-scale image showed significant segmental narrowing of the aorta in 9 cases. (b) Color Doppler demonstrated aliasing in the suspicious narrowed vessels of all cases. (c) On Spectral Doppler image, peak systolic velocity in the location of aorta coarctation was significantly elevated (range, 2.3~4.8 m/s). When infrarenal aorta was involved, a tardus-parvus waveform was only seen in the distal aorta. When suprarenal or inter-renal aorta was involved, a tardus-parvus pattern was seen in the distal aorta as well as renal artery. CONCLUSIONS: Significant segmental narrowing and a tardus-parvus waveform are the important ultrasonographic features in patients with MAS, the latter may be more reliable. Doppler ultrasound can be used as a simple screening method, especially for children and adolescents suspected of having a vascular cause of refractory hypertension.

[Investigation and analysis on difference of cultivation technique situation of Salvia miltiorrhiza].

Salvia miltiorrhiza is one of the commonly used bulk medicinal materials, which has significant effect on cardiovascular disease, and are heavy demanded in Asia, Europe, North America, Russia and Africa. Consequently, increasing the yield and quality of S. miltiorrhiza has become a major concern worldwide. With the current wild resources of S. miltiorrhiza gradually decreasing, cultivated products occupy most of the markets. However, the cultivation area is widely distributed and the cultivation techniques is different, which lead to the quality and yield of S. miltiorrhiza in consistent. This paper combined visiting survey with document analysis to carry out the cultivation situation of S. miltiorrhiza in main cultivation areas of Shandong, Henan, Sichuan, Shanxi and Hebei provinces. There exist big differences of the ecological environment, mode of cultivation, fertilization, pest control, harvesting processing among the producing areas. We should carry on the ecological suitability zoning analysis and suitable cultivation of each area study to form a pattern of high quality and high yield for the sustainable development of S. miltiorrhiza cultivation.

[An analysis of GNAS and THRA gene mutations in children with congenital hypothyroidism].

OBJECTIVE: To preliminarily investigate the relationship between stimulatory G protein α subunit (GNAS) and thyroid hormone receptor α (THRA) gene mutations and clinical phenotypes in children with congenital hypothyroidism (CH). METHODS: A total of 70 children with CH diagnosed by neonatal screening were enrolled. Their peripheral blood samples were collected to extract genomic DNA. GNAS and THRA genes were screened for mutations using next-generation sequencing. Bioinformatics software was used to analyze the pathogenicity of gene mutations. RESULTS: Of the 70 children with CH, nine missense mutations (three known mutations and six novel mutations) in the GNAS gene were detected in three patients (4%), and one gene polymorphism, c.508A>G(p.I170V), in the THRA gene was detected in four patients. The analysis results of bioinformatics software and ACMG/AMP guidelines showed that the two GNAS gene mutations [c.301C>T(p.R101C) and c.334G>A(p.E112K)] were more likely to be pathogenic. Three children with GNAS gene mutations showed different degrees of hypothyroidism. CONCLUSIONS: GNAS gene mutations are related to the development of CH, and children with CH have different clinical manifestations. THRA gene mutations may not be associated with CH.