Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.

OBJECTIVE: To explore the genetic characteristics of a child with Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS). METHODS: A child with FSGSNEDS who had visited Shengli Oilfield Central Hospital on September 15, 2019 was selected as the study subject. Clinical data of the child was collected, and trio-whole exome sequencing (trio-WES), Sanger sequencing, chromosomal karyotyping analysis, and copy number variation sequencing (CNV-seq) were used to analyze the child and his parents. RESULTS: The child, a 3-year-old boy, had manifested developmental delay, nephrotic syndrome, and epilepsy. Trio-WES and Sanger sequencing showed that he has carried a heterozygous c.1375C＞T (p.Q459*) variant of the TRIM8 gene, for which both his parents were of the wild type. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. No abnormality was found in the chromosomal karyotyping and CNV-seq results of the child and his parents. CONCLUSION The child was diagnosed with FSGSNEDS, for which the c.1375C＞T variant of the TRIM8 gene may be accountable.
Male ; Humans ; Child ; Child, Preschool ; DNA Copy Number Variations ; Glomerulosclerosis, Focal Segmental/genetics* ; Genomics ; Heterozygote ; Karyotyping ; Carrier Proteins ; Nerve Tissue Proteins

Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH₂) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH₂) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.

Objective:To investigate the value of cellular immune status before initial 131I treatment for predicting treatment response in young and middle-aged patients with papillary thyroid cancer (PTC). Methods:From March 2018 to April 2019, 150 young and middle-aged patients with PTC (46 males, 104 females, age (40.0±9.8) years) who underwent total thyroidectomy and neck lymph node dissection in the Affiliated Hospital of Qingdao University were enrolled retrospectively. All patients underwent radioablation 1-2 months after operation, and the serum lymphocyte subsets (CD3 + , CD4 + , CD8 + , CD4/CD8) as well as natural killer (NK) cells were detected 1 d before the initial 131I treatment. Patients were divided into excellent response (ER) group and non-ER group according to the response of 6-12 months after 131I treatment. Clinicopathological characteristics, preablative stimulated thyroglobulin (psTg), initial 131I dose and lymphocyte subsets that might affect the response to 131I treatment were analyzed (independent-sample t test, Mann-Whitney U test, χ2 test, multiple logistic regression analysis). ROC curve analysis was used to evaluate the predictive value of significant factors for non-ER. Results:Of 150 patients, 84 cases were in ER group (56.00%), and 66 cases (44.00%) were in non-ER group. Age ( z=-2.86, P=0.004), M stage ( χ2=13.64, P<0.001), psTg ( z=-8.94, P<0.001), initial 131I dose ( z=-7.60, P<0.001), CD4 + ( t=2.50, P=0.014), CD4/CD8 ( z=-2.22, P=0.027) of the two groups were significantly different. Multivariate analysis showed that psTg (odds ratio ( OR)=1.27, 95% CI: 1.16-1.40, P<0.001) and CD4/CD8 ( OR=0.39, 95% CI: 0.15-0.99, P=0.048) were independent factors for predicting 131I treatment response. The cut-off values of psTg and CD4/CD8 for predicting non-ER were 6.78 μg/L and 1.67, respectively. Conclusions:Cellular immune status before initial 131I treatment may predict treatment response in young and middle-aged patients with PTC. It indicates non-ER response when Tg is higher than 6.78 μg/L and CD4/CD8 is lower than 1.67.

ObjectiveTo understand the stress level of people seeking psychological counseling under the coronavirus disease 2019 （COVID⁃19） pandemic and to explore its related factors. MethodsAn online survey was conducted on 1 194 people who sought psychological counseling in Shanghai through the “health cloud” psychological counseling service platform. The questionnaire included demographic information，lifestyle and stress during the COVID-19 pandemic. ResultsParticipants with low，medium，high and very high stress levels accounted for 33.1% （395/1 194），34.6% （413/1 194），25.4% （303/1 194） and 7.0% （83/1 194），respectively. Women and participants aged 18 to 30 years had higher stress levels（Z=-5.368，P<0.001； Z=35.822，P<0.001） compared with other groups. Factors contributing to the rise in stress included reading too much information about COVID-19 （OR=2.057，95%CI：1.012‒4.181），large changes in sleep state （OR=3.496，95%CI：1.669‒7.325），lack of hobbies and interests （OR=2.852，95%CI：1.252‒6.500），and prone to anxiety/irritability/sadness （OR=4.098，95%CI：1.772‒9.480）. Conclusionpeople who sought psychological counseling show high levels of psychological stress during the COVID-19 pandemic. We should pay more attention to the vulnerable groups with the following characteristics： women，18‒30 years old， residents who pay too much attention to the pandemic information，sleep less， and almost lose interest in hobbies， and easily become anxious/irritable/sad.

Background At present, domestic and foreign studies on the association between dietary magnesium and diabetes risk are not consistent, and there are relatively few prospective studies in China and the study population is relatively limited. Objective To explore the association between dietary magnesium intake and diabetes risk in Chinese adults in 15 provinces (autonomous regions, municipalities), and to provide a scientific basis for revising dietary magnesium intake reference for Chinese residents. Methods A total of 8061 adults aged 18-64 who participated in at least two follow-up surveys in the China Health and Nutrition Survey in 2009, 2015, and 2018, had complete survey data, and did not report diabetes at baseline were selected as subjects. Food consumption data were collected from 3-day 24-hour dietary recalls and by weighing household cooking oil and condiments. The average daily dietary magnesium intake was calculated based on the food composition table. Multiple Cox proportional risk regression model and restricted cubic spline (RCS) model were used to analyze the association and dose-response relationship between dietary magnesium intake and diabetes risk. Diabetes was defined according to the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 edition). Results A total of 47237.46 person-years were followed up, with an average follow-up of 5.86 years. Among 8061 subjects, the incidence rate was 8.86%. Compared with those in the top quintile of magnesium intake (Q5), those with lower dietary magnesium intake were more likely to be female, have higher income, higher education, live in urban areas, and have lower intakes of energy, dietary fiber, and dietary calcium. After adjusting for demographic characteristics, lifestyle, and dietary factors, compared with adults in the lowest quintile of dietary magnesium intake, the results of Cox proportional risk regression model showed that the second (median: 220.96 mg·d⁻¹), third (median: 263.01 mg·d⁻¹), and fourth (median: 312.33mg·d⁻¹) quintile dietary magnesium intake reduced the risk of diabetes by 45% (HR=0.55, 95%CI: 0.43-0.71), 39% (HR=0.61, 95%CI: 0.47-0.78), and 34% (HR=0.66, 95%CI: 0.51-0.78), respectively. The results of RCS analysis showed that dietary magnesium intake and the risk of diabetes were U-shaped overall. Taking the 5th percentile magnesium intake as reference, when dietary magnesium intake was lower than 240 mg·d⁻¹, the risk of diabetes gradually decreased with the increase of magnesium intake; the risk was the lowest at 240 mg·d⁻¹, followed by a slight increase in risk at 240-400 mg·d⁻¹; and no statistical difference presented in the association between dietary magnesium and diabetes risk after 650 mg·d⁻¹. Conclusion The study findings suggest an association between dietary magnesium intake and diebetes risk. The association is negative and non-linear when dietary magnesium intake is below 240 mg·d⁻¹.

Background Diabetes is a major contributor to global burden of disease. The role of magnesium in the prevention of diabetes has aroused concern. However, the research results on the impact of dietary magnesium on the risk of diabetes are hitherto inconsistent. Objective To evaluate the association between dietary magnesium intake and the risk of diabetes through a systematic review. Methods PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang databases were searched for prospective studies that contained risk estimates for magnesium intake-associated diabetes and were published from January 1, 2000 to December 31, 2021. Two researchers independently screened the literature according to a set of pre-prepared inclusion and exclusion criteria, extracted the data according to an unified data extraction table, and evaluated the quality of included articles with Newcastle-Ottawa Scale (NOS). R 4.0.3 software and Stata SE16.0 software were used for meta-analysis and subgroup meta-analysis, and Higgins I² statistics were used to test the heterogeneity of the included studies. The sources of heterogeneity were analyzed by univariate meta regression. Results A total of 14 articles involving 17 prospective cohort studies (1065267 participants and 40506 patients with diabetes) were included in the study. The NOS scores ranged from 8 to 9, with an average of 8.6, indicating that the included studies were classified as being high quality. The highest quintile of magnesium intake group reduced the risk of diabetes by 22% (RR=0.78, 95%CI: 0.73-0.82) compared with the lowest quintile group. This association was not substantially modified by geographic region, sex, or follow-up length. The highest quintile of dietary magnesium intake in the Americas and Asia were associated with 22% and 26% reductions in the risk of type 2 diabetes respectively compared with the lowest quintile group (the Americas, RR=0.78, 95%CI: 0.73-0.84; Asia, RR=0.74, 95%CI: 0.63-0.88); The highest quintile of dietary magnesium intake in female, male and without gender stratified were associated with 22%, 19% and 46% reductions in the risk of type 2 diabetes respectively compared with the lowest quintile group (Female RR=0.78, 95%CI: 0.73-0.84; Male RR=0.81, 95%CI: 0.74-0.89; Both RR=0.54, 95%CI: 0.42-0.68); Compared with the lowest quintile groups, the groups with the highest quintile of dietary magnesium intake with a follow-up time of less than 10 years and more than 10 years reduced the risk of type 2 diabetes by 26% and 20% respectively (≤10 years, RR=0.74, 95%CI: 0.65-0.83; ＞10 years, RR=0.80, 95%CI: 0.75-0.85). After adjusting for hypertension, the highest quintile of dietary magnesium intake group reduced the risk of type 2 diabetes by 20% compared with the lowest quintile group (RR=0.80, 95%CI: 0.74-0.85). The year of publication (P<0.05) or the sex of the subjects (P<0.05) may be the source of heterogeneity by meta regression test. The results of Egger’s test for funnel plot asymmetry suggested publication bias. Conclusion The combined data supports a role for high magnesium intake in reducing the risk of type 2 diabetes. Because it is difficult to separate the effect of magnesium intake on diabetes risk from other factors, large-scale and clinical randomized controlled trials are needed to directly assess the impact of magnesium on the incidence rate of diabetes.

Background::The potential impact of β cell function and insulin sensitivity on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) remains uncertain. We aimed to investigate the association between β cell dysfunction, insulin resistance, and the composite adverse pregnancy outcomes.Methods::This observational study included 482 women diagnosed with GDM during pregnancy. Quantitative metrics on β cell function and insulin sensitivity during pregnancy were calculated using traditional equations. The association of β cell dysfunction and insulin resistance with the risk of the composite adverse pregnancy outcomes was investigated using multivariable-adjusted logistic regression models.Results::Multivariable-adjusted odds ratios (ORs) of adverse pregnancy outcomes across quartiles of homeostatic model assessment for insulin resistance (HOMA-IR) were 1.00, 0.95, 1.34, and 2.25, respectively ( P for trend = 0.011). When HOMA-IR was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 1.34 (95% confidence interval 1.16-1.56) for each 1-unit increase in HOMA-IR. Multivariable-adjusted ORs of adverse pregnancy outcomes across quartiles of homeostatic model assessment for β cell function (HOMA-β) were 1.00, 0.51, 0.60, and 0.53, respectively ( P for trend = 0.068). When HOMA-β was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 0.57 (95% CI 0.24-0.90) for each 1-unit increase in HOMA-β. However, other quantitative metrics were not associated with the composite adverse pregnancy outcomes. Conclusions::We demonstrated a significant association of β cell function and insulin sensitivity with the risk of adverse pregnancy outcomes. We have provided additional evidence on the early identification of adverse pregnancy outcomes besides the glycemic values.

Objective:To investigate the preoperative diagnostic value of 99Tc m-methoxyisobutylisonitrile (MIBI) planar imaging and SPECT/CT imaging for primary hyperparathyroidism (PHPT), and analyze the relevant factors affecting the imaging results. Methods:From June 2016 to September 2019, a total of 62 patients (15 males, 47 females, age range: 27-80 years) confirmed as PHPT by postsurgical pathology in Affiliated Hospital of Qingdao University were retrospectively enrolled. The diagnostic efficacies of 99Tc m-MIBI planar imaging and SPECT/CT imaging were compared using χ2 test. The differences of preoperative serum parathyroid hormone (PTH), Ca and the maximum diameter of lesion between the positive and negative groups of planar imaging were analyzed using independent-sample t test and Mann-Whitney U test. The region of interest (ROI) method was applied to calculate the uptake ratio of lesions to normal tissues at the early phase (T/Ne) and delayed phase (T/Nd) in positive cases of planar imaging. Pearson or Spearman correlation analysis was used to evaluate the correlation of T/Ne, T/Nd with preoperative serum PTH, Ca and the maximum diameter of lesion. The receiver operating characteristic (ROC) curves of preoperative serum PTH, Ca and positive planar imaging were drawn and the cut-off values were obtained. Results:The sensitivity of planar imaging and SPECT/CT imaging was 69.35%(43/62) and 87.10%(54/62) respectively ( χ2=5.729, P=0.017). The preoperative serum PTH, Ca levels and the maximum diameter of lesion in patients with positive planar imaging (253.32(107.00, 331.70) ng/L, 2.78(2.51, 2.87) mmol/L, (2.01±0.88) mm) were higher than those with negative planar imaging ((111.86±44.29) ng/L, (2.59±0.21) mmol/L, (1.42±0.55) mm; z values: -2.802, -1.978, t=3.300, all P<0.05). T/Ne was positively correlated with preoperative serum PTH ( rs=0.511, P<0.001) and the maximum diameter of lesion ( r=0.381, P=0.012), and T/Nd was positively correlated with preoperative serum PTH ( rs=0.538, P<0.001), Ca ( rs=0.348, P=0.022) and the maximum diameter of lesion ( r=0.463, P=0.002). The area under the ROC curve between preoperative serum PTH, Ca and planar imaging was 0.725 and 0.646, respectively. Preoperative serum PTH had a better predictive value with the optimal cut-off value of 150.4 ng/L. Conclusions:Preoperative serum PTH, Ca and the maximum diameter of lesion are positively correlated with 99Tc m-MIBI uptake in PHPT patients with positive planar imaging results. When preoperative serum PTH is lower than 150.4 ng/L, planar imaging is prone to false negative. SPECT/CT imaging has a significant value in preoperative diagnosis and the combination of PTH and CT can improve the positive rate.