Objective:To explore the mechanisms of oxaliplatin resistance mediated by TET2 methylation in the treatment of acute lymphoblastic leukemia (ALL) using bioinformatics methods.Methods:The data on drug-resistant and sensitive cell lines related to oxaliplatin treatment for ALL were download using the Genomics of Drug Sensitivity in Cancer (GDSC) database (updated in December 2023); the drug-resistant cell lines were screened based on half maximal inhibitory concentration ( IC50) > 10 μmol/L, and the difference in IC50 between drug-resistant and sensitive cell lines were analyzed using Mann-Whitney U test. The cancer driver mutation genes in drug-resistant cell lines were retrieved using the Cancer Cell Line Encyclopedia (CCLE) database (updated in December 2023). Using the protein-protein interaction (PPI) network functional enrichment analysis (STRING) database (updated in June 2024), PPI network analysis was performed on cancer driver mutation genes with biological functions. A confidence threshold of ≥ 0.7 (high confidence) and an average network node degree above 4 (high average) were selected to screen for cancer driver mutation genes with significant biological functions. Using the microRNA Data Integration Portal (mirDIP) database (updated in June 2024), the coexpression data of microRNA (miRNA) and mutant target genes were queried, miRNA-target gene pairs were screened according to the highest score threshold of 1% miRNA and interaction score > 0.9, and the regulatory effect of miRNA on mutant genes was analyzed. DNA methylation data were download from the Methylation in Human Cancer (MethHC) database (updated in June 2024) and the methylSig R software package was used to analyze the differentially methylated regions (DMR) of DNA methylation between drug-resistant and sensitive cell lines; genes with P < 0.05 and absolute difference > 0.2 were selected, and they were divided into high methylation gene group and low methylation gene group. Spearman correlation analysis and Spearman rank test were performed for the degree of methylation and gene expression, and the key genes with P < 0.01 were screened to reveal the relationship between methylation degree and gene expression. Results:As a result of searching the GDSC database, there were a total of 9 drug-resistant cell lines and 17 sensitive cell lines related to oxaliplatin treatment for ALL; after Z-score normalization of IC50 data between drug-resistant and sensitive cell lines, the average rank of drug-resistant cell lines was 21, and the average rank of sensitive cell lines was 8.5, with a statistically significant difference ( Z = -4.08, P < 0.01). Eight cancer driver mutation genes with significant biological functions that lead to drug resistance of the cell lines were screened using the CCLE database and STRING database. According to the mirDIP database, there were a total of 12 pairs of miRNA-target gene pairs with miRNA-target gene interaction scores >0.9. miRNA had strong regulatory effects on the expressions of NRAS and MAP2K1 target genes. In the MethHC database, the β values (numerical value of increased methylation level) of DMR for genes such as TP53, RXRG and SGIP in drug-resistant cell lines were 0.151, 0.165 and 0.149, respectively, compared to those in sensitive cell lines, the differences were statistically significant (all P < 0.01). The degree of methylation of SGIP gene was negatively correlated with the relative expression level of SGIP mRNA ( r = -0.71, P < 0.01), and SGIP gene underwent high methylation at promoter site 143886940. The cg08321569 locus in the TET2 gene domain of drug-resistant cell lines exhibited persistent high methylation, with a methylation level of β = 0.89. This locus was located 1.2 kb downstream of the transcription start point of exon 4, and the degree of TET2 methylation was negatively correlated with the relative expression level of TET2b mRNA ( r = -0.81, P < 0.01). Conclusions:TET2 methylation may be an important factor for oxaliplatin resistance in the treatment of ALL.

Objective:To explore the mechanisms of oxaliplatin resistance mediated by TET2 methylation in the treatment of acute lymphoblastic leukemia (ALL) using bioinformatics methods.Methods:The data on drug-resistant and sensitive cell lines related to oxaliplatin treatment for ALL were download using the Genomics of Drug Sensitivity in Cancer (GDSC) database (updated in December 2023); the drug-resistant cell lines were screened based on half maximal inhibitory concentration ( IC50) > 10 μmol/L, and the difference in IC50 between drug-resistant and sensitive cell lines were analyzed using Mann-Whitney U test. The cancer driver mutation genes in drug-resistant cell lines were retrieved using the Cancer Cell Line Encyclopedia (CCLE) database (updated in December 2023). Using the protein-protein interaction (PPI) network functional enrichment analysis (STRING) database (updated in June 2024), PPI network analysis was performed on cancer driver mutation genes with biological functions. A confidence threshold of ≥ 0.7 (high confidence) and an average network node degree above 4 (high average) were selected to screen for cancer driver mutation genes with significant biological functions. Using the microRNA Data Integration Portal (mirDIP) database (updated in June 2024), the coexpression data of microRNA (miRNA) and mutant target genes were queried, miRNA-target gene pairs were screened according to the highest score threshold of 1% miRNA and interaction score > 0.9, and the regulatory effect of miRNA on mutant genes was analyzed. DNA methylation data were download from the Methylation in Human Cancer (MethHC) database (updated in June 2024) and the methylSig R software package was used to analyze the differentially methylated regions (DMR) of DNA methylation between drug-resistant and sensitive cell lines; genes with P < 0.05 and absolute difference > 0.2 were selected, and they were divided into high methylation gene group and low methylation gene group. Spearman correlation analysis and Spearman rank test were performed for the degree of methylation and gene expression, and the key genes with P < 0.01 were screened to reveal the relationship between methylation degree and gene expression. Results:As a result of searching the GDSC database, there were a total of 9 drug-resistant cell lines and 17 sensitive cell lines related to oxaliplatin treatment for ALL; after Z-score normalization of IC50 data between drug-resistant and sensitive cell lines, the average rank of drug-resistant cell lines was 21, and the average rank of sensitive cell lines was 8.5, with a statistically significant difference ( Z = -4.08, P < 0.01). Eight cancer driver mutation genes with significant biological functions that lead to drug resistance of the cell lines were screened using the CCLE database and STRING database. According to the mirDIP database, there were a total of 12 pairs of miRNA-target gene pairs with miRNA-target gene interaction scores >0.9. miRNA had strong regulatory effects on the expressions of NRAS and MAP2K1 target genes. In the MethHC database, the β values (numerical value of increased methylation level) of DMR for genes such as TP53, RXRG and SGIP in drug-resistant cell lines were 0.151, 0.165 and 0.149, respectively, compared to those in sensitive cell lines, the differences were statistically significant (all P < 0.01). The degree of methylation of SGIP gene was negatively correlated with the relative expression level of SGIP mRNA ( r = -0.71, P < 0.01), and SGIP gene underwent high methylation at promoter site 143886940. The cg08321569 locus in the TET2 gene domain of drug-resistant cell lines exhibited persistent high methylation, with a methylation level of β = 0.89. This locus was located 1.2 kb downstream of the transcription start point of exon 4, and the degree of TET2 methylation was negatively correlated with the relative expression level of TET2b mRNA ( r = -0.81, P < 0.01). Conclusions:TET2 methylation may be an important factor for oxaliplatin resistance in the treatment of ALL.

Purpose This study uses the diffusion tensor imaging to explore diffusion metrics changes of corpus callosum subregion,and to further analyze the relationship among these changes and the cognitive and emotional in adults with primary hypothyroidism.Materials and Methods From October 2019 to September 2021,32 hypothyroidism patients were recruited from Gansu Provincial Hospital,whereas 33 healthy controls were recruited through advertisements.The comprehensive thyroid-related hormone levels tests,as well as neurocognitive/neuropsychiatric assessment and diffusion tensor imaging data of all participants were carried out.The differences in corpus callosum subgroups of diffusion metrics between the two groups were recorded and compared,the partial relationships between these diffusion metrics and thyroid-related hormone levels and neurocognitive/neuropsychiatric function were analyzed and measured.Receiver operating characteristic curves were constructed to evaluate the diagnostic performance.Results Lower fraction anisotropy,higher mean diffusivity and radial diffusivity in genu and body of the corpus callosum and higher axial diffusivity in genu of the corpus callosum were found in hypothyroidism compared with healthy controls(P<0.01).These diffusion metrics were negatively correlated with cognition and emotion(r=-0.448-0.440,P=0.010-0.043),and the fraction anisotropy value in genu of the corpus callosum had the largest area under the curve(0.777).Conclusion Hypothyroidism patients show widespread microstructural changes within the genu and body of the corpus callosum,which,respectively,associated with cognition and emotion.This study provides a new perspective to further understanding the pathophysiology of the cerebral impairment in hypothyroidism.

Objective To explore the association between interpregnancy weight change and the recurrence of gestational diabetes mellitus(GDM).Methods This study included women who had two delivery records and a history of GDM during their previous pregnancy at the Guangdong Women and Children Hospital between January 2017 and July 2022.Interpregnancy weight change was defined as the difference between the prepregnancy BMIs of two consecutive pregnancies.Interpregnancy weight change was categorized into four groups(＜-1,-1 to＜1,1 to＜3,≥3 kg/m2),with the-1 to＜1 kg/m2 group serving as the reference.Logistic regression analyses were used to assess the associations of interpregnancy weight changes with GDM recurrence and changes in glucose values during two consecutive pregnancies.Results Among 703 participants,326 individuals(46.4％)experienced GDM recurrence.Compared with the groups with an interpregnancy BMI change of-1 to＜1 kg/m2,the groups with a BMI change of 1 to＜3 or ≥3 presented an increased risk of GDM recurrence,with odds ratio(OR)[95％confi-dence intervals(CI)]of 2.16(1.52-3.08)and 2.56(1.44-4.56),respectively.The risk of GDM recurrence significantly in-creased with increasing interpregnancy weight gain(P for trend＜0.01).However,there was no significant association between a BMI change＜-1 kg/m2 and GDM recurrence,with an OR(95％CI)of 0.95(0.57-1.57).An increase of 1 kg/m2 in the in-terpregnancy BMI was associated with a higher risk of elevated fasting blood glucose and 1 h plasma glucose,with OR(95％C1)of 1.15(1.05-1.26)and 1.21(1.10-1.33),respectively.Conclusion Women with a history of GDM are at a high risk of GDM recurrence,and interpregnancy weight gain is associated with an increased risk of GDM recurrence.These findings under-score the importance of health education among women with a history of GDM who plan to conceive again and emphasize the im-portance of weight management in reducing the recurrence of GDM.

Objective: To study the effect of a space stabilizing device on the capacity for osteogenesis in the bone-grafted area. Methods: Patients with anterior teeth defects as well as labial alveolar ridge defects were randomly divided into two groups: the experimental group was treated using a space stabilization device after guided bone regeneration whereas the control group received regular guided bone regeneration. The CBCT data was analyzed prior to, immediately and 6 months after procedure to compare the osteogenesis with or without the device. Results: Seventeen bone-grafted sites were examined(7 in the experimental group and 10 in the control group). At 2 mm and 4 mm below the alveolar ridge, the horizontal bone resorption rate in the experimental group was significantly lower than the corresponding level in the control group(P=0.001). The horizontal bone resorption rate at 2 mm below the alveolar ridge of each group was significantly higher than that at 4 mm below the alveolar ridge in corresponding groups(P=0.003). Conclusion The space stabilizing device used in this study has a positive clinical impact on preserving space stability and minimizing bone resorption.

Subclinical hypothyroidism (SCH) is a mild impairment of thyroid function. Several existing studies suggest that SCH is associated with an increased risk of depression, but some studies have also found no correlation between SCH and depression. Therefore, whether there is an association between SCH and depression and the mechanism of interaction between the two remains controversial. Growing evidence suggested that SCH patients should not be routinely treated with levothyroxine, and the effect of the treatment of thyroid disease on various clinical psychiatric outcomes is also controversial. This article reviews the current research on the correlation between SCH and depression risk and whether drug intervention is needed.

Objective: To investigate the trends in mortality and life lost due to cancer among residents in Ouhai District, Wenzhou City from 2013 to 2020, so as to provide the evidence for formulating the cancer control strategy. Methods: The mortality data of cancer patients in Ouhai District from 2013 to 2020 were collected through Zhejiang Provincial Information Management System for Surveillance of Chronic Diseases. The crude mortality, standardized mortality, years of potential life lost ( YPLL ), years of potential life lost rate ( YPLLR ), standardized years of potential life lost ( SYPLL ), standardized years of potential life lost rate ( SYPLLR ), average years of life lost ( AYLL ) and annual percent change ( APC ) were estimated to analyze the trends in mortality and life lost due to cancer. Results: Totally 5 435 deaths occurred due to cancer in Ouhai District from 2013 to 2020, and the crude and standardized mortality rates were 154.10/105 and 119.41/105, respectively. The crude mortality of cancer was higher in men than in women ( 196.26/105 and 111.09/105; χ2=415.623, P<0.001 ). The standardized mortality of cancer among whole populations, the crude mortality in men and the standardized mortality in men showed a tendency towards a reduction ( P<0.05 ), with APC of -3.25%, -2.18% and -4.78%, respectively. The crude mortality of cancer showed an upward trend with age ( χ2trend=9 260.583, P<0.001 ). Lung cancer, liver cancer, stomach cancer, colorectal cancer and esophagus cancer were the five leading causes of cancer-related mortality, which accounted for 66.68% of all cancer mortality. Liver cancer, lung cancer, stomach cancer, colorectal cancer and brain cancer were the five leading causes of life lost, with YPLL of 11 191.50, 8 231.00, 6 000.00, 3 892.00 and 2 693.50 person-years, respectively. Leukemia was the primary cause of AYLL ( 25.17 years per person ). Conclusions Both the standardized mortality and the life lost due to cancer showed a tendency towards a reduction in Ouhai District from 2013 to 2020, and men and the elderly were high-risk populations. Lung cancer, liver cancer, stomach cancer, colorectal cancer, leukemia, brain cancer, and female breast cancer should be listed among cancers in Ouhai District prioritized for control

Objective:To improve the understanding of special type of atrioventricular septal defect (AVSD) and reduce clinical missed diagnosis and misdiagnosis by investigating its echocardiographic features.Methods:Echocardiographic images of patients with special type of AVSD diagnosed by echocardiography and confirmed by surgery in Pediatric Cardiovascular Center, Beijing Anzhen Hospital, Capital Medical University from November 2011 to November 2021 were retrospectively analyzed. Depending on the presence of ventricular septal defect(VSD), special type of AVSD were divided into two types, namely AVSD with intact ostium primum and AVSD with intact ostium primum and ventricular septum. The echocardiographic features of special type of AVSD were summarized.Results:Twenty-five cases of special type of AVSD were diagnosed by echocardiography and 13 cases were confirmed by surgery, including 12 cases with intact ostium primum and 1 case with intact ostium primum and ventricular septum. There were 5 cases without surgical indications, and 1 case was kept under observation due to small VSD. One patient with complex malformation only underwent pulmonary artery banding operation without treating intracardiac malformation. The other 4 cases of perimembrane VSD and 1 case of partial AVSD were misdiagnosed as special type of AVSD by echocardiography. All patients had mild to severe left atrioventricular regurgitation before surgery, and most patients remained left atrioventricular regurgitation of varying degrees after left atrioventricular valve formation. Characteristic sonographical findings included: ①The ostium primum was continuous and there was no ostium primum defect. ②The attachment points of the left and right atrioventricular valves were at the same level. ③The left atvioventricular valve was a trileaflet left atrioventricular valve and attached to the crest of the ventricular septum, forming the so-called "anterior mitral valve leaflet cleft". ④The two groups of papillary muscles of the left ventricle changed the normal anterolateral and posterolateral alignment, but showed a anteriorly and posteriorly relationship (counterclockwise transposition). ⑤In the presence of VSD, an inlet ventricular septal defect would be present. ⑥Color Doppler showed varying degrees of regurgitation signals from the left atrioventricular valve during systolic period. ⑦Other complex deformities may be combined with special type of AVSD.Conclusions:Echocardiography can make a definite diagnosis for special types of AVSD. The prognosis of this malformation is closely related to the left atrioventricular valve, and the shaping effect depends on the development of left atrioventricular valve and regurgitation.

Objective:To investigate the immune effects of Clostridium difficile toxoid B (CdtB) vaccine formulated with different mucosal adjuvants through microneedle immunization, and to provide ideas for the prevention and treatment of Clostridium difficile infection. Methods:CdtB vaccine was prepared with purified Clostridium difficile toxin B(TcdB) after formaldehyde detoxification. Female BALB/c mice were immunized with different doses of vaccine alone or in combination with mucosal adjuvants. The titers of specific serum IgG and fecal IgA were detected at 0 d, 7 d, 14 d, 28 d and 42 d after immunization. The protective effects of CdtB vaccine were evaluated by cell neutralization assay and Clostridium difficile challenge infection. Results:(1) With the increase of immune dose, the mice immunized with CdtB vaccine alone by microneedle not only produced better serum specific IgG, but also had higher level of IgA in feces. (2) When the mice were immunized with CdtB vaccine containing LT or CTB adjuvant by microneedle, the trend of serum specific IgG titer in each group increased with the increase of immune dose, especially in the group containing LT adjuvant. There were significant differences in the trend of specific IgA titer in feces between the adjuvant groups and the group without adjuvant, but the adjuvant effect was not obvious. (3) No significant difference in serum IgG titer was observed between the mice immunized with 10 μg CdtB by microneedle or intraperitoneal injection, but microneedle immunization significantly increased fecal IgA level. (4) The neutralization titers of specific antibodies in mouse serum after immunization and the test results of challenge protection in mice confirmed that the use of CdtB vaccine had certain protective effects.Conclusions:CdtB vaccine had better immune effects in mice through microneedle immunization, but the adjuvant effects of LT and CTB were not significant.

Homocysteine(Hcy) is an intermediate product of methionine metabolism.It is considered that Hcy is an independent etiological factor of cardiovascular disease,and blood Hcy level is closely related to many diseases.Patients with kidney disease may have different levels of homocysteine.The study has found that Hcy may not only be related to kidney damage,but also make the risk of cardiovascular disease in patients with kidney disease increased.The relationship between Hcy and kidney disease is briefly introduced in this article in order to provide a new basis for prevention,diagnosis and treatment of kidney disease and complications.