Objective:To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS).Methods:An adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was enrolled as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X).Results:Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c. 206+ 2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the patients mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+ PM2_Supporting). Conclusion:The heterozygous splice site variant c. 206+ 2T>G of the SMAD3 gene probably underlay the disease of this patient. The discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.

OBJECTIVE: To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS). METHODS: A adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was selected as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X). RESULTS: Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c.206+2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the proband's mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION The heterozygous splice site variant c.206+2T>G of the SMAD3 gene probably underlay the disease in this patient. Above discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.
Adult ; Humans ; Male ; Exome Sequencing ; Loeys-Dietz Syndrome/genetics* ; Mutation ; Pedigree ; Smad3 Protein/genetics*

Objective:To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS).Methods:An adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was enrolled as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X).Results:Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c. 206+ 2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the patients mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+ PM2_Supporting). Conclusion:The heterozygous splice site variant c. 206+ 2T>G of the SMAD3 gene probably underlay the disease of this patient. The discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.

Objective To understand the carrying situation and common variation of pathogenic genes of single gene hereditary disease in childbearing age population in Anhui province,to explore the establishment of clinical application network and referral model of carrier screening in Anhui province,and to explore the application value of expansible carrier screening(expanded carrier screening,ECS)in clinic.Methods Samples were collected from 604 individuals of childbearing age,all exhibiting a normal phenotype and a family history of inherited dis-ease.These samples were obtained during the first trimester or early stages of pregnancy(≤13+6 weeks).Based on high-throughput sequencing and special PCR analysis techniques,pathogenic variants associated with 220 disea-ses were detected,and related genes were detected in the spouses of positive carriers.Results As of May 16,2023,604 tested samples had been collected,and 340 carriers of the target disease had been detected;The posi-tive rate of pathogenic variation detection was 56.29％ ;A total of 499 pathogenic variants were detected,with each tested individual carrying 0-5 variants;216 cases,accounting for 35.76％ ,carried a single gene recessive dis-ease pathogenic variation,which was the most common.There were 95 cases carrying two types of single gene re-cessive genetic disease pathogenic variation,accounting for 15.73％ .As of now,302 couples have been reported,and a total of 7 high-risk couples have been found through screening,with a high-risk rate of 2.32％ .There are a total of 5 pairs with autosomal recessive genetic pattern(both spouses carry the same pathogenic gene),and 2 pairs with X-linked genetic pattern(the female carries the X-linked pathogenic gene).Conclusion In this study,we obtained the overall carrier and clinical application of target diseases as well as the carrier rates of causative genes of common single-gene genetic diseases in 604 subjects who underwent ECS testing,which could provide scientific guidance for the establishment of a clinical application network and referral model for carrier screening in Anhui Province.

Objective:To investigate the value of multi-parameter MRI habitat imaging in differentiating human epidermal growth factor receptor 2 (HER2) expression in breast cancer.Methods:This study was cross-sectional. A retrospective analysis was conducted on the clinical and imaging data of 86 cases of primary invasive breast cancer confirmed by pathology at the Second Affiliated Hospital of Shantou University from August 2018 to July 2023. All patients were female, aged 33 to 74 (51±10) years. All patients underwent breast MRI examinations, including T 1WI, T 2WI, diffusion-weighted imaging and dynamic contrast-enhanced MRI. The fuzzy C-means clustering algorithm was applied to cluster analysis of the volume ratio of the extracellular extravascular space (V e), the rate constant (K ep), the volume transfer constant (K trans), and the apparent diffusion coefficient (ADC) for all lesions. Different habitat subregions were segmented based on breast cancer. Blood perfusion of the lesion was quantified through mean values of K trans and K ep, and cell proliferation was evaluated by the mean values of ADC and V e in each subregion. Additionally, the percentage of each subregion′s volume in relation to the total lesion volume was calculated. The Mann-Whitney U test was used to compare the differences in the volume percentages of various habitat subregions between different HER2 expression status. The diagnostic performance of statistically significant parameters in determining HER2 status was evaluated using receiver operating characteristic curves and the area under the curve (AUC). Results:Among the 86 patients with invasive breast cancer, 27 were HER2 positive and 59 were HER2 negative. Among the HER2 negative patients, 37 had low and 22 had zero HER2 expression. The volume percentages of habitat subregions 1, 2, and 3 showed statistically significant differences between HER2 positive and HER2 negative patients ( Z=2.90, P=0.004; Z=-2.04, P=0.042; Z=-2.19, P=0.029), with AUC values of 0.696, 0.638, and 0.648, respectively, for predicting HER2 positive expression. The volume percentage of habitat subregion 2 showed a statistically significant difference between low and zero HER2 expression patients ( Z=2.85, P=0.004), with an AUC value of 0.724 for predicting low versus zero HER2 expression. Conclusions:The volume percentage of habitat subregion 1 effectively distinguishes HER2 status, and the volume percentage of habitat subregion 2 effectively distinguishes between low and zero HER2 expression patients. It has significant clinical implications for identifying potential candidates for HER2-targeted therapy.

Objective:To explore whether anlotinib or bevacizumab has better efficacy in patients with recurrent glioblastoma.Methods:The clinical characteristics and treatment data of patients with recurrent glioblastoma admitted to Ren Ji Hospital,Shanghai Jiao Tong University School of Medicine,were collected retrospectively.All patients received maximal resection of the tumor combined with postoperative adjuvant radiotherapy and chemotherapy,and the recurrence was detected by head contrast-enhanced MRI.According to the choice of anti-vascular therapy,the patients were divided into anlotinib group and bevacizumab group.Survival curves were drawn to compare the overall survival time of the two groups of patients,and subgroup analysis was performed according to the basic information of the patients and whether they received temozolomide chemotherapy or radiotherapy after recurrence.Results:A total of 37 patients were enrolled in the study,19 in the anlotinib group and 18 in the bevacizumab group.The median overall survival time was 16.3 months,with 19.6 months in the anlotinib group and 12.8 months in the bevacizumab group.However,survival analysis showed that there was no significant difference in survival time between the anlotinib group and the bevacizumab group(P=0.88).Further subgroup analysis showed that there was no significant difference in survival time between the two groups in all subgroups.Conclusion:This study provided an initial indication of the efficacy of anlotinib in patients with recurrent glioblastoma and suggested that oral anlotinib may be a viable option for patients who were unable to tolerate bevacizumab or who had.

Objective:To explore whether anlotinib or bevacizumab has better efficacy in patients with recurrent glioblastoma.Methods:The clinical characteristics and treatment data of patients with recurrent glioblastoma admitted to Ren Ji Hospital,Shanghai Jiao Tong University School of Medicine,were collected retrospectively.All patients received maximal resection of the tumor combined with postoperative adjuvant radiotherapy and chemotherapy,and the recurrence was detected by head contrast-enhanced MRI.According to the choice of anti-vascular therapy,the patients were divided into anlotinib group and bevacizumab group.Survival curves were drawn to compare the overall survival time of the two groups of patients,and subgroup analysis was performed according to the basic information of the patients and whether they received temozolomide chemotherapy or radiotherapy after recurrence.Results:A total of 37 patients were enrolled in the study,19 in the anlotinib group and 18 in the bevacizumab group.The median overall survival time was 16.3 months,with 19.6 months in the anlotinib group and 12.8 months in the bevacizumab group.However,survival analysis showed that there was no significant difference in survival time between the anlotinib group and the bevacizumab group(P=0.88).Further subgroup analysis showed that there was no significant difference in survival time between the two groups in all subgroups.Conclusion:This study provided an initial indication of the efficacy of anlotinib in patients with recurrent glioblastoma and suggested that oral anlotinib may be a viable option for patients who were unable to tolerate bevacizumab or who had.

Objective:To evaluate the role of nucleotide-binding oligomerization domain-2 (NOD2) in dorsal root ganglion in the development of neuropathic pain (NP) in rats.Methods:Thirty-two adult male SPF Sprague-Dawley rats, weighing 240-260 g, aged 2-3 months, were divided into 4 groups ( n=8 each) using a random number table method: control group (group C), NP group (group S), negative control siRAN group (group N), and NOD2-siRNA group (group R). In N and R groups, 1×10 8 IFU/ml negative control siRNA and NOD2-siRNA 10 μl were intrathecally injected, respectively, once a day for 3 consecutive days.Normal saline 10 μl was intrathecally injected once a day for 3 consecutive days in C and S groups.The model of NP was established using spared nerve injury (SNI) at 2 weeks after intrathecal injection.The mechanical paw withdrawal threshold (MWT) was measured at 1 day before surgery and 1, 3, 7, 10, 14 and 28 days after SNI.Animals were sacrificed after measuring pain threshold on day 28, and the dorsal root ganglions (DRGs) of the lumbar segment (L 4-6) were removed for determination of the expression of NOD2 (by Western blot) and expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), IL-6 and NOD2 mRNA (using quantitative real-time polymerase chain reaction). Results:Compared with group C, MWT was significantly decreased at each time point after SNI, and the expression of NOD2 protein and mRNA and TNF-α, IL-1β and IL-6 mRNA in DRGs was up-regulated in group NP ( P<0.01). Compared with group NP, MWT was significantly increased at each time point after SNI, and the expression of NOD2 protein and mRNA and TNF-α, IL-1β and IL-6 mRNA in DRGs was down-regulated in group R ( P<0.01), and no significant change was found in the parameters mentioned above in group N ( P>0.05). Conclusion:The mechanism underlying the development of NP may be related to the up-regulation of NOD2 expression in DRGs, thus further promoting the expression of pro-inflammatory factors in rats.

To analyze the prognostic factors for patients with or without cardiovascular diseases after craniotomy for aneurysm clipping, and to provide evidences for the improvement of perioperative management in these patients.
 Methods: We collected 297 patients who underwent craniotomy for aneurysm clipping in Xiangya Hospital of Central South University from May 2016 to February 2017. The patients were divided into two groups: the cardiovascular disease group and the non-cardiovascular disease group. The perioperative clinical data, neurological function assessments at admission and discharge and Glasgow Outcome Scale (GOS) scores of one-year-follow-up after discharge were analyzed. The primary outcome of this study was the GOS scores collected at one year after discharge. The secondary outcomes were the lengths of their ICU stay, neurological functions at discharge and adverse events morbidity during the hospitalization.
 Results: A total of 241 patients were eventually enrolled. There was no significant difference in their general data between the two groups except for their ages. The GOS scores of the one-year-follow-up were significantly different between the two groups (P=0.007). The lengths of ICU stay, neurological dysfunctions at discharge and adverse events morbidity during hospitalization were also significantly different (P=0.036, P=0.011, P=0.005, respectively). A multivariate logistic regression analysis in which GOS score was the dependent variable with age adjusted also supported the previous results that long-term prognosis was not significantly correlated with the age of patients (P>0.05), but it was correlated with cardiovascular disease and sanity at admission (P=0.001). In patients with cardiovascular diseases, there was significantly different in perioperative mortality and neurological recovery of patients who had or had not cardiovascular events (P=0.006, P=0.001, respectively).
 Conclusion: Undergoing craniotomy for aneurysm clipping, patients with cardiovascular diseases have worse outcomes in both of short and long terms. Perioperative treatments for cardiovascular disease could not only improve postoperative neurological deficits, but also reduce mortality for these patients.
Craniotomy ; Humans ; Intracranial Aneurysm ; Postoperative Period ; Prognosis ; Treatment Outcome

Objective To explore the prognostic values of telomerase reverse transcriptase promoter (TERTp) mutation and 1p/19q co-deletion in newly-diagnosed O6-methylguanine-DNA methyltransferase (MGMT) promoter un-methylated/isocitrate dehydrogenase (IDH) wild-type glioblastoma multiform (GBM). Methods A total of 82 patients pathologically newly-diagnosed MGMT promoter un-methylated/IDH wild-type GBM, admitted to our hospitals from March 2016 to November 2018, were included in this study. TERTp mutations (TERTp wild-type and TERTp mutation [C228 mutation and C250 mutation]) in GBM specimens were detected by PCR sequencing, 1p/19q co-deletion in GBM specimens was detected by fluorescence in situ hybridization (FISH), and clinical data, adverse reactions and prognoses of patients with different molecular typing were compared. Results There were 33 patients in the TERTp wild type group with mean age of 48 years, and 49 patients in the TERTp mutation group with mean age of 59 years; the difference of age was significant (P<0.05); there were no statistical differences in gender distribution, Karnofsky performance status (KPS) scores, tumor sites and surgical resection degrees between the two groups (P>0.05). There were 8 patients with 1p/19q co-deletion and 74 patients without 1p/19q co-deletion; no significant differences in above clinical parameters were noted between the two groups. There were no statistically significant differences in the incidences of bone marrow suppression, digestive tract response and fatigue, disease progression rate, or survival rate between patients from TERTp wild type group and TERTp mutation group, and between patients with 1p/19q co-deletion and patients without 1p/19q co-deletion (P>0.05). No significant differences in above clinical parameters, disease progression rate, and survival rate were noted between patients with C228 mutation and C250 mutation (P>0.05). Conclusion TERTp typing and 1p/19q co-deletion status do not have prognostic value in newly-diagnosed MGMT un-methylated/IDH wild-type GBM patients; patients with TERTp mutations have older age than wild-type patients; patients with C250 mutation trend to have higher survival rate than those with C228 mutation.