Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective To explore the predictive value of CXC chemokine receptor 2(CXCR2)and Zonula occluden-1(ZO-1)for postoperative cerebral vasospasm in subarachnoid hemorrhage(SAH)patients with ruptured intracranial aneurysm.Methods A total of 215 SAH patients with ruptured intracranial aneurysm admitted to our hospital between May 2020 and October 2023 were recruited,and according to occurrence of postoperative cerebral vasospasm or not,they were separated into a spasm group(70 cases)and a non-spasm group(145 cases).The spasm group was further divided into mild,moderate and severe subgroups(14,38 and 18 cases,respectively).ELISA was applied to detect the serum levels of CXCR2 and ZO-1;Spearman and Pearson corre-lation analyses,multivariate logistic regression analysis,and ROC curve analysis were applied to test the correlation,influencing factors,and predictive value of indicators,and their AUC values were calculated.Results The spasm group had significantly higher CXCR2 and ZO-1 levels,inci-dence of intracranial hemorrhage,and larger proportions of Glasgow coma scale(GCS)score of 3-8 at admission,Hunt-Hess grade Ⅲ,and Fisher grades m and Ⅳ than the non-spasm group(P＜0.01).Intracranial hemorrhage volume,Hunt-Hess grade and Fisher grade were positively correlated with CXCR2 and ZO-1 levels,and the GCS score at admission was negatively correlated with the levels of the two indicators in the SAH patients with ruptured intracranial aneurysm(P＜0.01).CXCR2 and ZO-1 were independent risk factors for postoperative cerebral vasospasm in these patients(P＜0.01).The AUC value of CXCR2,ZO-1 and their combination in predicting postoperative cerebral vasospasm was 0.839(95％CI:0.780-0.898),0.813(95％CI:0.750-0.876),and 0.910(95％CI:0.869-0.951),with the combination showing better predictive per-formance(Z=2.391,Z=3.266,P＜0.05).The serum levels of CXCR2 and ZO-1 in the severe subgroup were significantly higher than those in the moderate subgroup and then followed by the mild subgroup in order,with statistical differences(P＜0.01).Conclusion Serum CXCR2 and ZO-1 levels are associated with postoperative cerebral vasospasm in SAH patients with ruptured intracranial aneurysm,and can be used as potential biomarkers for prognosis prediction.

Alzheimer's disease (AD) is associated with the impairment of white matter (WM) tracts. The current study aimed to verify the utility of WM as the neuroimaging marker of AD with multisite diffusion tensor imaging datasets [321 patients with AD, 265 patients with mild cognitive impairment (MCI), 279 normal controls (NC)], a unified pipeline, and independent site cross-validation. Automated fiber quantification was used to extract diffusion profiles along tracts. Random-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with NC. Machine learning models using tract-based features showed good generalizability among independent site cross-validation. The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups. We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.
Humans ; White Matter/diagnostic imaging* ; Diffusion Tensor Imaging/methods* ; Alzheimer Disease/complications* ; Reproducibility of Results ; Cognition ; Cognitive Dysfunction/complications* ; Brain/diagnostic imaging*

Objective:To explore the characteristics of BCR-ABL1 kinase domain mutations in imatinib-resistant chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) patients from Northeast China and their impact on prognosis. Methods:The clinical data of 252 CML patients and 49 Ph + ALL patients who were admitted to the First Hospital of Jilin University from January 2013 to October 2018 were retrospectively analyzed. The samples of bone marrow or peripheral blood were collected from patients when imatinib treatment was not effective. Nested polymerase chain reaction (PCR) was used to amplify the BCR-ABL1 kinase domain, and Sequencing Analysis v5.4 software was used to analyze the mutation of BCR-ABL1 kinase domain. Patients were followed up for 6-48 months, and the survival analysis was performed. Results:Among 252 CML patients, the mutations in ABL1 kinase domain were found in 57 patients (22.6%), including 25 patients in the chronic phase, 21 patients in the accelerated phase and 11 patients in the blast crisis; 50 patients had 20 types of single point mutation, and the most common mutation types were E255K (16.0%, 8/50), T315I (14.0%, 7/50), M244V (8.0%, 4/50) and G250E (8.0%, 4/50), which were all concentrated in the P-loop and C-helix domains; 7 patients had double mutations; patients with multiple mutations had the worst prognosis, with a median overall survival (OS) time of 3.2 months. Among 49 Ph + ALL patients, 17 cases (34.7%) were positive for mutations in the BCR-ABL1 kinase domain, 14 patients had 12 types of single point mutation, and 3 patients had multiple mutations; the median OS time of patients with multiple mutations, mutations located in the P-loop and C-helix domains and mutations located in the other domains was 2.0, 8.0 and 18.0 months, and the difference in OS among the three groups was statistically significant ( P < 0.01). Conclusions:Among the imatinib-resistant CML and Ph + ALL patients from Northeast China, point mutations in the P-loop and C-helix domains are most commonly found. Multiple mutations, mutations in the P-loop and C-helix domains are related to the poor prognosis of the patients.

Objective:To analyze clinical phenotypes and pathogenic mutations of a patient with classic tuberous sclerosis complex.Methods:Clinical data was collected from a patient with classic tuberous sclerosis complex. Next-generation sequencing was performed to screen pathogenic gene variants, and Sanger sequencing to verify the mutations. Minigene plasmids were constructed and transfected into the human renal epithelial cell line 293T, and RNA was extracted for transcriptional analysis.Results:The patient clinically presented with recurrent epileptic seizures, facial angiofibroma, periungual fibroma, pulmonary lymphangioleiomyomatosis, renal angiomyolipoma and multiple osteosclerosis. Next-generation sequencing revealed a suspected pathogenic variant in the TSC2 gene in the patient. Sanger sequencing identified a heterozygous mutation c.336_336+15delGGTAAGGCCCAGGGCG in exon 4 of the TSC2 gene in the patient, but not in his parents or 100 unrelated healthy controls. Moreover, this mutation had not been previously reported. The minigene experiment showed changed mRNA sequence of the TSC2 gene in this patient with loss of the authentic splice site in exon 4 and insertion of a 74-bp intron, which shifted the splice site 90 bp downstream (r.336delins336+16_336+90) .Conclusion:The novel heterozygous mutation c.336_336+15delGGTAAGGCCCAGGGCG in exon 4 of the TSC2 gene can lead to aberrant splicing, and may contribute to tuberous sclerosis complex in this patient.

Objective:To investigate the relationship between monocyte-to-lymphocyte ratio (MLR) in serum and the all-cause mortality in patients with acute paraquat (PQ) poisoning.Methods:Patients with acute PQ poisoning in the First Affiliated Hospital of Nanchang University from December 2013 to October 2018 were retrospectively selected and followed up until July 1, 2019. The primary endpoint was all-cause mortality. Patients were classified into quartiles based on serum MLR and also dichotomized based on the optimal cutoff at a MLR of 0.61, determined from the receiver operating characteristic (ROC) curve analysis. The Kaplan-Meier curve was used for survival analysis. Multivariate Cox regression analysis was performed to identify risk factors, and ROC curve was applied to analyze the predictive efficacy of MLR in all-cause mortality of acute PQ patients.Results:Of the 117 patients included in the study, 49 (41.88%) patients were male and 68 (58.12%) were female with a mean age of 36.91±16.00 years. The total mortality was 59.8% (70/117). On the Kaplan-Meier analysis, patients in quartile 4 had worse prognosis than patients in quartiles 1, 2 and 3 (Log-rank=33.376, P<0.01), and patients with MLR≥0.61 had a significantly higher all-cause mortality than those with MLR<0.61 (Log-rank=26.451, P<0.01). Cox regression model analysis showed that MLR was an independent predictor of all-cause mortality on the quartile analysis (quartile 4 vs. quartile 1: hazard ratio 2.773, 95% confidence interval ( CI): 1.250 to 6.154, P=0.012). ROC curve showed that the optimal cut-off value of MLR was calculated to be at 0.61, the area under the curve (AUC) was 0.684 (95% CI: 0.591-0.767, P=0.0002), with a sensitivity of 47.14% and a specificity of 91.49%. Conclusions:High MLR was associated with mortality risk in patients with acute PQ poisoning, and MLR may be an effective predictor of all-cause mortality in this population.

OBJECTIVE: To explore the genetic basis for a patient diagnosed with tuberous sclerosis complex (TSC). METHODS: Peripheral blood samples of the patient and his parents were collected for the extraction of genomic DNA. Next generation sequencing (NGS) was carried out to detect potential variant, and the result was verified by Sanger sequencing. RESULTS: The patient was found to harbor a heterozygous c.1053delG (p.Glu352SerfsX10) frameshifting variant of the TSC2 gene. The same variant was not found in his unaffected parents and 100 unrelated healthy controls. Based on the American College of Medical Genetics and Genomics guidelines, the variant was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION The novel c.1053delG (p.Glu352SerfsX10) frameshifting variant of the TSC2 gene probably underlay the TSC in this patient.
Genomics ; Heterozygote ; Humans ; Mutation ; Tuberous Sclerosis/genetics* ; Tuberous Sclerosis Complex 2 Protein/genetics*

Objective:This paper aimed to explore the problems and solutions in the management of Investigator-Initiated Trail (IIT) in medical institutions, to provide suggestions particularly in the absence of relevant high-level policy support.Methods:By combining literature review with working practice experiences, this paper analyzed the current situation of IIT’s management and the rationale, put forward suggestions.Results:IIT related problems identified including as the responsible entities of the management, research topics selection, protocol design, continuity, research team construction, ethical review and the cultivation of research management personnel. The centralized management will help the standardized management of such projects, the training of investigators and team building, the review awareness strengthening of the ethics committee, improvement of management ability.Conclusions:IIT plays an important role in promoting the development of medical scientific research. Medical institutions should integrate resources, provide platforms, train investigators assure the quality of IITs.

OBJECTIVE: To identify pathogenic mutation of TSC1 and TSC2 genes in a patient with long-time misdiagnosis of epilepsy. METHODS: Peripheral blood samples and clinical data of the patient and her 2 parents were collected. Potential mutation of TSC1 and TSC2 genes were detected by direct sequencing. RESULTS: The patient had frequent episodes of epilepsy in addition with Shagreen patches for 10 years. A frame-shifting mutation c.2509_2512delAACA was detected in exon 20 of the TSC1 gene. This same mutation was not found in her unaffected parents. CONCLUSION The recurrent frame-shifting mutation c.2509_2512delAACA (p.Asn837ValfsX11) of the TSC1 gene probably underlies the disease in this patient.
Diagnostic Errors ; Epilepsy ; diagnosis ; genetics ; Female ; Frameshift Mutation ; Humans ; Tuberous Sclerosis ; diagnosis ; genetics ; Tuberous Sclerosis Complex 1 Protein ; genetics ; Tuberous Sclerosis Complex 2 Protein ; genetics

Objective: To identify pathogenic mutation of TSC1 and TSC2 genes in a patient with long-time misdiagnosis of epilepsy. Methods: Peripheral blood samples and clinical data of the patient and her 2 parents were collected. Potential mutation of TSC1 and TSC2 genes were detected by direct sequencing. Results: The patient had frequent episodes of epilepsy in addition with Shagreen patches for 10 years. A frame-shifting mutation c. 2509_2512delAACA was detected in exon 20 of the TSC1 gene. This same mutation was not found in her unaffected parents. Conclusion The recurrent frame-shifting mutation c. 2509_2512delAACA (p.Asn837ValfsX11) of the TSC1 gene probably underlies the disease in this patient.