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.

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 investigate the relationship between caspase recruitment domain protein 9 (CARD9) level and inflammatory response in cerebral tissue of ischemic brain injury mice.Methods:Totally 24 SPF BALB/c male mice were randomly(random number) divided into 4 groups: sham operated group, ischemia 3 h group, ischemia 6 h group, and ischemia 12 h group, 6 mice in each group. The permanant middle cerebral artery occlusion (pMCAO) model in the ischemia groups was established by using line embolism to block blood flow. Mice in each group were sacrificed at the predetermined time point after operation. CARD9 and p-p65NF-κB levels were detected by Western blot, and the inflammatory factors mRNA and protein including TNF-ɑ, IL-lβ and IL-6 were detected by RT-PCR and ELISA, respectively. The data were analyzed by SPSS 21.0 software, the comparison of measurement data between each two groups was analyzed by independent sample t test, and the correlations between CARD9 and inflammatory factors were analyzed by Pearson analysis. Results:Compared with the sham operated group, the CARD9 levels in the ischemia 3 h, 6 h and 12 h groups were increased significantly [(0.325±0.011) vs. (0.462±0.019), P=0.036; (0.735±0.036), P=0.003; (0.903±0.024), P=0.001], the p-p65NF-κB levels in the ischemia 3 h, 6 h and 12 h groups were increased significantly [(0.227±0.016) vs. (0.316±0.017), P=0.041; (0.445±0.021), P=0.016; (0.671±0.039), P=0.008], the TNF-ɑ levels in the ischemia 3 h, 6 h and 12 h groups were significantly increased [(0.53±0.06) vs. (1.06±0.10), P=0.009; (1.47±0.15), P=0.004; (2.78±0.18), P=0.001], the IL-lβ levels in the ischemia 3 h, 6 h and 12 h groups were significantly increased [(0.55±0.07) vs. (1.01±0.11), P=0.009; (2.13±0.16), P=0.003; (3.09±0.18), P=0.001], and the IL-6 levels in the ischemia 3 h, 6 h and 12 h groups were significantly increased [(1.99±0.18) vs. (4.10±0.41), P=0.006; (8.54±0.84), P=0.002; (11.56±0.96), P=0.001]. Pearson analysis showed that CARD9 was positively correlated with the p-p65NF-κB and TNF-ɑ, IL-lβ, IL-6 ( r=0.894, P=0.001; r=0.747, P=0.008; r=0.810, P=0.001; r=0.773, P=0.007). Conclusions:A positive correlation exists between CARD9 and inflammatory responses in the early stage of ischemic brain injury in mice

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: To investigate the effect of 1q21 amplification (1q) on the therapeutic response and prognosis of bortezomib(Btz) in the treatment of newly diagnosed multiple myeloma (MM) patients. Methods: A total of 180 newly diagnosed MM were included for analyses of clinical characteristics, cytogenetics, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), retrospectively. Gene expression profiling (GEP) was analyzed using publicly available R2 platform. Results: ① In 180 patients, 1q was found in 51.1% cases. Of them, 174 patients had complete follow-up data, including 88 cases with 1q and 86 without 1q (non-1q). ②Incidence of 1q was positively associated with percentage of IGH rearrangement (72.2%, P=0.017) and 1p deletion (1p) (27.8%, P=0.040). ③ The median PFS was 15.0 and 20.3 months for the 1q group and non-1q group, and the median OS was 29.4 and 44.0 months, respectively. Both PFS and OS of 1q group was significantly shorter than those of the non-1q group (P=0.029 and 0.038, respectively). Multivariate analysis further revealed that 1q was an independent prognostic factor for both PFS (HR=1.910, 95% CI 1.105-3.303, P=0.020) and OS (HR=2.353, 95% CI 1.090-5.078, P=0.029). ④ In 91 evaluable cases with 1q, very good partial remission (VGPR) rate was higher after treatment with Btz than those without Btz (62.1% vs 40.0%, P=0.032). Of note, the patients with 1q who received auto-HSCT after induction with Btz had significantly longer PFS than those without auto-HSCT (19 months vs 13 months, P=0.048). ⑤GEP analysis revealed that 1q21 amplification predominantly up-regulated expression of >50% genes within 1q21 region, and also altered expression of 28% genes in chromosome 1 and 10% genes in whole genome, particularly related to DNA repair and cell cycle. Conclusions 1q is an independent adverse prognostic factor in patients with newly diagnosed MM. It is often associated with 1p deletion and IGH rearrangement. Patients with 1q respond well to Btz-based regimen, but they fail to gain long-term benefit from this treatment itself. However, auto-HSCT following Btz induction might improve survival of patients with 1q, suggesting a potential strategy to treat this high-risk subset of MM. GEP analysis warrants further attention in understanding the mechanisms underlying the high-risk of 1q.

Objective: To explore the relationship among somatostatin (SS), neuron-specific enolase (NSE) and early vascular dementia.Methods: A total of 40 patients with early vascular dementia treated in our hospital were selected as vascular dementia group, another 40 inpatients with cerebral infarction (CI) treated during the same period were enrolled as CI group.Plasma NSE and SS levels were compared between two groups during different periods.Results: Compared with CI group at onset, one month and three months after CI, there was significant rise in plasma NSE level[(22.08±7.05) ng/ml vs.(26.39±6.80) ng/ml, (23.92±4.25) ng/ml vs.(28.12±4.06) ng/ml, (25.55±4.72) ng/ml vs.(30.10±4.33) ng/ml], and significant reduction in plasma SS level[(1084.50±133.00) ng/ml vs.(748.30±129.10) ng/ml, (836.40±160.20) ng/ml vs.(624.25±140.50) ng/ml, (690.25±146.30) ng/ml vs.(432.70±151.00) ng/ml]in vascular dementia group, P<0.05 or <0.01.Plasma NSE level gradually rose and SS level gradually reduced along with the time went by(P<0.05 or <0.01).Conclusion: Early dynamic detection of somatostatin and neuron-specific enolase levels in patients with cerebral infarction may help to early diagnosing and treatment of vascular dementia.

Objective: To investigate the community promotion feasibility of superficial needling plus club swing for post-stroke motion impairment of the shoulder joint. Methods:A total of 180 cases (duration <1.5 years) with post-stroke motion impairment of the shoulder joint were recruited from three community health centers in Changning District, 60 from each community. They were randomly allocated into an observation group (n=90) and a control group (n=90). Patients in both groups received standard internal and rehabilitation care. Patients in the observation group received additional superficial needling plus club swing. The visual analogue scale (VAS) was conducted before and 60 d after the treatment to evaluate the severity of shoulder pain. The active movement of the shoulder joint and activities of daily living (ADL) were also observed. Results:There were no between-group statistical differences before the treatment (allP>0.05). After a 60-day treatment, the shoulder pain severity, active range of motion of the shoulder joint and ADL in the observation group were significantly improved than those in the control group (allP<0.01). In addition, no adverse events were reported by participants in the observation group. Conclusion:Superficial needling plus club swing plays a positive role in improving post-stroke motion impairment of the shoulder joint. This safe, reliable and economical therapy has good patient compliance and is suitable for community promotion.

Objective To identify Chinese character writing related cortex (WRC) and its relationship with hand motor cortical areas. Methods Ten native Chinese-speaking, right-hand volunteers were recruited in the study. NTMS mapping was conducted during picture naming task. The WRC were mapped based on nTMS-induced impairment of Chinese character writing. The extent and area of WRC was calculated. The right-hand motor representations were mapped while motor-evoked potentials were produced under nTMS stimulation. EMG data and coordinates of positive stimulus were recorded. The relationship between WRC and hand motor cortex (HMC) was analyzed on the basis of area comparison and distance calculation. Results The cortical areas related to Chinese character writing were mapped successfully in all subjects by nTMS. WRC was primarily centered in left posterior middle frontal gyrus (pMFG) (86%,55/64). The mean WRC area (161.03 mm2 ±62.58mm2) was significantly smaller than the mean HMC area (589.50 mm2±227.34mm2) (P<0.001). The WRC and HMC were not conjoined or overlapped in the dominant hemisphere. The distance between those two was 12.58mm±2.71mm. Conclusions NTMS can provide reliable assistance in mapping WRC areas. The WRC is relatively fixed and centralized in pMFG but is not overlapped with the HMC.

OBJECTIVETo investigate the expressions of gamma aminobutyric acid transporter 1 (GAT-1) and glutamate decarboxylase 65 (GAD65) mRNA in different brain regions at brain propofol uptake equilibrium in dogs.

METHODSEighteen 12- to 18-month-old healthy hybrid dogs were randomized equally into control group (group C), low dose group (group L), and high dose group (group H). In groups L and H, anesthesia was administered by intravenous injection of 5.5 and 7.0 mg/kg propofol followed by propofol infusion at a constant rate of 55 and 70 mg·kg(-1)·h(-1) for 50 min, respectively. Blood samples were taken from the internal carotid artery and jugular vein to measure plasma propofol concentrations, and the brain tissues of the hypothalamus, sub thalamus, dorsal thalamus, hippocampus, pons, parietal lobe and frontal lobe were examined for GAT-1 and GAD65 mRNA expressions using quantitative real-time PCR.

RESULTSIn groups L and H, propofol infusion at a constant rate for 50 min resulted in comparable plasma propofol concentrations between the internal carotid artery and jugular vein (P>0.05), but the concentrations differed significantly between the two groups (P<0.01). GAT-1 mRNA levels in the hypothalamus and hippocampus were significantly higher in groups L and H than in group C (P<0.05 and P<0.01), but comparable between the former two groups. The variations of GAT-1 mRNA levels between the hypothalamus and hippocampus were similar in both group L [(61.26∓7.17)% and (79.34∓39.95)%, P>0.05] and group H [(74.64∓19.63)% and (97.12∓32.31)%, P>0.05]. GAT-1 mRNA levels in other brain regions showed no significant difference among the 3 groups. GAD65 mRNA levels were similar between group L and group H, but both significantly higher than that in group C (P<0.01). GAD65 mRNA in other brain regions had no significant difference among the 3 groups.

CONCLUSIONGAT-1 mRNA in the hypothalamus and hippocampus and GAD65 mRNA in the dorsal thalamus are upregulated when propofol uptake reaches an equilibrium in the brain of dogs.

Animals ; Brain ; drug effects ; metabolism ; Dogs ; GABA Plasma Membrane Transport Proteins ; genetics ; metabolism ; Glutamate Decarboxylase ; genetics ; metabolism ; Hippocampus ; drug effects ; metabolism ; Hypothalamus ; drug effects ; metabolism ; Propofol ; pharmacology ; RNA, Messenger ; genetics ; Thalamus ; drug effects ; metabolism