Enhanced Multiscale Human Brain Imaging by Semi-supervised Digital Staining and Serial Sectioning Optical Coherence Tomography.

A major challenge in neuroscience is to visualize the structure of the human brain at different scales. Traditional histology reveals micro- and meso-scale brain features, but suffers from staining variability, tissue damage and distortion that impedes accurate 3D reconstructions. Here, we present a new 3D imaging framework that combines serial sectioning optical coherence tomography (S-OCT) with a deep-learning digital staining (DS) model. We develop a novel semi-supervised learning technique to facilitate DS model training on weakly paired images. The DS model performs translation from S-OCT to Gallyas silver staining. We demonstrate DS on various human cerebral cortex samples with consistent staining quality. Additionally, we show that DS enhances contrast across cortical layer boundaries. Furthermore, we showcase geometry-preserving 3D DS on cubic-centimeter tissue blocks and visualization of meso-scale vessel networks in the white matter. We believe that our technique offers the potential for high-throughput, multiscale imaging of brain tissues and may facilitate studies of brain structures.

[The Mutated Gene Sequenced by NGS and the Correlation of Their Coexistent Mutual Exclusiveness in NPM1 Mutated Acute Myeloid Leukemia].

OBJECTIVE: To analyze the clinicobiological heterogeneity of NPM1 mutated (NPM1mut) acute myeloid leukemia (AML) detected by next generation sequencing (NGS) and their coexistence and mutual exclusivity relationship in the AML subtype. METHODS: The NGS data based on 112 genes related to blood disease in 238 newly diagnosed patients with NPM1mut were collected. The χ2 test and non-parametric test were used to analyze the distribution correlation between the genes in the mutational spectrum. RESULTS: Among all the patients, at least one co-mutation was detected out. The median number per case of the mutated genes, including NPM1mut was 4.5 (range 2－14), among them, there were 5.0 (range 2－10) for NPM1mut/FLT3-ITD+ and 4.0 (range 2－14) for NPM1mut/FLT3-ITD- cases, but it was no significant difference between the two groups (P=0.378). A total of 240 NPM1 mutational events were detected out in entire 238 NPM1mut patients, of which 10 (4.2%) were missense mutations, and were all found in NPM1mut/FLT3-ITD- patients. Most (9/10, 90%) of these NPM1 missense mutations were accompanied by AML subtype-defining cytogenetic or molecular abnormalities, of which 7 patients were in low risk or 2 in high risk. The most common NPM1mut coexisting mutations were DNMT3A (104, 43.7%), followed were FLT3-ITD (95, 39.9%) and FAT1 (57, 23.9%), FLT3-ITD and DNMT3A showed significant coexistence (P=0.005). FLT3-ITD showed significantly reciprocal exclusivity with FLT3-nonITD (P<0.001), NRAS (P<0.001), PTPN11 (P=0.017) and IDH1 (P=0.005), and showed an exclusivity inclination with KRAS (P=0.073). In addition, FLT3-nonITD along with KRAS (P=0.035), NRAS along with KRAS (P=0.008) and PTPN11 (P=0.039) coexisted significantly. CONCLUSION: Prognoses of AML involving less common NPM1 missense mutations should be stated on a case by case basis. The mutational landscape and co-occurrence and mutual exclusivity correlations of NPM1mut AML provide a mechanism explaining biological diversity and clinical heterogeneity in this AML subset.

A novel treatment regimen of granulocyte colony-stimulating factor combined with ultra-low-dose decitabine and low-dose cytarabine in older patients with acute myeloid leukemia and myelodysplastic syndromes.

BACKGROUND: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) unfit for intensive chemotherapy are emergent for suitable treatment strategies. Hypomethylating agents and low-dose cytarabine have generated relevant benefits in the hematological malignancies over recent decades. We evaluated the efficacy and safety of the novel treatment regimen consisting of ultra-low-dose decitabine and low-dose cytarabine, with granulocyte colony-stimulating factor (G-CSF) in this population of patients. METHODS AND MATERIALS: Patients aged more than 60 years with newly diagnosed AML/MDS were enrolled to receive therapy combined of 300 µg subcutaneously per day for priming, decitabine 5.15-7.62 mg/m2/d intravenously and cytarabine 15 mg/m2/d twice a day subcutaneously and G-CSF for consecutive 10 days every 28 days. The study enrolled 28 patients unfit for standard intensive chemotherapy. The median age of patients was 68 years (range 60-83 years) and 20 (71.4%) patients harbored AML. The primary outcome was to evaluate overall response rate. RESULTS: Overall, this novel ultra-low-dose treatment regimen was well tolerated, with 0% of both 4- and 8-week mortality occurrence. Objective response rate (CR + CRi + PR in AML and CR + mCR + PR in MDS) was 57.1% after the first treatment course. Responses of hematologic improvement (HI) aspect were achieved in 18 of 28 (64.3%) patients, 11 (39.3%), 12 (42.9%), and eight patients (28.6%) achieved HI-E, HI-P, HI-N, respectively. CONCLUSIONS: Untreated elderly with AML/MDS were well tolerated and benefited from this novel ultra-low-dose treatment regimen.

Prognostic significance of monosomal karyotype in myelodysplastic syndrome: a meta-analysis.

OBJECTIVES: In myelodysplastic syndrome (MDS), the prognostic role of monosomal karyotype (MK), defined as at least two autosomal monosomies or a single monosomy associated with at least one additional structural abnormality, remained controversial. Therefore, we conducted a meta-analysis to address this issue. METHODS: PubMed, Embase, Web of Science, Medline, and the Cochrane Library were retrieved. We extracted hazard ratios (HRs) and the corresponding 95% confidential intervals (CIs) for overall survival (OS) on patients with MK versus those without, as well as on MK patients with monosomies of chromosome 7 and/or 5 versus those without from the available studies. RESULTS: Seventeen studies covering 7500 patients were included this meta-analysis. The pooled HRs indicated MK had a negative impact on OS in MDS (pooled HR: 2.484, 95%CI: 2.033-3.036, P < .001), in MDS patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) (pooled HR: 2.150, 95%CI: 1.861-2.48, P < .001), and in MDS with complex karyotype (CK) (pooled HR: 2.56, 95%CI: 2.032-3.036, P = .01). However, monosomies of chromosome 5 and/or 7 had no impact on OS in MDS with MK (pooled HR: 1.330, 95%CI: 0.827-2.139, P = .240). Meta-regression indicated that therapy was the origin of the heterogeneity (P = .012). DISCUSSION: Our meta-analysis indicated that MK has a negative impact on OS in MDS, in MDS patients undergoing allo-HSCT, and MDS with CK, but monosomies of chromosome 5 and/or 7 have no impact on OS in MDS with MK. The heterogeneity reflected the biologic and therapeutic heterogeneity of MDS. CONCLUSION: MK is associated with poor prognosis in MDS, the underlying mechanism needs further exploring.

Chronic Myelomonocytic Leukemia following Multicentric Castleman Disease.

Multicentric Castleman disease (MCD) is a rare nonmalignant lymphoproliferative disorder presenting systemic symptoms such as fever, night sweats, fatigue, anemia, effusions, and multifocal lymphadenopathy. The etiology of MCD has not been clarified to date. The coexistence of MCD with chronic myelomonocytic leukemia (CMML) has been rarely reported. Although the pathogenesis remains unclear, this association probably reflects an incidental and fortuitous finding rather than the alteration of a common pluripotent stem cell precursor. Herein, we report on one case of MCD coexisting with CMML and elucidate the underlying mechanism of pathology in some aspects.

Arsenic trioxide induces apoptosis in human platelets via C-Jun NH2-terminal kinase activation.

Arsenic trioxide (ATO), one of the oldest drugs in both Western and traditional Chinese medicine, has become an effective anticancer drug, especially in the treatment of acute promyelocytic leukemia (APL). However, thrombocytopenia occurred in most of ATO-treated patients with APL or other malignant diseases, and the pathogenesis remains unclear. Here we show that ATO dose-dependently induces depolarization of mitochondrial inner transmembrane potential (ΔΨm), up-regulation of Bax and down-regulation of Bcl-2 and Bcl-XL, caspase-3 activation, and phosphotidylserine (PS) exposure in platelets. ATO did not induce surface expression of P-selectin and PAC-1 binding, whereas, obviously reduced collagen, ADP, and thrombin induced platelet aggregation. ATO dose-dependently induced c-Jun NH2-terminal kinase (JNK) activation, and JNK specific inhibitor dicumarol obviously reduced ATO-induced ΔΨm depolarization in platelets. Clinical therapeutic dosage of ATO was intraperitoneally injected into C57 mice, and the numbers of circulating platelets were significantly reduced after five days of continuous injection. The data demonstrate that ATO induces caspase-dependent apoptosis via JNK activation in platelets. ATO does not incur platelet activation, whereas, it not only impairs platelet function but also reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia in patients treated with ATO.