The cooccurrence of NPM1, FLT3-ITD, and DNMT3A mutations (i.e., triple mutation) is related to dismal prognosis in patients with acute myeloid leukemia (AML) receiving chemotherapy alone. In this multicenter retrospective cohort study, we aimed to identify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut AML across four transplant centers in China. Fifty-three patients with triple-mutated AML receiving allo-HSCT in complete remission were enrolled. The 1.5-year probabilities of relapse, leukemia-free survival, and overall survival after allo-HSCT were 11.9%, 80.3%, and 81.8%, respectively. Multivariate analysis revealed that more than one course of induction chemotherapy and allo-HSCT beyond CR1 were associated with poor survival. To our knowledge, this work is the largest study to explore the up-to-date undefined role of allo-HSCT in patients with triple-mutated AML. Our real-world data suggest that allo-HSCT could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut in AML.
Humans ; Nucleophosmin ; Leukemia, Myeloid, Acute/mortality* ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; DNA Methyltransferase 3A ; Adult ; China ; Retrospective Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics* ; Middle Aged ; Prognosis ; fms-Like Tyrosine Kinase 3/genetics* ; Mutation ; Young Adult ; Transplantation, Homologous ; Nuclear Proteins/genetics* ; Adolescent ; Aged

(±)-Penicithrones A-D (1a/1b-4a/4b), four novel pairs of anthrone-cyclopentenone heterodimers characterized by a distinctive bridged 6/6/6-5 tetracyclic core skeleton, together with three previously identified compounds (5-7), were isolated from the crude extract of the mangrove-derived fungus Penicillium sp., guided by heteronuclear single quantum correlation (HSQC)-based small molecule accurate recognition technology (SMART 2.0) and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based molecular networking. The structural elucidation of new compounds was accomplished through comprehensive spectroscopic analysis, and their absolute configurations were determined using DP4+ ¹³C nuclear magnetic resonance (NMR) calculations and electronic circular dichroism (ECD) calculations. Compounds 1a/1b-4a/4b demonstrated moderate cytotoxicity against three human cancer cell lines HeLa, HCT116 and MCF-7 with half maximal inhibitory concentration (IC₅₀) values ranging from 15.95 ± 1.64 to 28.56 ± 2.59 μmol·L^-1.
Humans ; Penicillium/chemistry* ; Molecular Structure ; Cyclopentanes/isolation & purification* ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology* ; Tandem Mass Spectrometry ; Dimerization ; HeLa Cells ; Magnetic Resonance Spectroscopy

Zhuye Shigaotang， first recorded in ZHANG Zhongjing's Synopsis of the Golden Chamber （《金匮要略》）， is a commonly used prescription for treating heat syndrome in modern times. However， physicians of the past dynasties have different opinions on the mechanism of Zhuye Shigaotang in disease treatment. Based on HUANG Yuanyu's theory of Qi circulation， this paper holds that the root cause of the diseases treated by Zhuye Shigaotang is the deficiency of spleen and stomach in the middle energizer and the dysfunction of ascending and descending. The failure of Yin ascending leads to the failure of Yang transformation， and the failure of Yang descending causes the failure of Yin generation. As a result， heat and fire become predominant in the heart， lung， and stomach， which causes Qi counterflow and fluid consumption. Based on this pathogenesis， Zhuye Shigaotang is mainly composed of pungent， warm， sweet， and cold herbs. The combination of these herbs can protect the spleen and stomach and recover the Qi movement in the middle energizer， thereby clearing heat and fire， descending Qi， and promoting the generation of Qi and fluid. In clinical practice， this prescription can be applied to treating the syndromes of deficiency in spleen and stomach， dysfunction of middle energizer in transportation， dysfunction of ascending and descending， excessive heat and fire， and Qi counterflow and fluid consumption. The interpretation of Zhuye Shigaotang from the theory of Qi circulation can provide a new idea for differentiating syndromes， seeking causes， and developing prescriptions， which broadens the scope of clinical application of this prescription and provides a reference for interpreting ZHANG Zhongjing's method of compatibility.

Hydrocephalus is often treated with a cerebrospinal fluid shunt (CFS) for excessive amounts of cerebrospinal fluid in the brain. However, it is very difficult to distinguish whether the ventricular enlargement is due to hydrocephalus or other causes, such as brain atrophy after brain damage and surgery. The non-trivial evaluation of the consciousness level, along with a continuous drainage test of the lumbar cistern is thus clinically important before the decision for CFS is made. We studied 32 secondary mild hydrocephalus patients with different consciousness levels, who received T1 and diffusion tensor imaging magnetic resonance scans before and after lumbar cerebrospinal fluid drainage. We applied a novel machine-learning method to find the most discriminative features from the multi-modal neuroimages. Then, we built a regression model to regress the JFK Coma Recovery Scale-Revised (CRS-R) scores to quantify the level of consciousness. The experimental results showed that our method not only approximated the CRS-R scores but also tracked the temporal changes in individual patients. The regression model has high potential for the evaluation of consciousness in clinical practice.

Objective:To observe whether parathyroid hormone (PTH) 1-34 can block the negative osteogenesis of advanced glycation end products (AGEs) on bone marrow mesenchymal stem cells (BMSCs) in rats and its possible signaling pathways.Methods:BMSCs from 4-week-old SD rats were isolated and cultured with whole bone marrow method. The osteogenic induction fluid, bovine serum albumin(BSA), AGEs, AGEs combined with PTH1-34 were pretreated respectively. After 7 days, realtime fluorescence quantitative PCR (RT-PCR) was used to measure alkaline phosphatase (ALP), collagen-Ⅰ (COL-Ⅰ) mRNA expression level, and the expressions of β-catenin, osterix (OSX), runt-related transcription factor 2 (RUNX2), and receptor for advanced glycation end products protein were examined by Western blotting. Alizarin red staining mineralized nodules and quantitative detection were performed on 21 days. After the addition of Wnt pathway specific blocker Dickkopf-1 (DKK1) (1 μg/ml) to 10 -8 mmol/L of PTH1-34, the protein expression levels of β-catenin, OSX, and RUNX2 were detected again by Western blotting. Results:AGEs significantly inhibited the expression of ALP, COL-Ⅰ mRNA, β-catenin, OSX, and RUNX2 proteins ( P<0.05). PTH1-34 inhibited AGEs after pretreatment, the expression of ALP, COL-Ⅰ mRNA, and β-catenin, OSX, RUNX2 protein were higher than those of AGEs group ( P<0.05). The mineralized nodules stained with alizarin red showed reddish brown and increased OD value was detected quantitatively in PTH1-34 group, which was higher than that of AGEs group ( P<0.05). DKK1(1 μg/ml) reduced the expression of β-catenin, OSX proteins as compared with the BSA group ( P<0.05). Conclusion:PTH1-34 blocks AGEs′ negative osteogenesis to BMSCs through Wnt/β-catenin signaling pathway.