From Multiple Myeloma to Acute Myeloid Leukemia: A Case Report of a 61-year-old Woman after 8 Years of Chemotherapy and Immunotherapy.

BACKGROUND: As the second most prevalent hematologic malignancy, multiple myeloma (MM) affects plasma cells and is characterized by chromosomal abnormalities, particularly involving the immunoglobulin heavy chain switch region. MM represents a biologically and clinically heterogeneous hematological malignancy that serves as a clonal evolution model, exhibiting clonal heterogeneity throughout all stages from monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM. Although significant progress has been made in the treatment of MM, leading to improved patient outcomes, concerns are arising regarding disease relapse due to the presence and selection of pre-existing resistant clones or selective pressure during therapy. CASE PRESENTATION: We present a case of multiple myeloma (MM) in a female patient, who underwent an 8-year course of treatment, including chemotherapy, immunomodulators, hematopoietic stem cell transplantation, CD38 monoclonal antibody, and chimeric antigen receptor T-cell (CAR-T), and was recently diagnosed with concurrent progressive MM and acute myeloid leukemia (AML). This patient has witnessed the evolution of MM treatment paradigms. CONCLUSION: In this course, disease relapses occurred twice, one of which was manifested by a light chain escape (LCE). Moreover, through the course of the disease in this patient, we review the process of clonal evolution that may be relevant.

Optimal Rituximab Monotherapy in Splenic Marginal Zone Lymphoma (SMZL): A Case Report and Brief Review.

INTRODUCTION: Splenic marginal zone Lymphoma (SMZL) is a rare, chronic B lymphocyte proliferative disease. Generally, SMZL is accompanied by circulating atypical villous lymphocytes, known as SMZL with villous lymphocytes. Rituximab is a chimeric monoclonal antibody to CD20; recent but limited studies have confirmed its effectiveness in treating SMZL. Given the low incidence and selection of treatment, statistical comparisons of rituximab monotherapy with other available treatment options with the full range of data from previous clinical studies remain sparse. Here, we report a case of SMZL with villous lymphocytes treated by rituximab monotherapy, which is especially infrequently reported. CASE REPORT: A 63-year-old Chinese female was presented to the hospital with complaints of splenomegaly and pain in the spleen area. Immunohistochemistry analysis was positive for IGH, IGK, and IGL clonal rearrangement. Villous lymphocytes were found in peripheral blood and bone marrow, along with further immunotyping results. The case was considered as SMZL with villous lymphocytes. Based on the SMZLSG prognosis assessment, we applied rituximab monotherapy. After eight cycles of rituximab treatment, the patient's condition improved markedly, with blood constituent and size of the spleen returning to normal levels, achieving complete response, with no significant side effect observed. DISCUSSION: The patient provides a typical SMZL with villous lymphocytes case treated with rituximab monotherapy. Currently, the main treatment options include splenectomy and rituximab. After synthesizing a series of current views, we put forward our opinion about the selection of therapy for SMZL patients in order to gain maximum benefits for patients in need of treatment. CONCLUSION: Our analysis found no statistically significant difference between rituximab monotherapy and rituximab combined with chemotherapy, while rituximab treatments resulted in better therapeutic effects than chemotherapy. Rituximab monotherapy has favorable therapeutic effects and minor adverse effects (AEs) in treating SMZL.

Update on histone deacetylase inhibitors in peripheral T-cell lymphoma (PTCL).

Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.

Machine Learning and Deep Learning CT-Based Models for Predicting the Primary Central Nervous System Lymphoma and Glioma Types: A Multicenter Retrospective Study.

Purpose and Background: Distinguishing primary central nervous system lymphoma (PCNSL) and glioma on computed tomography (CT) is an important task since treatment options differ vastly from the two diseases. This study aims to explore various machine learning and deep learning methods based on radiomic features extracted from CT scans and end-to-end convolutional neural network (CNN) model to predict PCNSL and glioma types and compare the performance of different models. Methods: A total of 101 patients from five Chinese medical centers with pathologically confirmed PCNSL and glioma were analyzed retrospectively, including 50 PCNSL and 51 glioma. After manual segmentation of the region of interest (ROI) on CT scans, 293 radiomic features of each patient were extracted. The radiomic features were used as input, and then, we established six machine learning models and one deep learning model and three readers to identify the two types of tumors. We also established a 2D CNN model using raw CT scans as input. The area under the receiver operating characteristic curve (AUC) and accuracy (ACC) were used to evaluate different models. Results: The cohort was split into a training (70, 70% patients) and validation cohort (31,30% patients) according to the stratified sampling strategy. Among all models, the MLP performed best, with an accuracy of 0.886 and 0.903, sensitivity of 0.914 and 0.867, specificity of 0.857 and 0.937, and AUC of 0.957 and 0.908 in the training and validation cohorts, respectively, which was significantly higher than the three primary physician's diagnoses (ACCs ranged from 0.710 to 0.742, p < 0.001 for all) and comparable with the senior radiologist (ACC 0.839, p = 0.988). Among all the machine learning models, the AUC ranged from 0.605 to 0.821 in the validation cohort. The end-to-end CNN model achieved an AUC of 0.839 and an ACC of 0.840 in the validation cohort, which had no significant difference in accuracy compared to the MLP model (p = 0.472) and the senior radiologist (p = 0.470). Conclusion: The established PCNSL and glioma prediction model based on deep neural network methods from CT scans or radiomic features are feasible and provided high performance, which shows the potential to assist clinical decision-making.

Imbalance in the Gut Microbiota of Children With Autism Spectrum Disorders.

Background: Autism spectrum disorder (ASD) are complex behavioral changes manifesting early in childhood, which impacts how an individual perceives and socializes with others. The study aims to assess the disparities in gut microbiota (GM) amongst healthy controls and children with ASD. Methods: The study was performed on 25 children with ASD and 20 healthy children. Autistic symptoms were diagnosed and assessed with the Diagnostic and Statistical Manual for Mental Disorders and the Autism Treatment Evaluation Checklist (ATEC). Gastrointestinal (GI) symptoms were assessed with a GI Severity Index (GSI) questionnaire. The fecal bacteria composition was investigated by the high-throughput sequencing of the V3-V4 region of the 16S rRNA gene. The alpha diversity was estimated using the Shannon, Chao, and ACE indexes. The unweighted UniFrac analysis and the PCA plots were used to represent the beta diversity. LDA and LEfSe were used to assess the effect sizes of each abundant differential taxon. Results: Children with high GSI scores had much higher ATEC Total scores than those with lower GSI-scores. GI symptoms were strongly associated with symptoms of ASD. There was no difference in Chao, ACE, and Shannon indexes between ASD patients and healthy controls. Both groups showed a significant microbiota structure clustering in the plotted PCAs and significant differences in its composition at the family, order, genus, and phyla levels. There were also noteworthy overall relative differences in Actinobacteria and Firmicutes between both groups. Conclusions: This study shows the relationship between the clinical manifestations of Autistic symptoms and GI symptoms. ASD patients have dysbiosis of gut microbiota, which may be related to the onset of ASD. These findings may be beneficial for developing ASD symptoms by changing gut microbiota.

Identification of Key Genes and Pathways Associated with Hepatosplenic T-Cell Lymphoma (HSTCL) by Bioinformatics Analysis.

BACKGROUND: Prognosis of Hepatosplenic T-Cell Lymphoma (HSTCL) is very poor, while the molecular mechanism of this disease has rarely been investigated and remains mysterious. The aim of the study is to screen differentially expressed genes (DEGs) of patients with HSTCL and normal controls, explore the pathogenesis, and provide guidance for the gene diagnosis and precise treatment of HSTCL. METHODS: The genetic chip data GSE57520 of HSTCL was searched from the GEO database, and the quality control and DEGs screening were performed through BART online tools. In addition, FunRich software was used to perform gene enrichment and pathway analysis on the screened DEGs. Subsequently protein interaction network (PPI) was constructed via the STRING database and analyzed using the visual module of Cytoscape software. RESULTS: A total of 4,759 DEGs were obtained, including 2,501 up-regulated genes and 2,258 down-regulated genes (p < 0.05). The analysis of gene ontology (GO) showed that DEGs in cytology component (CC) mainly involved cytoplasm, nucleus, plasma membrane, Golgi apparatus, lysosome, and endoplasmic reticulum. Besides, DEGs in molecular function (MF) mainly included transcription factor activity, catalytic activity, transporter activity, transcription regulator activity, receptor signaling pathway complex, receptor activity. Moreover, DEGs in biological processes (BP) are mainly involved in base regulation, transport, energy pathways, metabolism, protein metabolism, and apoptosis. The results of the Kyoto Gene and Genome Encyclopedia (KEGG) analysis showed that the DEGs mainly include TRAIL, Beta1 integrin, integrin family, proteoglycan, S1P, and ErbB. Combined with Cytoscape software cytoHubba plug-in, protein interaction network (PPI) analysis showed that KIF20A, DLGAP5, PBK, TOP2A, ASPM, NEK2, KIF14, and DEPDC1B were the most abundant core genes. Module analysis showed that the three gene modules with the highest scores were mainly related to mitosis, epithelial cell adhesion and signal transduction, and the process of DNA damage. CONCLUSIONS: The DEGs of HSTCL patients versus healthy control groups were obtained through a variety of bioinformatics methods. KIF20A and DLGAP5 may become potential therapeutic targets for HSTCL. Also, the most abundant signaling pathway in DEGs was the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) - related pathway. Besides, related genes and expression characteristics of HSTCL pathogenesis were reanalyzed from distinctive perspectives, which might provide specific diagnostic markers and targeted therapy for HSTCL.

Discovery of Dysimmunity in Large Granular Lymphocytic Leukemia (LGLL) using Bioinformatic Analysis.

BACKGROUND: Large granular lymphocytic leukemia (LGLL) is a chronic lymphoproliferative disorder characterized by the clonal proliferation of large granular lymphocytes (LGL), classified as T and NK subtypes. Although JAK/STAT pathway gene mutation, such as STAT3/STAT5B, is the dominant driver in the proliferation of LGLL, immune abnormality remains an unsolved puzzle in the pathogenesis. METHODS: By means of bioinformatic method through the GEO dataset GSE39838, we performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, as well as protein-protein interaction network (PPI) module calculation. RESULTS: As a consequence, differentially expressed genes (DEGs) involved in immune regulation were detected to be related with LGLL, including C1QA, C1QC and CD163 etc. Among all the DEGs, 147 genes were up-regulated, while the number of down-regulated genes was 1,296. In the KEGG pathway of LGLL, infection and immunity were the primary alteration, including tuberculosis and rheumatoid arthritis (RA). However, meticulous experiments are required to validate. CONCLUSIONS: To sum up, dysimmunity might be another internal anomaly of LGLL, thus it is a reminder that immune regulation of LGLL should be paid more attention. Moreover, immune microenvironment studies in LGLL covering T, B, and NK cells probably contribute to the molecular pathology, aiming to contribute to the molecular pathology of the LGLL. Additionally, pharmaceutical development directed at immune molecules might be pre-dictive of targeted therapy era in LGLL.

Therapeutic effect of placenta-derived mesenchymal stem cells on hypoxic-ischemic brain damage in rats.

BACKGROUND: Oxidative stress is involved in the development of hypoxic-ischemic brain damage (HIBD). In this study, we investigated the therapeutic effects of placenta-derived mesenchymal stem cells (PD-MSCs) and explored the NF-E2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway in treating HIBD. METHODS: P7 rats were subjected to hypoxic-ischemic brain injury and randomly divided into four groups (control, HIBD, HIBD+PD-MSCs, and HIBD+fibroblasts). Forty-eight hours after the induction of HIBD, 5×10(5) of PD-MSCs were injected into cerebral tissue in the HIBD+PD-MSCs group, while the same dose of fibroblasts were injected in the HIBD+fibroblasts group. Morris Water Maze, gross and pathological changes were tested at P28. The level of malondialdehyde (MDA) was detected in rats' hippocampus. RT-PCR and western blot analysis were used to evaluate the changes of Nrf2/HO-1. RESULTS: The HIBD group showed significantly longer escape latency and a lower frequency of original platform crossing in the Morris Water Maze compared with the control group. Rats receiving PD-MSCs showed significant improvement of HIBD. The pathological changes were evident after HIBD, but ameliorated in the PD-MSCs group. Compared with the control group, HO-1 and Nrf2 were up-regulated at gene and protein levels in the HI brain, beginning at 6 hours and peaking at 48 hours (P<0.05). The expression of HO-1 and Nrf2 in the PD-MSCs treatment group was more pronounced than in the HIBD group (P<0.01). PD-MSCs also decreased MDA production in the brain tissue. CONCLUSION: These results demonstrate that PD-MSCs have neuroprotective effect during the treatment of HIBD and that the mechanism may be partly due to alleviating oxidative stress.

A divide-conquer-recombine algorithmic paradigm for large spatiotemporal quantum molecular dynamics simulations.

We introduce an extension of the divide-and-conquer (DC) algorithmic paradigm called divide-conquer-recombine (DCR) to perform large quantum molecular dynamics (QMD) simulations on massively parallel supercomputers, in which interatomic forces are computed quantum mechanically in the framework of density functional theory (DFT). In DCR, the DC phase constructs globally informed, overlapping local-domain solutions, which in the recombine phase are synthesized into a global solution encompassing large spatiotemporal scales. For the DC phase, we design a lean divide-and-conquer (LDC) DFT algorithm, which significantly reduces the prefactor of the O(N) computational cost for N electrons by applying a density-adaptive boundary condition at the peripheries of the DC domains. Our globally scalable and locally efficient solver is based on a hybrid real-reciprocal space approach that combines: (1) a highly scalable real-space multigrid to represent the global charge density; and (2) a numerically efficient plane-wave basis for local electronic wave functions and charge density within each domain. Hybrid space-band decomposition is used to implement the LDC-DFT algorithm on parallel computers. A benchmark test on an IBM Blue Gene/Q computer exhibits an isogranular parallel efficiency of 0.984 on 786 432 cores for a 50.3 × 10(6)-atom SiC system. As a test of production runs, LDC-DFT-based QMD simulation involving 16 661 atoms is performed on the Blue Gene/Q to study on-demand production of hydrogen gas from water using LiAl alloy particles. As an example of the recombine phase, LDC-DFT electronic structures are used as a basis set to describe global photoexcitation dynamics with nonadiabatic QMD (NAQMD) and kinetic Monte Carlo (KMC) methods. The NAQMD simulations are based on the linear response time-dependent density functional theory to describe electronic excited states and a surface-hopping approach to describe transitions between the excited states. A series of techniques are employed for efficiently calculating the long-range exact exchange correction and excited-state forces. The NAQMD trajectories are analyzed to extract the rates of various excitonic processes, which are then used in KMC simulation to study the dynamics of the global exciton flow network. This has allowed the study of large-scale photoexcitation dynamics in 6400-atom amorphous molecular solid, reaching the experimental time scales.

Enhanced charge transfer by phenyl groups at a rubrene/C60 interface.

Exciton dynamics at an interface between an electron donor, rubrene, and a C(60) acceptor is studied by nonadiabatic quantum molecular dynamics simulation. Simulation results reveal an essential role of the phenyl groups in rubrene in increasing the charge-transfer rate by an order-of-magnitude. The atomistic mechanism of the enhanced charge transfer is found to be the amplification of aromatic breathing modes by the phenyl groups, which causes large fluctuations of electronic excitation energies. These findings provide insight into molecular structure design for efficient solar cells, while explaining recent experimental observations.

[In vitro effects of Wnt3a gene modification on mitigating damage of mouse bone marrow mesenchymal stem cells induced by Ara-C].

This study was aimed to investigate the protective effect of Wit3a gene modification on mouse bone marrow mesenchymal stem cells against the injury induced by Ara-C. The gene-modified MSC steadily expressing Wnt3a were established by adenovirus system. The acute direct damage effects of different concentrations of Ara-C on the unmodified MSC and the gene-modified MSC were assessed by using an in vitro culture system, and the corresponding controls were set. The proliferation and apoptosis of MSC exposed to Ara-C were detected by cell count kit-8 (CCK-8) and flow cytometry. The expression of BCL-2 protein related with cell apoptosis was assayed by Western blot. The results indicated that as compared with unmodified MSC, Ara-C exhibited a less inhibitory effect on the proliferation of gene-modified MSC. There was obvious difference between unmodified MSC and gene-modified MSC (p < 0.05). The proliferation of gene-modified MSC began to recover at 72 hours after removal of Ara-C. However, unmodified MSC showed sustained suppression of proliferation after withdrawal of Ara-C. In apoptosis, the apoptosis rate of gene-modified MSC induced by Ara-C was significantly lower than those of unmodified MSC (p < 0.05). In addition, the expression levels of BCL-2 protein in gene-modified MSC were up-regulated compared with unmodified MSC (p < 0.05). It is concluded that Wnt3a gene modification can significantly mitigate the damage of mouse bone marrow MSC induced by Ara-C.

Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia.

This randomized trial was performed to investigate the efficacy of low-dose rituximab in combination with glucocorticoids for treatment of patients with immune thrombocytopenia (ITP). Sixty-two patients were randomly separated into the glucocorticoids (control) and the experimental (glucocorticoids + rituximab) groups. Patients in both groups received dexamethasone 40 mg/day on days 1-4, followed by decrements of prednisone 60, 30, 15, 10 mg/day on days 5-7, 8-14, 15-21, 22-28, respectively. Patients in the experimental group also received rituximab 100 mg on days 7, 14, 21, 28. The overall response (OR) was similar in both groups at day 28 (experimental group vs. glucocorticoids group: 80.6 vs. 74.2%, P = .938); however, sustained response (SR) was more pronounced in the experimental group as compared to that in the glucocorticoids group (77.4 vs. 38.7%, P < .001). Both groups showed similar incidence of adverse events (experimental group vs. glucocorticoids group: 9.7 vs. 6.5%, P = .325). As expected, B cell depletion was seen in the experimental group. In addition, both groups experienced a significant up-regulation in Treg cell levels, but the up-regulation in the experimental group was maintained at an even higher level and persisted a longer time than those in the glucocorticoids group. Thus, low-dose rituximab combined with short-term glucocorticoids provides an alternative treatment for ITP prior to splenectomy.

[Effect of Wnt3a-transduced bone marrow mesenchymal stem cells on the proliferation of T lymphocytes].

OBJECTIVE: To observe the effect of Wnt3a-transduced mouse bone marrow mesenchymal stem cells (MSC) on the proliferation of T lymphocytes. METHODS: MSC were isolated from C57BL/6 mouse bone marrow and expanded in vitro, then identified by flow cytometry and their differentiation capacity into osteocytes and adipocytes were determined. Recombinant plasmids containing Wnt3a gene, were transfected with lipofectamine into HEK293 cells by the AdEasy system. Viral particles were collected to infect MSC and adenovirus vector expressing GFP (Ad-GFP) was used as control. The expression of GFP in MSC was observed using fluorescence microscopy and the protein levels of Wnt3a and ß-catenin were determined by Western blot. Wnt3a-transduced and Ad-GFP transduced MSC were separately cocultured with spleen lymphocytes stimulated by ConA, at the ratio of 1:100, 1:50 or 1:10 respectively. The proliferation rate of T lymphocytes was estimated by Cell Cout Kit-8 (CCK-8) and the level of cytokine by ELISA. RESULTS: FCM analysis showed that the MSC were highly positive for CD90.2, CD44 and negative for CD34, CD45, they could differentiate into osteoblasts and adipocytes after induction; The titer of recombinant adenoviruses was up to 1 × 10(10) pfu/ml. After infected with the adenoviruses, MSC had the strongest GFP expression at 72 h and the efficiency of infection was 50%-60%. The expressions of Wnt3a and ß-catenin protein in the Wnt3a-transduced MSC were significantly increased. MSC could suppress the proliferation of T lymphocytes in a dose-dependent manner. When MSC cocultured with spleen lymphocytes at 1:10 ratio, T lymphocyte proliferation rate and the level of IFN-γ were (55.41 ± 1.75)% and (326.70 ± 14.41) pg/ml respectively in Ad-GFP transduced MSC group, while in Wnt3a-transduced MSC group, they were (37.27 ± 2.66)% and (218.80 ± 12.93) pg/ml respectively. There was no effect on the production of IL-2. CONCLUSION: Compared to Ad-GFP transduced MSC, Wnt3a-transduced MSC exhibit a more potent inhibitory effect on the proliferation of T lymphocytes.