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This study investigated the role of constructing a dual network in toughening bio-based long-chain polyamide 610 (PA610) composites. Rheological studies were conducted to reveal the effects of toughening agent type and content on the material properties. According to the variation trend of mechanical properties and the appearance of a rheological low-frequency plateau of the materials, the percolation network concentration ϕ c of the toughening agent in the PA610 matrix was determined to be 13.5 vol.%. The interfacial interaction of the composite was evaluated through the percolation theory, and the scaling value v = 1.36 for both indicated the good affinity between PA610 and the toughening agent. Rheology results found that the combination of ethylene terpolymer (PTW) and maleic anhydride-g-styrene-b-(ethylene-butylene)-b-styrene (MAH-SEBS) could achieve an optimal balance between the mechanical properties and fluidity of the composites. Furthermore, the addition of ultra-high-molecular-weight polytetrafluoroethylene (PTFE), in conjunction with the toughening agent, facilitated the construction of a dual semi-interpenetrating network. The strengthened intermolecular interactions restricted the relative slippage and mobility of the polymer chains and therefore enhanced the strength and toughness of the material. This study provides new possibilities and approaches for optimizing the comprehensive properties of bio-based polyamide materials.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Entangled polymer solutions show different rheological behavior from melts in fast extensional flow. This discrepancy is not expected according to the classic tube model and is an urgent issue to be solved in polymer physics. While in the tube model the polymer concentration is considered to be homogeneous, we show that extensional flow-induced concentration gradient may happen in polymer solutions even with chemically identical solutes and solvents. Through labeling an aggregation-induced emission (AIE) probe on oligomeric solvents, the flow-induced concentration gradient is visualized by combining extensional rheology and ex situ fluorescence microscopy. Microdomains of oligomeric solvents with a length scale of tens of micrometers are observed, and their influence on rheological behavior cannot be ignored.

The jamming effect is critical in processing short fiber-reinforced thermoplastics (FRTs). Fiber jamming can induce discontinuous shear thickening (DST) in simple shear and result in fiber-matrix separation in more complex flows such as injection molding and compression molding of FRTs. The confinement effect commonly induces local jams and strongly enhances fiber jamming. However, the transient evolution of local fiber jams under confinement and its correlation with the tumbling of fibers are still elusive. In this study, we adopted rheo-PIV (particle image velocity) techniques to study this effect for glass fiber-reinforced thermoplastics (FRTs). The translational and tumbling motion of fiber were determined during rheological measurements, and the distribution of fiber orientation was determined by X-ray CT. Three shear banding regions appeared after the viscosity overshoot under high shear stress in suspensions with high fiber content, which was associated with the three regions of fiber orientation across the gap due to confinement. Shear banding was ascribed to the different tumbling speeds across the gap because of the different initial orientations and different wall confinements near and far from the wall. The local shear thickening and jamming behavior became most significant under intermediate confinement, and were affected by shear strain, shear stress, and fiber contents. 3D state diagrams were constructed to show the confinement effect on the evolution of shear banding and jamming.

Diffuse Large B Cell Lymphoma (DLBCL) is the most common form of blood cancer. Among the subtypes, the activated B-cell (ABC) subtype is typically more aggressive and associated with worse outcomes. However, the underlying mechanisms are not fully understood. In this study, we performed microarray analysis to identify potential ABC-DLBCL-associated genes. We employed Kaplan-Meier methods and cox univariate analysis to explore the prognostic value of the identified candidate gene Coiled-coil domain containing 50 (CCDC50). Additionally, we used DLBCL cell lines and mouse models to explore the functions and mechanisms of CCDC50. Finally, we isolated CCDC50-bearing exosomes from clinical patients to study the correlation between these exosomes and disease severity. Our results demonstrated that CCDC50 not only showed significantly positive correlations with ABC subtype, tumor stage and number of extranodal sites, but also suggested poor outcomes in DLBCL patients. We further found that CCDC50 promoted ABC-DLBCL proliferation in vitro and in vivo. Mechanistically, CCDC50 inhibited ubiquitination-mediated c-Myc degradation by stimulating the PI3K/AKT/GSK-3β pathway. Moreover, CCDC50 expression was positively correlated with c-Myc at protein levels in DLBCL patients. Additionally, in two clinical cohorts, the plasma CCDC50-positive exosomes differentiated DLBCL subtypes robustly (AUC > 0.80) and predicted disease severity effectively (p < 0.05). Our findings suggest that CCDC50 likely drives disease progression in ABC-DLBCL patients, and the CCDC50-bearing exosome holds great potential as a non-invasive biomarker for subtype diagnosis and prognosis prediction of DLBCL patients., (© 2023. The Author(s).)

Male sterility in plants provides valuable breeding tools in germplasm innovation and hybrid crop production. However, genetic resources for dominant genic male sterility, which hold great promise to facilitate breeding processes, are extremely rare in natural germplasm. Here we characterized the Sanming Dominant Genic Male Sterility in rice and identified the gene SDGMS using a map-based cloning approach. We found that spontaneous movement of a 1978-bp long terminal repeat (LTR) retrotransposon into the promoter region of the SDGMS gene activates its expression in anther tapetum, which causes abnormal programmed cell death of tapetal cells resulting in dominant male sterility. SDGMS encodes a ribosome inactivating protein showing N-glycosidase activity. The activation of SDGMS triggers transcription reprogramming of genes responsive to biotic stress leading to a hypersensitive response which causes sterility. The results demonstrate that an ectopic gene activation by transposon movement can give birth to a novel trait which enriches phenotypic diversity with practical utility., (© The Author(s) 2023. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

The self-assembly behaviors of AB n miktoarm star copolymers as one typical type of asymmetric architecture have been studied well in the past few decades due to their deflected phase boundaries. In particular, recently, they have attracted renewed theoretical interest due to their expanded spherical phase region that stabilizes complex Frank-Kasper spherical phases. However, previous theoretical studies have never considered AB n copolymers with unequal arm lengths, which is more or less the case for synthesized copolymers. In this work, we investigate the self-assembly behaviors of AB n miktoarm star copolymers with unequal B-arms using self-consistent field theory. We propose an intramolecular polydispersity index ( iĐ ) to quantify the distribution of unequal B-blocks. Accordingly, we further propose a simple quantity of an effective arm number n equ = n / iĐ for quantitatively comparing the phase boundaries between various AB n copolymer samples with different arm numbers or different distributions of B-blocks. Our results indicate that different AB n copolymers with equal n equ exhibit similar phase diagrams. On the other hand, we also found that the phase boundaries of two different samples with same n equ are not exactly overlapped. We speculate that the effect of spontaneous curvature may be mainly controlled by n equ , but the packing frustration of B-blocks may also be dependent on the other quantities that are closely related to the shape of the distribution of B-arms, such as higher order polydispersity indexes.

Background: Diffuse large B-cell lymphoma (DLBCL) is a kind of highly heterogeneous non-Hodgkin lymphoma, both in clinical and genetic terms. DLBCL is admittedly categorized into six subtypes by genetics, which contain MCD, BN2, EZB, N1, ST2, and A53. Dyslipidemia is relevant to a multitude of solid tumors and has recently been reported to be associated with hematologic malignancies. We aim to present a retrospective study investigating dyslipidemia in DLBCL based on the molecular subtypes., Results: This study concluded that 259 patients with newly diagnosed DLBCL and their biopsy specimens were available for molecular typing. Results show that the incidence of dyslipidemia (87.0%, p <0.001) is higher in the EZB subtype than in others, especially hypertriglyceridemia (78.3%, p = 0.001) in the EZB subtype. Based on the pathological gene-sequencing, patients with BCL2 gene fusion mutation are significantly correlative with hyperlipidemia (76.5%, p = 0.006) and hypertriglyceridemia (88.2%, p = 0.002). Nevertheless, the occurrence of dyslipidemia has no remarkable influence on prognosis., Conclusion: In summary, dyslipidemia correlates with genetic heterogeneity in DLBCL without having a significant influence on survival. This research first connects lipids and genetic subtypes in DLBCL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Shen, Shi, Zhao, Zhen, Sun, Li, Zhou, Yang, Wang, Huang, Wei, Huang, Meng, Yu, Tong, Jin and Xie.)

Recently, a few AB-type multiblock copolymers have been successfully designed to form stable square cylinder phase based on self-consistent field theory (SCFT) calculations. The previous works only identify the stability region of the square phase but not analyzing its stability, which is closely related to the free-energy landscape. In this work, we have reexamined the stability of the square phase in $\mathrm{B&#95;1 A&#95;1 B&#95;2 A&#95;2 B&#95;3}$ linear pentablock and $\mathrm{(B&#95;1AB&#95;2)&#95;5}$ star triblock copolymers by drawing the free-energy landscape with respect to the two dimensions of a rectangular unit cell. Our results demonstrate that the square phase continuously transfers to the rectangular phase as the degree of packing frustration is gradually released. Moreover, the prolate contour lines of the free-energy landscape indicate the weak stability of the square phase in the $\mathrm{B&#95;1 A&#95;1 B&#95;2 A&#95;2 B&#95;3}$ copolymer. In contrast, the stability of the square phase is notably improved in the $\mathrm{(B&#95;1AB&#95;2)&#95;5}$ copolymer due to its enhanced concentration of bridging configurations. Our work sheds light on the understanding of the stability of the square cylinder phase in block copolymers. Accordingly, we propose some possible strategies for further designing new AB-type block copolymer systems to obtain more stable square phase., (© 2023 Wiley-VCH GmbH.)

In this work, the microscopic distribution of antioxidant 1010 (AT1010) in blends of isotactic polypropylene (iPP) with an ethylene-octene copolymer (POE) was investigated in situ using the atomic force microscopy-infrared (AFM-IR) technique. Pellets of an iPP/POE blend containing AT1010 at a mass ratio of 79.5 : 20 : 0.5 were extruded at different screw speeds, and were then injection-molded into plates. The domain size of the POE disperse phase in the pellets was about 1 μm, regardless of the screw speed, and remained unchanged in the injection molding. AFM-IR analyses revealed that AT1010 preferred to stay in the POE disperse phase rather than in the iPP matrix, with a concentration ratio of ∼1.2 in the extruded pellets independent of the screw speed, which was further increased to ∼1.5 in the molded plates. The preferred concentration of AT1010 in the POE was in line with its higher solubility in rubber than in iPP, and the enhanced partition of AT1010 in the molded plates was attributed to a longer processing time in the molten state than that for the extruded pellets, which was verified by AFM-IR analyses of pellets extruded with different residence times.

Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy that strongly correlates with poor clinical outcomes. Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death which plays an important role in various human cancers. Nevertheless, the prognostic significance and functions of ferroptosis-related genes (FRGs) in AML have not received sufficient attention. The aim of this article was to evaluate the association between FRGs levels and AML prognosis using publicly available RNA-sequencing datasets. The univariate Cox regression analysis identified 20 FRGs that correlate with patient overall survival. The LASSO Cox regression model was used to construct a prognostic 12-gene risk model using a TCGA cohort, and internal and external validation proved the signature efficient. The 12-FRGs signature was then used to assign patients into high- and low-risk groups, with the former exhibiting markedly reduced overall survival, compared to the low-risk group. ROC curve analysis verified the predictive ability of the risk model. Functional analysis showed that immune status and drug sensitivity differed between the 2 risk groups. In summary, FRGs is a promising candidate biomarker and therapeutic target for AML.

To investigate the prognostic implication of minimal residual disease (MRD) evaluation in chronic myelomonocytic leukemia (CMML), we conducted a restropective study included a total of 174 CMML patients in our hospital from January 2010 to March 2021. In which 50/174 (29%) bone marrow samples were conducted by multiparameter flow cytometry (FCM) assessed MRD analysis after the first three cycles of treatment and were included in this study. MRD was detected by six- to eight-colour FCM. The achievement of early MRD negativity had better clinical outcomes in patients with CMML, which fared better prognosis in terms of not only PFS (P=0.006) but also OS (P=0.02) after the first cycle, and PFS (P=0.023 and P=0.041) after the second and third cycles, whereas no significantly influence in OS. In addition, MRD negative after initial treatment remained its independent prognostic value associated with PFS (adjusted hazard ratio [HR] 0.161, 95 CI 0.035-0.738; P=0.019) and OS (adjusted HR 0.136; 95 CI 0.017-1.077; P=0.059), indicating that patients with MRD-negative after the initial treatment alone could obtain the greatest clinical benefit. According to MRD level, the patients were divided into 4 different groups: very low risk (fewer than 10 -4 cells) in 15 cases, low risk (10 -4 to 10 -3 cells) in 6; and 6 were at intermediate risk (fewer than 10 -3 to 10 -2 cells). The rest of 23 patients were were assigned to the high-risk grades (more than 10 -2 residual cells), we find this risk stratification model is significantly associated with better PFS (P=0.002) but marginal significantly associated with OS (P=0.068). Notably, patients with DNMT3A mutation fared a shorter PFS in the MRD positive subgroup (P=0.068). MRD is highly predictive of prognosis, and its combination with molecular profile may help identify patients at increased risk for progression to further improve the management of patients with CMML. Large-scaled investigations are warranted to validate our conclusions and its potential in clinical practice., Competing Interests: None., (AJCR Copyright © 2022.)

Chronic myeloid leukemia (CML) is triggered primarily by the t(9;22) (q34.13; q11.23) translocation. This reciprocal chromosomal translocation leads to the formation of the BCR-ABL fusion gene. Patients in the chronic phase (CP) experience a good curative effect with tyrosine kinase inhibitors. However, cases are treatment refractory, with a dismal prognosis, when the disease has progressed to the accelerated phase (AP) or blast phase (BP). Until now, few reports have provided a comprehensive description of the mechanisms involved at different molecular levels. Indeed, the underlying pathogenesis of CML evolution comprises genetic aberrations, chromosomal translocations (except for the Philadelphia chromosome), telomere biology, and epigenetic anomalies. Herein, we provide knowledge of the biology responsible for blast transformation of CML at several levels, such as genetics, telomere biology, and epigenetic anomalies. Because of the limited treatment options available and poor outcomes, only the therapeutic response is monitored regularly, which involves BCR-ABL transcript level assessment and immunologic surveillance, with the optimal treatment strategy for patients in CP adapted to evaluate disease recurrence or progression. Overall, selecting optimal treatment endpoints to predict survival and successful TFR improves the quality of life of patients. Thus, identifying risk factors and developing risk-adapted therapeutic options may contribute to a better outcome for advanced-phase patients., Competing Interests: The authors declare that they have no competing financial interests., (© 2021 Wang et al.)

Retaining nitrogen for polyacrylonitrile (PAN) based carbon anode is a cost-effective way to make full use of the advantages of PAN for sodium-ion batteries (SIBs). Here, a simple strategy has been successfully adopted to retain N atoms in situ and increase production yield of a novel composite PAZ by mixing 3 wt % of zinc borate (ZB) with poly (acrylonitrile-co-itaconic acid) (PANIA). Among the prepared carbonised fibre (CF) samples, PAZ-CF-700 maintains the highest N content, retaining 90 % of the original N from PANIA. It represents the highest capacity storage contribution (80.55 %) and the lowest impedance R ct (117 Ω). Consequently, the specific capacity increases from 60 mAh g -1 of PANIA-CF-700 to 190 mAh g -1 of PAZ-CF-700 at a current density of 100 mA g -1 . At the same time, PAZ-CF-700 exhibits a good rate performance and excellent long-term cycling stability with a specific capacity of 94 mAh g -1 after 4000 cycles at 1.6 A g -1 ., (© 2021 Wiley-VCH GmbH.)

The primary aim of the present retrospective study was to investigate lipid profiles and kinetics in acute promyelocytic leukemia (APL) patients. We analyzed 402 newly diagnosed APL patients and 201 non-APL patients with acute myeloid leukemia (as control). Incidence of hypertriglyceridemia in APL patients and non-APL patients was 55.82% and 28.4% ( p = 0.0003). The initial levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were higher in APL patients than in control (all p < 0.0001). In APL patients, triglyceride levels were significantly increased during induction treatment with all-trans retinoic acid and arsenic. Multivariable analysis showed that age, being overweight (body mass index ≥25) and APL were independent risk factors for hypertriglyceridemia in all patients before treatment. High triglyceride levels were not significantly associated with disease-free survival or overall survival in the APL patients. In summary, in the current study triglyceride levels were significantly elevated in APL patients before treatment, and they increased during induction treatment, but there were no significant corresponding effects on survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Sun, Lou, Zhu, Shen, Zhou, Zhu, Yang, Xie, Li, Huang, Zhu, Zheng, Xie, Ye, Jin and Zhu.)

Development of resistance to tyrosine kinase inhibitors (TKIs) targeting the BCR/ABL fusion protein represents a major challenge in the treatment of chronic myeloid leukemia (CML). Since apoptosis resistance is the fundamental mechanism impeding TKIs' therapeutic effects, alternative approaches that induce nonapoptotic cell death are being pursued to treat TKI-resistant CML. Induction of necroptosis, a distinct, caspase-independent form of programmed cell death, may be a valuable strategy in this respect. The present study shows that shikonin, an herbal compound used in traditional Chinese medicine, overcomes TKI resistance in BCR/ABL-positive CML cells by inducing necroptosis via activation of RIPK1/RIPK3/MLKL signaling. This effect occurs both in vitro and in vivo and involves downregulation of miR-92a-1-5p, a poor-prognosis marker frequently overexpressed in leukemia patients. Based on gene expression experiments, we conclude that miR-92a-1-5p promotes CML progression by inhibiting MLKL expression. Accordingly, we show that antagomiR-mediated in vivo inhibition of miR-92a-1-5p reduces the growth of CML tumors in mice through necroptosis induction. Our research suggests that therapies that relieve MLKL suppression by targeting miR-92a-1-5p may represent a useful strategy to treat TKI-refractory CML.

Recurrent chromosomal and molecular abnormalities characterize acute lymphoblastic leukemia (ALL) subtypes in both adult and pediatric patients and are of great value for diagnosis, risk stratification, disease monitoring and treatment selection. The Philadelphia (Ph) chromosome, which creates a novel hybrid gene called BCR-ABL1, is the most common cytomolecular genetic abnormality in adult ALL patients. As the understanding of the genetic characteristics of Ph-positive ALL continues to improve, the prognostic value of cytogenetic abnormalities is becoming increasingly recognized. It is likely that the clinical guidelines and recommendations will also evolve. Accordingly, it will be very important to effectively and economically utilize current knowledge to guide treatment decisions within the clinical context of each patient. In this review, we will summarize the advances in the understanding of cytogenetic abnormalities in adult patients with Ph+ ALL, with an emphasis on the incidence, characteristics and prognosis of different types of abnormalities, to provide a basis for the clinical prognostic stratification and precise individualized treatment of these patients., Competing Interests: None., (AJCR Copyright © 2020.)

Diffuse large B-cell lymphoma (DLBCL) is a complex and aggressive malignancy originating from B lymphocytes and characterized by extensive clinical, phenotypic and molecular heterogeneity. Although research conducted over the past decades has substantially improved our understanding of DLBCL, its pathogenesis has not yet been fully elucidated. The development of RNA sequencing technology has allowed the identification of numerous long noncoding RNAs (lncRNAs) that exhibit aberrant expression in DLBCL. These lncRNAs play crucial roles in DLBCL development and pathogenesis and are thus good candidates for use as diagnostic biomarkers or therapeutic targets. In this review, we describe the lncRNAs associated with DLBCL, summarize their characteristics and molecular functions, and discuss their relationships with clinical practice., Competing Interests: The authors declare that they have no competing interests., (© 2020 Huang et al.)

Background: Canonical Wnt/β-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. γ-catenin was previously demonstrated to be associated with the nuclear localization of β-catenin, the central mediator, and to exert oncogenic effects in AML; however, the underlying mechanisms remain unclear. Our study aimed to investigate the expression characteristics of γ-catenin in AML patients, explore the mechanisms by which γ-catenin regulates β-catenin, and discuss the feasibility of targeting γ-catenin for AML treatment., Methods: The mRNA expression levels of γ-catenin in AML patients were measured by qRT-PCR. Cell proliferation was examined via Cell Counting Kit-8 (CCK-8) assays. The expression levels of related proteins were measured via Western blotting. Specific siRNA was used to modulate the expression level of the γ-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of γ-catenin and β-catenin was examined via immunofluorescence with a confocal laser scanning microscope., Results: Overexpression of γ-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of γ-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked β-catenin nuclear translocation. Interestingly, γ-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited β-catenin nuclear localization. Moreover, our data implied the relationship between γ-catenin and GSK3β (whose effect on β-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of γ-catenin inhibition., Conclusion: Taken together, our results revealed a potential role of γ-catenin in AML pathogenesis-mainly through the inhibition of GSK3β-mediated nuclear localization of β-catenin-and indicate that targeting γ-catenin might offer new AML treatments., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Qian et al.)

Background: Recently, unprecedented clinical efficacy was observed during treatment of many solid tumors because of the introduction of programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint inhibitors. Preliminary clinical data indicates that checkpoint inhibition also represents a promising therapeutic strategy for certain lymphoid malignancies. However, PD-1/PD-L1 expression levels on neoplastic cells and in the tumor microenvironment vary among subtypes and their prognostic implications remain uncertain., Main Body: Here, we review the clinicopathological significance of PD-1/PD-L1 expression in lymphomas. Increased infiltration of PD-1+ tumor-infiltrating lymphocytes (TILs) is a favorable prognostic factor in diffuse large B-cell lymphoma (DLBCL) but not in Hodgkin's lymphoma (HL). Higher numbers of PD-1+ TILs were observed in follicular lymphoma (FL) than in other subtypes of B-cell lymphoma; however, its prognostic significance remains controversial. Infiltration of PD-L1+ immune cells showed a trend toward better overall survival in nasal natural killer (NK)/T-cell lymphoma and adult T-cell leukemia/lymphoma, more likely to be classified as activated macrophages and dendritic cells in microenvironment but its biological effect is not clarified. Peripheral PD-1+ T cells could be detected in blood samples from DLBCL and chronic lymphocytic leukemia (CLL) and correlated with disease progression and poor prognosis. PD-1+ neoplastic T cells were more frequently observed in cutaneous T-cell lymphoma, including Sézary syndrome and mycosis fungoides, which may be involved in the progression of epithelial-derived T lymphoma. Studies on PD-L1 expression in neoplastic cells mostly focused on DLBCL. PD-L1+ neoplastic cells were observed only in a small subset of DLBCL, mainly associated with activated B cell (ABC) subtypes and Epstein-Barr virus (EBV) positivity; however, its prognostic role remains controversial. In either T or B lymphoma, elevated serum or plasma levels of soluble PD-L1 represent adverse prognostic factors. Notably, in clinical trials of classical HL, the frequency of 9p24.1 chromosome alterations increases the abundance of PD-1 ligand expression, appearing to predict responses to anti-PD-1/PD-L1 therapy. The cytogenetic alterations affecting chromosome 9p24.1 including the CIITA rearrangement were also frequently observed in certain specific subtypes of large B-cell lymphomas., Conclusions: The clinical roles of PD-1/PD-L1 expression vary between subtypes of lymphoma. Future studies should delineate the prognostic and predictive roles of PD-1 and PD-L1 expression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The development of drug resistance and the persistence of leukemia stem cells are major obstacles for the use of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The induction of autophagic death in tumor cells represents a new route for leukemia treatment. Our previous study showed that infection of CML cells with oncolytic viruses carrying the autophagy gene Beclin1 downregulated BCR/ABL protein expression and significantly increased the killing effect of the oncolytic viruses on CML cells via autophagy activation. However, the specific molecular mechanisms underlying the regulation of BCR/ABL and Beclin1-dependent CML cell killing remain unclear. Methods: A physical interaction between BCR/ABL and Beclin1 was characterized via GST-pulldown, co-IP and dual-luciferase reporter assays. Cell proliferation was examined via CCK-8 and clone formation assays. The expression levels of the related proteins were measured via Western blotting. Autophagosomes were observed under transmission electron microscopy. Lentiviral vectors carrying Atg7/UVRAG shRNA or the Beclin1 gene were used to modulate the expression levels of the indicated genes. Immunofluorescence were performed to examine colocalization of BCR/ABL and p62/SQSTM1. CD34 + CD38 - cells were isolated from bone marrow samples from CML patients via fluorescence-activated cell sorting. Results: In this study, we observed that Beclin1 directly interacts with BCR/ABL. Beclin1 inhibited the activity of the BCR/ABL promoter to downregulate the level of BCR/ABL protein and to promote the downstream colocalization of p62/SQSTM1 and BCR/ABL to autolysosomes for degradation via activation of the autophagy signaling pathway. In CML cell lines, primary cells and CD34 + CD38 - leukemia stem cells, Beclin1 overexpression significantly inhibited cell growth and proliferation and induced autophagy. Conclusion: Taken together, our results suggest that autophagy induction via Beclin1 overexpression might offer new approaches for treating TKI-resistant CML and for promoting the clearance of leukemia stem cells, both of which have important clinical implications., Competing Interests: The authors report no conflicts of interest in this work.

Purpose: To perform a retrospective analysis of the prognostic relevance of clinicopathologic parameters in a well-documented cohort of patients treated with all-trans-retinoic acid (ATRA)-based induction regimens in order to discover which indicators can predict a high risk of early death (ED) and patient survival., Patients and Methods: We analyzed data of 288 newly diagnosed adult acute promyelocytic leukemia patients in Hangzhou, China. The median follow-up time was 32 months (range, 6-78 months)., Results: The 3-year disease-free and overall survival rates were 90.83% and 91.69%, respectively. In the multivariable analysis, older age (≥ 60 years) was the only independent risk factor for ED (hazard ratio [HR] = 15.057; P = .004). High white blood cell count was not a risk factor for ED (P = .055), but it was for relapse (HR = 2.7; P = .009). FLT3 mutation (HR = 3.9; 95% confidence interval, 1.4 to 10; P = .007) and older age (≥ 60 years) (HR = 5.3; 95% confidence interval, 2.4 to 11; P < .001) were prognostic factors for poorer disease-free and overall survival. Interestingly, CD15 negativity (HR = 0.23; P = .049) was a prognostic factor for relapse. The ED rate was 5.9% (17/288 patients)., Conclusion: The perceived impact of the identification of these high-risk factors should be described in order to decide whether any modifications to treatment strategy should be entertained., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Resistance to regulated cell death is one of the hallmarks of human cancers; it maintains cell survival and significantly limits the effectiveness of conventional drug therapy. Leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance. As the majority of chemotherapeutic and targeted drugs kill leukemia cells by triggering apoptosis, the observed resistance indicates the need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia. Necroptosis is a regulated form of necrosis that is precisely modulated by intracellular signaling pathways and thus provides potential molecular targets for rational therapeutic intervention. Indeed, accumulating evidence indicates that many current antitumor agents can activate necroptotic pathways and thereby induce leukemia cell death. Elucidation of the complete regulatory mechanism of necroptosis is expected to accelerate the development of novel therapeutic strategies for overcoming apoptosis resistance in leukemia. Here, we review the latest research advances in the regulatory mechanisms of necroptosis and summarize the progression of necroptosis-based therapeutic strategies in leukemia.

Background: Exosomes derived from tumor cells (TEXs) are involved in both immune suppression, angiogenesis, metastasis and anticancer stimulatory, but the biological characteristics and role of diffuse large B cell lymphoma (DLBCL)-derived exosomes have been less investigated., Methods: Exosomes (EXOs) were isolated from OCI-LY3, SU-DHL-16, and Raji cells and biological characteristics of EXOs were investigated using electron microscopy, flow cytometry analysis, and Western blot analysis. The protein expression of EXOs was determined by an antibody array. Next, the communication between EXOs and lymphoma cell, stromal cell, dendritic cells (DCs), and T cells was evaluated. Finally, effect of DLBCL TEXs on tumor growth in vivo was investigated., Results: We demonstrated that EXOs derived from DLBCL cell lines displayed malignancy molecules such as c-Myc, Bcl-2, Mcl-1, CD19, and CD20. There was a different protein expression pattern between DLBCL TEXs and Burkitt lymphoma TEXs. DLBCL TEXs were easily captured by DCs and lymphoma cells, and mainly acted as an immunosuppressive mediator, evidenced by induction of apoptosis and upregulation of PD-1 in T cells. Furthermore, the TEXs stimulated not only cell proliferation, migration of stromal cells but also angiogenesis. As a result, the TEXs promoted tumor growth in vivo. On other hand, DLBCL TEXs did not induce apoptosis of DCs. After pulsed with the TEXs, DCs could stimulate clonal expansion of T cells, increase the secretion of IL-6 and TNFα, and decrease the production of immunosuppressive cytokine IL-4 and IL-10. The T cells from tumor bearing mice immunized by TEX were shown to possess superior antilymphoma potency relative to immunization of tumor lysates., Conclusions: This study provides the framework for novel immunotherapies targeting TEXs in DLBCL.

Burkitt's lymphoma (BL) is a highly aggressive malignancy molecularly characterized by deregulation of the C-MYC proto-oncogene. Recently, it has been confirmed that phosphatidylinositol-3-kinase (PI3K) pathway activation is a crucial element in the malignant transformation of the B cells in BL. Despite the better outcome of adults with BL treated with high-intensity chemotherapy regimens, the overall survival rate for patients older than 60 years remains dismal. Shikonin, a natural naphthoquinone derived from Chinese herbal medicine plant, has the potential to induce cell death in a series of human cancer. In the present study, we investigated the effect and molecular mechanisms of Shikonin in treatment with BL. Shikonin suppressed cellular proliferation and induced caspase-dependent apoptosis in BL cells. Inhibition of C-MYC and suppression of PI3K/AKT/mTOR pathway played critical roles in SHK-induced apoptosis in BL both in vitro and in vivo. Besides, Shikonin potentiated doxorubicin-induced growth inhibition and apoptosis in vitro. Furthermore, the growth of a subcutaneous xenograft tumor model of BL was significantly inhibited by shikonin. Importantly, we did not find the effect of shikonin on liver function in mice. In summary, these data suggest that shikonin may be an encouraging chemotherapeutic agent in the clinical treatment of BL.

Primary testicular lymphoma (PTL) is a rare and aggressive form of extranodal lymphoma. Approximately 80-98% of PTLs are diffuse large B-cell lymphoma (PT-DLBCL). The prognosis of DLBCL patients has improved with the addition of rituximab to systemic chemotherapy, but outcomes of PT-DLBCL remain poor. This may be explained by the high rate of relapse in the central nervous system (CNS) and contralateral testis. We analyzed 1,132 newly diagnosed DLBCL patients (37 with PT-DLBCL) who were treated at our hospital between January 2009 and December 2014. Twenty-five patients finished follow-up. We analyzed clinical characteristics, response to chemotherapy, overall survival, and relapse in the CNS and contralateral testis. All patients underwent orchiectomy. The median age was 60 (range: 43-82) years. Eleven patients had stage III/IV disease. Five patients experienced CNS relapse, and three experienced relapse in the contralateral testis. Median overall survival (OS) was not reached at the time of reporting. The 3-year OS rate was 57%. None of the nine patients who received radiotherapy to the contralateral testis experienced relapse in that location. Intrathecal prophylaxis did not reduce the risk of CNS relapse. All five patients who experienced CNS relapse had the germinal center B-cell-like subtype of DLBCL., Competing Interests: CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest.

In this study, we present a rare case of fatal breakthrough Candida tropicalis infection in a patient with acute lymphoblastic leukemia (ALL) while on posaconazole prophylaxis. Then, we explore the mechanisms underlying azole resistance by focusing on enhanced efflux pumps and changes in the azole target enzyme Erg11p, which was encoded by the ERG11 gene. Our study demonstrates that Y132C substitution of Erg11p combined with MDR1 overexpression may be the pan-azole resistance mechanisms in Candida tropicalis ., (Copyright © 2017 You et al.)

A deeper understanding of the complex pathogenesis of multiple myeloma (MM) continues to lead to novel therapeutic approaches. Prior studies suggest that 3-phosphoinositide-dependent kinase 1 (PDK1) is expressed and active, acting as a crucial regulator of molecules that are essential for myelomagenesis. In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasone-resistant cell line, but not in human normal cells. Insulin-like growth factor-1 could not rescue GSK-470-induced cell death. Moreover, GSK-470 down-modulates phosphor-PDK1, thereby inhibiting downstream phosphor-AKT at Thr308 and mTOR complex 1 (mTORC1) activity. However, GSK-470 could not affect mTORC2 activity and phosphor-AKT at Ser473. RPMI 8226 and OPM-2 cells with low expression of PTEN show relative resistant to GSK-470. Knockout of PTEN by shRNA resulted in a partial reversion of GSK-470-mediated growth inhibition, whereas overexpression of PTEN enhanced myeloma cell sensitivity to GSK-470, suggesting that the sensitivity to GSK-470 is correlated with PTEN expression statue in MM cells. Combining PP242, a dual mTORC1/C2 inhibitor, with GSK-470, had greater antimyeloma activity than either one alone in vitro and in MM xenograft model established in immunodeficient mice. In particular, this combination was able to result in a complete inhibition of mTORC1/C2 and full activity of AKT. Together, these findings raise the possibility that combining PDK1 antagonist GSK-470 with mTORC1/C2 inhibitors may represent a novel strategy against MM including drug-resistant myeloma, regardless of PTEN expression status.

Despite great progress made in the treatment of multiple myeloma (MM), it is still incurable. Promising phase II clinical results have been reported recently for oncolytic vaccinia virus (OVV) clinic therapeutics. One reason for this has focused on the critical therapeutic importance of the immune response raised by these viruses. However, few studies have performed their applications as an optimal delivery system for therapeutic gene, especially miRNA in MM. In this study, we constructed two novel OVVs (TK deletion) that express anti-tumor genes, miR-34a and Smac, respectively, in MM cell lines and xenograft model. The results demonstrated that the novel OVV can effectively infect MM cell lines, and forcefully enhance the exogenous gene (miR-34a or Smac) expression. Furthermore, utilization of VV-miR-34a combined with VV-Smac synergistically inhibited tumor growth and induced apoptosis in vitro and in vivo. The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac-induced cell apoptosis. Our study is the first to utilize OVV as the vector for miR-34a or Smac expression to treat MM, and lays the groundwork for future clinical therapy for MM.

To investigate the effects of organic loading rate (OLR) on performance and stability of mesophilic co-digestion of rice straw (RS) and chicken manure (CM), benchtop experiments (40 L) were carried out at OLRs of 3.0, 3.6, 4.2, 4.8, 6.0, 8.0, and 12.0 kg volatile solid (VS)/(m(3)·day) with volatile solid (VS) ratio of 1:1 (RS/CM) which was based on batch tests. Anaerobic co-digestion was slightly and severely inhibited by the accumulation of ammonia when the digester was overloaded at an OLR of 6 and 12 kg VS/(m(3)·day), respectively. The recommended OLR for co-digestion is 4.8 kg VS/(m(3)·day), which corresponds to average specific biogas production (SBP) of 380 L/kg VS and volumetric biogas production rate (VBPR) of 1.8 m(3)/(m(3)·day). An OLR of 6-8 kg VS/(m(3)·d) with SBP of 360-440 L/kg VS and VBPR of 2.1-3.5 m(3)/(m(3)·day) could be considered, if an Anaerobic digestion (AD) system assisted by in situ removal of ammonia was adopted.

Development of drug resistance due to BCR-ABL point mutations and the persistence of leukemia initiating cells has become a major obstacle for tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The BCR-ABL protein is an important client protein of heat shock protein 90 (Hsp90). BIIB021, an orally available Hsp90 inhibitor, has activity against various cancer cells. However, little is known about the inhibitory effect of BIIB021 on CML cells. We evaluated the inhibitory effects of BIIB021 on K562, K562/G (an imatinib-resistant cell lines), as well as 32D mouse leukemic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and T315I mutant BCR-ABL (32Dp210-T315I) cells. Our data showed that BIIB021 induced significant growth inhibition and apoptosis that was predominantly mediated by the mitochondrial pathway. BIIB021 also resulted in proteasomal degradation of BCR-ABL proteins. In addition to induction of apoptosis, we report for the first time that BIIB021 induced autophagic response as evidenced by the formation of autophagosome, increased conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, decreased p62 (SQSTM1) protein levels. Further study suggested that Akt-mTOR-Ulk1 signaling pathway was involved in BIIB021-triggered autophagy. Moreover, blocking autophagy using pharmacological inhibitor 3-methyladenine and bafilomycin A1 significantly enhanced cell death and apoptosis induced by BIIB021, indicating the cytoprotective role of autophagy in BIIB021-treated CML cells. Collectively, these data provide possible molecular mechanisms for the antileukemic effect of BIIB021 on imatinib-sensitive and -resistant CML cells and provide new insights into the future application of BIIB021 in the clinical treatment of CML.

Recently, much progress has been achieved in the treatment of multiple myeloma (MM). However, the major challenge of chemotherapeutic drugs is acquired resistance. Oncolytic virotherapies offer promising alternatives; with the possibility of their integration with current therapeutic strategies. In the present study, we assessed the potential of ZD55-TRAIL (an oncolytic adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand) as an oncolytic agent for MM. Our results clearly indicated that ZD55 armed with TRAIL was more cytotoxic to drug-sensitive as well as drug-resistant MM cell lines, than the virus alone. Furthermore, it was also observed that ZD55-TRAIL induced apoptosis through the activation of the caspase pathway. In particular, ZD55-TRAIL significantly inhibited insulin-like growth factor-1 receptor (IGF-1R) and NFκB. However, IGF did not abrogate ZD55‑TRAIL-induced cell death. Combination of ZD55-TRAIL with the PI3K inhibitor LY294002 in RPMI‑8226 cells inhibited the virus‑mediated activation of mTOR and AKT, thus, promoting cell death. Combined treatment of ZD55-TRAIL and MG132 (a proteasome inhibitor) robustly increased the expression of death receptor 5 (DR5), which enhanced the apoptosis response without significant toxicity to normal liver cells. Collectively, our results suggest that combined treatment of TRAIL-armed oncolytic adenovirus and a PI3K inhibitor or a proteosome inhibitor may serve as a promising therapy for MM.

Parvoviridae, which are classified into two subfamilies Parvovirinae and Densovirinae, can infect both vertebrate and insects and are related to a wide range of diseases in insects, animals, and humans. In this report, several new parvoviruses were identified in swine sera collected in southeastern China. The sequence analyses showed that the parvoviruses detected in southeastern China formed a distinct sublineage within the subfamily Parvovirinae. Based on these results, we propose a novel parvovirus sublineage, Cnvirus, to describe these parvoviruses.