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In this work, the microscopic distribution of antioxidant 1010 (AT1010) in blends of isotactic polypropylene (iPP) with an ethylene-octene copolymer (POE) was investigated

We present a comprehensive computational and theoretical analysis of diffusion through flake composites in which the flakes are of rectangular shape, spanning the entire spectrum from squares to ribbons. Following a large number of detailed 3D simulations in realistic Representative Volume Elements (RVEs), each containing 1000s of individual flakes, we propose a scaling which, for the first time in the technical literature, introduces the planar aspect ratio r of the flakes as a parameter affecting the barrier properties of the resulting composite. Subsequently, we examine the effect of r in several cases of practical significance, such as under the assumptions of (i) constant number-density N/Δ V and flake volume fraction ϕ, (ii) constant N/Δ V and flake diagonal and (iii) constant ϕ and varying N/Δ V—describing the problem of the fragmentation of ribbons into flakes. Both deterministic and stochastic systems in terms of r, are considered. One key result is that square flakes offer the best barrier performance compared to flakes of general rectangular shape—as long as N/Δ V and ϕ or the diagonal of the flakes remain constant. Randomness in flake aspect ratio only moderately impacts the barrier improvement factor as long as ϕ and N/Δ V remain constant but has a strong effect under the assumption of constant N/Δ V and flake diagonal. Finally, we show that, for r < 10 and M < 1, the scaling proposed in this work is valid not only for unidirectional flakes but also for flakes showing random in-plane orientations.

Background: The increase in glucose consumption during aerobic glycolysis of cancer cells, known as the Warburg effect, is associated with dismal prognosis. Warburg effect secondary to diffuse large B‑cell lymphoma (DLBCL) is rare and there is no specific treatment regimen. Case presentation: We here described a case of patient who presented with hemophagocytic lymphohistiocytosis and developed hyperlactacemia inducing by Warburg effect, then he was successfully treated by continuous renal replacement therapy (CRRT) and diagnostic chemotherapy. Eventually, he was diagnosed as DLBCL. Conclusion: Existing evidence shows that Warburg effect can be secondary to diffuse large B-cell lymphoma, CRRT combined with diagnostic chemotherapy was effective in this case. Additive attention should be paid to this phenomenon and effective strategy remains to be explored.

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.

Background: This article is performed to assess the significance of minimal residual disease (MRD) after one course of therapy in patients with chronic myelomonocytic leukemia (CMML). Methods: From January 2010 to January 2022, a total of 158 patients who were newly diagnosed with CMML were enrolled, in which 58/158 (37%) patients were conducted by multiparameter flow cytometry (FCM) assessed MRD analysis after on cycle treatment and were included in this study. MRD was detected by six- to eight- colour FCM. Result: After one course of therapy, twenty-one (36%) patients achieved MRD0.01% (MRD1+). The patients in the MRD1+ group had lower platelet counts, higher 𝛽2-microglobulin, ferritin and BM1 myeloblasts (bone marrow myeloblasts after one cycle of therapy) than that of the MRD1- group (P=0.005, P=0.023, P=0.026 and P=0.007, respectively). Furthermore, a greater propotion of patients had JCK2 and SETBP1 mutation in MRD1- patients than in MRD1+ group (both P=0.037). At a median follow up time of 25.8 months (95%CI, 15.01-36.59), those patients who achieved MRD0.01%, and 2-year OS rate (90% vs. 30%; PConclusion: MRD is highly predictive of prognosis, and it 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.

Purpose The present study aims to explore the clinical features, imaging manifestations, pathologic characteristics, treatment, and prognosis of aggressive splenic lymphoma (ASL) patients.Methods From January 2001 to March 2021, patients who were histologically proven splenic lymphoma were enrolled in this study. The survival curves of overall survival (OS) and progressive-free survival (PFS) were calculated by the Kaplan–Meier survival analysis and log-rank test. Univariate and multivariate Cox regression analyses were performed to estimate the potential prognostic factors.Results Sixty-nine patients who were histologically proven ASL in this study. The median follow-up time was 76.3 months (95%CI, 60.194-92.406). Patients with ASL underwent the splenectomy had better PFS and OS than that of patients who did not (OS 61% vs 35%, P=0.084; PFS 57% vs 25%, P=0.061), yet the difference was not remarkably significant. In addition, splenic lymphomas of T-cell origin (OS HR, 3.398[95%CI, 1.327-8.704], P=0.011; PFS HR, 2.776[95%CI, 1.107-6.959], P=0.029) and present with B symptoms (OS HR, 2.703[95%CI, 1.219-5.994], P=0.014; PFS HR, 2.890[95%CI, 1.348-6.194], P=0.006) were independent risk factors correlated with OS and PFS. After establishing a risk-stratified model in combination with cell of origin (COO) and B symptom to divide patients into three risk subgroups: 36 were in low-risk group, 28 were in intermediate-risk group, and 5 were in high-risk group. The differences between each group were statistically significant (OS: χ2=41.000, PConclusion Splenic T-cell lymphoma patients with B symptom at initial diagnosis had the worst outcome among aggressive splenic lymphoma.

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.

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.

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.

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 Rct (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 .

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.

Although the treatment of adult T-cell acute lymphoblastic leukemia (T-ALL) has been significantly improved, the heterogeneous genetic landscape of the disease often causes relapse. Aberrant activation of mammalian target of rapamycin (mTOR) pathway in T-ALL is responsible for treatment failure and relapse, suggesting that mTOR inhibition may represents a new therapeutic strategy. In this study, we investigated whether the mTOR complex 1 (mTORC1) inhibitor everolimus could be used as a therapeutic agent against human T-ALL. We showed that rapamycin and its analog RAD001 (everolimus) exerted only mild inhibition on the viability of Jurkat, CEM and Molt-4 cell lines (for everolimus the maximum inhibition was

Background Hemophagocytic lymphohistiocytosis (HLH) is a cytokine-driven inflammatory syndrome associated with hereditary or acquired immune-dysregulation. The frontline therapy for secondary HLH in adult patients is HLH-1994 regimen, however overall survival of these patients remains suboptimal. Janus family kinases JAK1 and JAK2 are hallmarks of the final common pathway in HLH, and ruxolitinib (an oral JAK inhibitor) has shown favorable efficacy and safety in murine models and clinical trials. Recently, Lauren K. Meyer et al demonstrate that hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative dexamethasone resistance, and this apoptotic potential is restored both in vitro and vivo when exposure to ruxolitinib. This finding provide rationale for combining dexamethasone and ruxolitinib to enhance the lymphotoxic effects of dexamethasone and thus improve the outcomes for patients with HLH. We were very interested in this finding and conducted this pilot trial in adult patients with secondary HLH. Methods We managed 8 newly diagnosed HLH patients with ruxolitinib combined with dexamethasone or methylprednisolone from April 1, 2021 to May 31, 2021 in the First Affiliated Hospital of Medical School of Zhejiang University. All patients fulfilled at least five of the eight HLH-2004 diagnostic criteria and the etiology was not identified at the time. The regimen in detail was ruxolitinib 15mg po. bid d1-56, dexamethasone 10mg/m 2 d1-14, 5mg/ m 2 d15-28, 2.5 mg/m 2 d29-42, 1.25mg/m 2 d43-49, reduce the dosage until withdrawal d50-56 (For patients with liver insufficiency, dexamethasone is replaced with the same equivalent of methylprednisolone). Once the patient's primary cause had been identified, we wound begin primary disease treatment immediately. Results Eight newly diagnosed HLH patients without previous treatment were enrolled in this study with a median follow-up of 102 (2-122) days, including 5 cases of lymphoma-associated HLH, one case of bacterial infections-associated HLH, and 2 cases of unknown etiology. The overall response rate at the end of HLH treatment was 87.5% (7/8), with 50% (4/8) in complete response (CR), 37.5% (3/8) in partial response (PR), and 12.5% (1/8) in no response. Among the patients achieving CR, 100% (4/4) maintained CR condition for＞2 months. 2-month overall survival was 75% (6/8), one patient was dead because of lymphoma associated HLH progression, another patient was dead because of bronchiectasis with massive hemoptysis after the HLH was under control. For the lymphoma-associated HLH subgroup, 4 of 5 patients responded to ruxolitinib combined with dexamethasone, three patients successfully bridged to chemotherapy after diagnosis of lymphoma; One patient defused to chemotherapy because she was 77 years old and had severe bronchiectasis; the patient with NR was dead in 2 days due to the rapid progression of disease. No treatment-related deaths were observed. Conclusions In our trial, ruxolitinib combined with dexamethasone regimen initially demonstrated favorable efficacy in newly diagnosed adult patients with secondary HLH. Especially for patients with lymphoma-associated hemophagocytic syndrome, it is an efficient and safe bridging therapy while waiting for pathological diagnosis. This novel treaiment is promising, and should be evaluated in larger sample size studies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

// De Zhou 1, * , Changqian Bao 2, * , Xiujin Ye 1 , Lixia Zhu 1 , Jingjing Zhu 1 , Li Li 1 , Mingyu Zhu 1 , Xiudi Yang 1 , Yanlong Zheng 1 , Xianbo Huang 1 , Mixue Xie 1 and Wanzhuo Xie 1 1 Department of Hematology, the First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, Zhejiang Province, China 2 Program in Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China * These authors contributed equally to this work Correspondence to: Xiujin Ye, email: yxjsunny@zju.edu.cn Keywords: primary testicular lymphoma, diffuse large B-cell lymphoma, RCHOP, intrathecal prophylaxis, radiation therapy Received: December 12, 2016 Accepted: July 23, 2017 Published: July 31, 2017 ABSTRACT 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.

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.

// Chunmei Yang 1, * , Xianbo Huang 1, * , Hui Liu 1 , Feng Xiao 1 , Jueying Wei 1 , Liangshun You 1 and Wenbin Qian 1 1 Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China * Co-author Correspondence to: Wenbin Qian, email: qianwenb@hotmail.com Keywords: multiple myeloma, PDK1, mTOR, PTEN Received: February 08, 2017 Accepted: March 06, 2017 Published: March 29, 2017 ABSTRACT 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.

In order to develop a time-saving method for determination of ultimate methane production, obtain the hydrolysis kinetic constant, and identify a determination method for the nonbiodegradable organic fraction of substrate (VSNB) of green and air-dried corn stover, the kinetics of methane production and hydrolysis were studied using batch tests. The results showed that the conventional first-order hydrolysis kinetic model was not suitable for describing the entire hydrolysis process of corn stover, because there were two first-order decay periods for hydrolysis of corn stover. The hydrolysis kinetic constants kH,1 and kH,2 of the first and second periods were 0.1701 and 0.0415 1/d for green stover and 0.1052 and 0.0360 1/d for air-dried stover. The value of VSNB could be obtained by the graphical method rather than by the hydrolysis kinetic model. The obtained VSNB contents were 12.9% and 24.7% of VS (volatile solid) for green and air-dried stover, respectively. The ultimate methane production and corresponding digestion time could be understood through the methane production kinetic model by digestion experiments within a short time. The ultimate methane productions were 347.1 and 319.4 mL/g based on VS and the corresponding digestion times were 69.2 and 182.3 days for green and air-dried stover, respectively.

Utilizing renewable resources and accelerating thermal stabilization have been two main effective technical means to reduce the cost of poly(acrylonitrile) (PAN) based carbon fibre (CF). In this work, cross-linked poplar lignin (CPPL) with higher carbon content and 15 times the weight-average molecular weight of poplar lignin (PPL) was formed by doping boron phosphate (BP) in situ composites, which was blended with poly(acrylonitrile-co-vinyl acetate) (PANVA) to prepare a low-cost partially bio-based composite PANVA/CPPL-BP. During thermal stabilization, the C1s curve-fitting of x-ray photoelectron spectroscopy (XPS) spectra showed that the conjugated ladder structure of PANVA/CPPL-BP started to form at 230 °C, which was 20 °C lower than PANVA. And the acceleration in forming conjugated ladder structures was further confirmed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric (TG), and TG-FTIR. During simulated low-temperature carbonization for composites stabilized at 230 °C in advance, the addition of CPPL-BP greatly improved the order of graphitic structure for PANVA. The mechanical property of CF mats has also been obviously improved by CPPL-BP. The possible mechanism that CPPL-BP accelerating the formation of conjugated ladder structures for PANVA/CPPL-BP during thermal stabilization was proposed. With such improvement on accelerating thermal stabilization and utilizing cheap bio-material at the same time, this PANVA/CPPL-BP composite has a great potential in developing low-cost CF.

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.

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.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).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).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.

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.

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 .

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 Sezary 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.

BACKGROUND: Resistance to cell death and metabolic reprogramming are common features of tumor cells. Although the introduction of selective BCR/ABL tyrosine kinase inhibitors (TKIs) has dramatically improved the outcomes and survival rates of chronic myeloid leukemia (CML) patients, some patients (20-30%) develop TKI resistance. The most aggressive and treatment-resistant CML is the subtype harboring BCR/ABL with the T315I mutation, and this subtype is refractory to nearly all TKI-induced apoptosis. Thus, alternative approaches that induce apoptosis-independent cell death are thought to compensate for apoptotic-resistant cells. Recently, necroptosis (also called programmed necrosis), which is generally driven by RIPK1/RIPK3/MLKL activation, has been demonstrated to be a new type of programmed cell death mode that is different from apoptosis. Thus, a deeper understanding of the molecular mechanisms regulating necroptosis might lead to the development of new therapeutic strategies that could remarkably improve the treatment-responses and outcomes of patients with TKI-resistant CML. RESULTS: Shikonin, a compound purified from traditional Chinese medicine, has been reported to induce cell death in various tumor cell lines via a wide range of mechanisms. In our current study, we found that shikonin can effectively inhibit proliferation and induce necrosis-like morphological alterations (Fig. A and B) accompanied by RIPK1/RIPK3/MLKL signaling activation ((Fig. C) in CML cell lines, including the T315I mutant type (32Dp210-T315I). The effects of shikonin can be attenuated by the necroptosis-specific inhibitor (essentially a RIPK1 inhibitor) Nec-1, but not by the pan-apoptosis inhibitor z-VAD-fmk, indicating the occurrence of necroptosis in these cells ((Fig. B and C). Our data also show that shikonin has in vivo anti-CML activity via necroptosis induction in 32Dp210-T315I cells xenografted into NOD/SCID mice via subcutaneous injection ((Fig. D). miRNAs play an important role in tumorigenesis mainly via regulation of gene expression. Our next generation sequencing-based microRNA expression profiling showed significant dysregulation of miR-92a-1-5p expression in a shikonin-treated CML cell line (K562) (Fig. E). We then measured the miR-92a-1-5p expression levels in bone marrow samples from CML patients and patients with nonhematologic malignant diseases. The data showed that the miR-92a-1-5p expression level was higher in primary cells obtained from CML-BC patients than in those from non-CML-CP patients, suggesting that miR-92a-1-5p upregulation is correlated with poor outcomes (Fig. F). Bioinformatics analyses and a dual luciferase reporter gene assay proved that MLKL, a downstream factor in the necroptosis pathway that usually acts as the necroptosis executor, is a direct target of miR-92a-1-5p (Fig. G). Overexpression of miR-92a-1-5p in vitro led to decreased MLKL protein abundance in CML cells (Fig. G). Inhibition of miR-92a-1-5p via use of a specific antago-miRNA could inhibit CML xenograft tumor growth and induce necroptosis via MLKL upregulation in vivo (Fig. H). Hence, we believe that miR-92a-1-5p plays a role in promoting the proliferation and survival of CML via downregulating the abundance of MLKL, the necroptosis executor. CONCLUSIONS: In conclusion, our study proves that shikonin can overcome TKI resistance and induce necroptosis in CML cells, mainly via a mechanism involving RIPK1/RIPK3/MLKL activation. Our study also suggests that miR-92a-1-5p is frequently overexpressed in CML patients with poor outcomes and that it can promote tumor survival by inhibiting MLKL expression. For the first time, we demonstrated that miR-92a-1-5p inhibition via antago-miRNA can potentially be used to treat CML via necroptosis induction. Since necroptosis has not yet been considered to be a therapeutic strategy for tumor treatment, our research confirms that it might indeed serve as a new modality to better control drug-resistant CML. Figure Disclosures No relevant conflicts of interest to declare.

Introduction Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. The pathogenesis of ITP mainly included immune-mediated platelet destruction and megakaryocyte maturation disorder. The first line therapy is steroid, but about one-third of patients do not respond to steroid. Recent studies have shown abnormalities in megakaryocyte growth and development and poorly compensated thrombopoiesis. It may be presumed that patients with these abnormalities may respond poorly to steroid and may be a candidate for therapy with thrombopoietin (TPO). The morphological classification of megakaryocytes in bone marrow may reflect the development of megakaryocytes, and may be associated with the response to steroid. Here, we intended to find out whether megakaryocytic morphology could be used to differentiate steroid-sensitive patients from primary ITP. Methods We retrospectively analyzed 170 patients with primary ITP who presented to the First Affiliated Hospital, Zhejiang University between May 2015 and Dec 2018. The diagnosis was made according to the International Working Group classification. Cases with secondary diseases that may cause thrombocytopenia were excluded. All patients were initially started on prednisolone 2 mg/kg. Response to steroid was defined as rise in platelet count to 50*109/L in 14 days. The patients who did not respond to steroid were given TPO along with the continuing dose of steroid. According to efficacy, patients were classified into 2 groups: steroid-sensitive and non-steroid-sensitive. Bone marrow aspiration was performed at the time of diagnosis. The total number of megakaryocytes on whole slide was calculated by low-power microscope, and the morphology of as many as 50 megakaryocytes was analyzed by oil lens and classified to naïve, granular, thromocytogenic and naked nucleus megakaryocytes. The correlation between the patients' clinical parameters and steroid-sensitive ITP was assessed using univariate logistic regression analyses. ROC curve analysis was performed to determine optimal cut-off values. We categorized these variables according to the cutoff values, and included these categorized variables for further multivariate logistic regression analyses. Then we constructed the predictive index on the basis of the independent factors included in the final multivariable logistic model. Results The clinical parameters of the included patients are shown in Table 1. A total of 109 and 61 patients were diagnosed as steroid-sensitive ITP and non-steroid-sensitive ITP. In univariate logistic model, the variables significantly associated with steroid-sensitive ITP were gender, thromocytogenic megakaryocyte count (TMC), the ratio of granular megakaryocyte count to total megakaryocyte count (GMC/TM ratio), and the ratio of naked nucleus megakaryocyte count to total megakaryocyte count (NNMC/TM ratio). Among the variables, female, reduced TMC with a cut-off value of 7, increased GMC/TM ratio with a cutoff value of 70% and elevated NNMC/TM ratio with a cutoff value of 1% showed diagnostic values with AUC values more than 0.5 in predicting steroid-sensitive ITP. Multivariate logistic regression was used for the four significant variables identified by univariate analysis. According to the cut-off values, patients were classified into two categories. Gender (female; OR=2.569, 95%CI 1.29-5.08; P=0.007), reduced TMC (≤6; OR=2.7, 95%CI 1.29-5.63; P=0.008) and increased GMC/TM ratio (≥70%; OR=3.27, 95%CI 1.23-8.65; P=0.017) were found to be significantly independent predictors of steroid sensitivity (Table 2). On the basis of the regression coefficient and odds ratios, weighted risk scores of 1 were assigned to gender, TMC and GMC/TM ratio, respectively. The index resulted in total risk scores between 0 and 3. ROC analysis showed that an index greater than or equal to 2 points had the best AUC value (0.63) with 47.7% of sensitivity and 78.7% of specificity for predicting steroid sensitivity. The non-steroid-sensitive ITP were subsequently treated with TPO, and 73% (30/41) responded to treatment. Conclusions The results showed that megakaryocytic morphology could be a good predictive marker for steroid-sensitivity. Steroid-sensitive ITP could be identified when primary ITP patients have a predictive index ≥ 2 points. These findings may help guide early treatment strategy in ITP. Disclosures No relevant conflicts of interest to declare.

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.

Three types of polyamide 6 based blends are prepared, in which the intermolecular interactions are different, ranging from ‘no interaction’ to strong interaction. Under two extreme cooling conditions, the melts of the blends crystallized and then the crystalline structure and melting behaviors are examined, respectively. The results suggest that depending upon the degree of intermolecular interaction and the amount of the second component, PA6 may have different crystal forms.