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Background The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843). Objective This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial. Patients/methods Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. Results Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30×109 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n=339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. Conclusion The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

Although long non-coding RNA (lncRNA) HCP plays essential roles in human cancers, its function and mechanism in multiple myeloma (MM) have not crystallized. HCP5 level in MM was assessed through qRT-PCR. A series of functional investigations were conducted to evaluate the influences of HCP5 on proliferation and apoptosis. Bioinformatics analysis and RIP/RNA pull-down assays were carried out to determine the relationships among HCP5, miR-128-3p, and PLAGL2. Relative protein level was determined through Western blot. A xenograft tumor model was applied for validating the roles of HCP5/miR-128-3p/PLAGL2 axis in vivo. HCP5 was significantly increased in MM. HCP5 knockdown effectively thwarted the proliferative rate and cell cycle of MM cell lines and suppressed tumor growth. HCP5 regulated PLAGL2 expression by sponging miR-128-3p. PLAGL2 overexpression effectively rescued cells from influences by sh-HCP5 on cell proliferative and apoptotic rates. Additionally, HCP5 knockdown significantly inhibited Wnt/β-catenin/cyclin D1 signaling, and these effects were eliminated by PLAGL2 overexpression. Our study revealed that HCP5/miR-128-3p/PLAGL2 is closely correlated to MM development by modulating Wnt/β-catenin/cyclin D1 signaling. HCP5 promoted cell proliferation and tumor formation of MM cells by activating the Wnt/β‐catenin/CCND1 signaling pathway by sponging miR-128-3p to increase PLAGL2 expression

Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.

INTRODUCTION Decitabine-based chemotherapy regimens have shown efficacy in the treatment of elderly patients with acute myeloid leukemia (AML). However, it remains unclear whether any molecular alteration is correlated with the therapeutic effect of such treatment regimens. METHODS Gene mutations were detected using next-generation sequencing, and their impact on survival was investigated in elderly AML patients receiving decitabine-based chemotherapy. RESULTS A higher incidence of gene mutations was identified in elderly AML patients than in the younger cohorts. Elderly patients more frequently carried DNMT3A, IDH2, ASXL1, TET2, RUNX1, CEBPA single mutation (CEBPAsingle-mut ), and TP53 mutations. Survival analysis showed that DNMT3A, FLT3-ITD, and TP53 mutations were associated with inferior overall survival (OS) and event-free survival (EFS) in younger AML patients receiving standard treatment. However, in elderly patients treated with decitabine-based chemotherapy, FLT3-ITD, and ASXL1 mutations, but not DNMT3A and TP53 mutations, were associated with poor OS and EFS. Moreover, contrary to CEBPA double mutation (CEBPAdouble-mut ), CEBPAsingle-mut was identified as an unfavorable prognostic factor. CONCLUSION This study comprehensively analyzed the prognostic implications of gene mutations in elderly AML patients under decitabine-based treatment modality. Identification of genetic biomarkers to predict the subgroup of elderly AML patients who can benefit from decitabine-based regimens might have an immediate clinical utility to optimize the treatment of elderly AML patients.

Introduction Skp2 is an E3 ubiquitin ligase that plays an important role in modulating tumor progression. The mechanisms underlying Skp2 in the promotion of proliferation and its function in the primary resistance to tyrosine kinase inhibitors (TKIs) in human CML remain to be determined. This study aimed to investigate the function of Skp2 in CML progression as well as its effects on TKI sensitivity. Methods Expression of Skp2 in leukocytes from patients with CML and normal blood samples was analyzed by qRT-PCR. Cell proliferation was analyzed by EdU incorporation and cell counting assays. Luciferase reporter and chromatin immunoprecipitation assays were used for examination of the effects of CREB on Skp2 expression. The apoptosis in vitro of K562 cells was analyzed by MTT and caspase 3/7 activity assays. Results The present study demonstrates that Skp2 was expressed at a higher level in patients with CML compared with healthy donors, and the elevated expression of Skp2 is critical for CML cell proliferation. Mechanistically, Skp2 was transcriptionally upregulated by CREB responsive to the PI3K/Akt signaling pathway. Furthermore, inhibition of Skp2 expression by shRNAs or blocking the PI3K/Akt/CREB pathway greatly enhances the sensitivity of CML cells to Imatinib treatment. Conclusion We conclude that the PI3K/Akt/CREB axis regulates the sensitivity of K562 cells to Imatinib via mediating Skp2 expression. The present study revealed an unknown role of Skp2 in CML progression and provided new aspects on the Skp2-modulated TKI sensitivity in CML, contributing to the development of potential therapeutic anticancer drugs.

This study is to assess the clinical value of in vitro primary cell high-efficiency expansion and high-throughput drug sensitivity screening (HEHDS) system in leukemia, and we evaluated a cohort of 121 patients with acute myeloid leukemia (AML) and 27 patients with acute lymphoblastic leukemia (ALL) using HEHDS. Bone marrow aspirates were collected from patients with leukemia. Purified leukemic cancer cells were obtained, cultured, and screened with a panel of 247 FDA-approved compounds by HEHDS technology. Ninety-six patients received HEHDS-guided therapy while 52 patients who were subjected to physician directed therapy served as controls. ALL patients who received treatment guided by HEHDS showed higher rate of complete remission (CR) than that of patients in the non-HEHDS group (90.91% vs. 56.25%). Similarly, AML patients received HEHDS-guided therapy were found to have greater CR rate, when compared with patients who received physician-directed therapy (45.88% vs. 25%). There was a significantly higher rate of CR in HEHDS-guided therapy group compared to the non-HEHDS group. The application of HEHDS could be beneficial for leukemia treatment.

KIF2A has been shown to be involved in the regulation of AML pathology, however, the mechanistic role of KIF2A in AML has not been fully identified. The present study aimed to identify the underlying mechanism of KIF2A regulation of AML cell function and chemosensitivity. A total of 58 patients with AML and 30 healthy subjects were enrolled for clinical analysis. AML cells (KG‑1 and Kasumi‑1) were transfected with KIF2A or control small interfering (si)RNA. PI3K/AKT pathway activator (740 Y‑P) and RhoA overexpression plasmid were added to rescue the effect of KIF2A siRNA. Cell proliferation, apoptosis, chemosensitivity to ADR and AraC, expression levels of mRNA/proteins associated with PI3K/AKT and RhoA/ROCK pathways were measured by Cell Counting Kit‑8, flow cytometry, reverse transcription‑quantitative PCR and western blotting. KIF2A was overexpressed, and correlated with higher levels of bone marrow blast, poor risk classification, lower treatment response and unfavorable survival profile in patients with AML. KIF2A siRNA inhibited proliferation but enhanced apoptosis and chemosensitivity to ADR and AraC in KG‑1 and Kasumi‑1 cells, which also inactivated PI3K/AKT and RhoA/ROCK pathways. Subsequent rescue experiments showed that 740 Y‑P and RhoA overexpression plasmid promoted cell survival and decreased chemosensitivity, which reversed the effect of KIF2A siRNA in KG‑1 and Kasumi‑1 cells. KIF2A was correlated with worse clinical features and survival in patients with AML; its knockdown promoted apoptosis and chemosensitivity by inactivating PI3K/AKT and RhoA/ROCK signaling pathways in AML cells. These data suggested KIF2A may be a potential prognostic marker and treatment target for AML management.

Multiple myeloma (MM) is a malignancy of plasma cells that leads to marrow failure and bone lesions. Numerous studies have verified the link between long non‑coding RNAs (lncRNAs) and MM. The present study aimed to examine the role and underlying mechanism of differentiation antagonizing non‑protein coding RNA (DANCR) in MM cells. The relative expression levels of DANCR, microRNA (miR)‑135b‑5p and Krüppel‑like factor 9 (KLF9) were examined using reverse transcription‑quantitative PCR. Cell viability was assessed using the MTT assay, while relative cell migration and invasion were evaluated using Transwell assays. Moreover, the dual‑luciferase reporter assay was used to examine the interplay between DANCR, miR‑135b‑5p and KLF9. Western blotting was performed to determine the expression level of KLF9. It was found that lncRNA DANCR and KLF9 were downregulated, while miR‑135b‑5p was upregulated in the serum of patients with MM and in MM cells compared with the controls. Overexpressing DANCR or knocking down miR‑135b‑5p reduced the viability of the MM cells, as well as restrained MM cells from migrating and invading. Furthermore, DANCR directly targeted miR‑135b‑5p and was negatively correlated with miR‑135b‑5p. It was also found that KLF9 was targeted by miR‑135b‑5p and was inversely correlated with miR‑135b‑5p expression. The impact of lncRNA DANCR‑mediated suppression on cell viability, invasion and migration was partially abolished by short hairpin RNA KLF9 or miR‑135b‑5p mimics transfection in MM cells. Thus, it was suggested that lncRNA DANCR repressed the viability, migration and invasion of MM cells by sponging miR‑135b‑5p to target KLF9.

The rapid development of SDEN (Service Dynamic Extended Network) has led to an expansion of its related concepts and inter-concept relationships. How to formally and normatively express SDEN system from the knowledge level is of great significance to realize intelligent management of SDEN domain knowledge and support status monitoring and evaluation of SDEN system. Firstly, the characteristics of SDEN and its implementation principle are summarized; Then, SDEN domain knowledge is analyzed to extract ontology concepts and their attributes; Nextly, inter-concept relationships are analyzed to establish SDEN-Ontology; Finally, the specific application and effect of SDEN-Ontology are verified through two application scenarios based on customized inference rules.

Background Numerous long non-coding RNAs (lncRNAs) are reported to affect the progression of multiple myeloma (MM). This study is aimed to explore the role and downstream mechanism of lncRNA LINC01003 in MM. Materials and methods Xenograft tumor assay was used to assess the function of LINC01003 in MM in vivo. The mRNA expression levels of LINC01003, miR-33a-5p, and PIM1 were determined by quantitative real-time polymerase chain reaction. Cell viability was examined by MTT assay. Relative protein levels of apoptosis-related factors (Bcl-2 and Bax) and proviral integration site of the Moloney leukemia virus kinase 1 (PIM1) were detected via western blot. Adhesion-related proteins were measured by Enzyme-linked immunosorbent assay was used to determine the levels of adhesion-related proteins. Besides, the target relation among LINC01003, miR-33a-5p and PIM1 was tested via dual-luciferase reporter assay. Results Low expression of LINC01003 was observed in MM cell lines and peripheral blood samples of MM patients. Both LINC01003 up-regulation and miR-33a-5p down-regulation repressed cell viability and adhesion, and promoted apoptosis of MM cells. Moreover, LINC01003 suppressed the growth of xenograft tumor in mice. We then identified miR-33a-5p as a downstream target of LINC01003, and confirmed that PIM1 was a direct target gene of miR-33a-5p. Both high expression of miR-33a-5p and low expression of PIM1 reversed the suppressive effects of LINC01003 overexpression on cell adhesion and viability, and the promoting effect on apoptosis in MM cells. Conclusion LINC01003 functioned as a sponge of miR-33a-5p to inhibit the development MM by regulating PIM1 expression.

Additional file 1: Table S1. Investigators per site. Table S2. Dose adjustments of hetrombopag during the double-blind treatment period and open-label treatment period. Table S3. Dose adjustments of eltrombopag for patients in the Placebo-eltrombopag group during the double-blind treatment period and open-label treatment period. Table S4. Platelet responses (platelet counts ≥ 50 × 109/L at week 8) were observed across all subgroups of baseline platelet counts, sex, age, and splenectomy status. Table S5. Proportion of responders at different time points within 8 weeks after treatment.

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies.

Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20+) DLBCL randomly received IBI301 (375 mg/m2) plus the standard CHOP or rituximab (375 mg/m2) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin. Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI − 9.1%–1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05). IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20+ DLBCL. This trial is registered on ClinicalTrials.gov (NCT02867566).

Leukemia accounts for a significant mortality across the globe every year. The main objective of the present research work was directed towards studying the anticancer effects of scutellarin-a plant flavone, against K562 human leukemia cells, along with examining its effects on cellular apoptosis, cell cycle, cell migration and cell invasion as well as Raf/MEK/ERK signalling pathway.Cell viability of K562 leukemia cells was evaluated by WTS-1 assay, while apoptotic effects induced by scutellarin in K562 cells were examined by fluorescence microscopy, flow cytometry, and western blot methods. Effects on cell cycle were measured by flow cytometry. Transwell Matrigel assay was performed to evaluate whether scutellarin induces inhibition of cell migration and cell invasion effects in K562 cells.Scutellarin was shown to suppress the viability of the K562 cells dose-dependently with an IC50 of 6 μM. Further, scutellarin was shown to induce apoptosis which was initially exhibited by DAPI and annexin-V/propidium iodide (PI) staining and then confirmed by western blot in which it was shown to trigger regulation of Bax and downregulation of Bcl-2 in K562 human leukemia cells. Scutellarin also induced G0/G1 cell cycle arrest which was accompanied by suppression of cell migration and invasion. Scutellarin also led to the decline of the expression of p-Raf, p-MEK1/2 and p-ERK1/2 in a concentration-dependent manner.In conclusion, scutellarin could inhibit the growth of K562 human leukemia cells by inducing apoptosis, cell cycle arrest, inhibition of cell migration and invasion and downregulating the expressions of p-Raf, p-MEK1/2 and p-ERK1/2.

In this work, we prepared ultrathin MoS2 nanosheets with exposed active edge sites and high electric conductivity that can sufficiently absorb light in the visible region to enable solar energy conversion. The gold nanocrystal-decorated MoS2 nanosheets facilitate sufficiently enhanced photoelectrochemical water splitting in the UV-visible region. Different Au nanostructures, such as Au nanoparticles and nanorods, were modified on the surface of MoS2 nanosheets to promote photoelectrochemical water decomposition. By spin-coating a synthetic gold-modified MoS2 hybrid photoanode on a FTO substrate, the efficiency of photoelectrochemical water oxidation was significantly enhanced, by 2 times (nanorods) and 3.5 times (nanoparticles) in the visible-infrared region; furthermore, the average optical resistance was reduced by a factor of two compared to the MoS2 photoanode without Au, and the photocurrent increases exponentially when the system bias was greater than 0.7 volts. The Au-MoS2 metal-semiconductor interface plays an important role in studying the surface plasmon interactions, charge transfer mechanism, and electric field amplification. This rational design for such a unique hybrid nanostructure explains the plasmon-enhanced photoelectrochemical water splitting. This current contribution provides a new path for using the plasmonic metal/semiconductor heterostructure to effectively harvest UV-visible light for solar fuel generation.

Chimeric antigen receptor (CAR)-T-cell is a safe and effective therapy of B-cell cancers but it is unknown if this is so in persons with prior hepatitis B virus (HBV) infection. We studied 70 subjects with advanced B-cell cancers receiving CAR-T-cell therapy, 12 of whom had chronic HBV-infection (HBsAg positive) and 29 with resolved HBV-infection (HBsAg negative and anti-HBc positive). Safety and efficacy were compared with 29 subjects without HBV-infection. HBV was reactivated in 2 subjects with chronic HBV-infection and 1 with resolved HBV-infection. There was no HBV-related hepatitis flare. Responses to CAR-T-cell therapy in the three cohorts were not significantly different. There was no significant difference in the incidence or severity of cytokine release syndrome (CRS) and neurologic toxicity between the cohorts. Our data suggest that chronic and resolved HBV-infection do not affect the safety and efficacy of CAR-T-cell therapy.

Cu doped Zn–In–S quantum dots (CZIS QDs) were synthesized by a hydrothermal method. The absorption and fluorescence peaks of CZIS QDs shifted monotonically to longer wavelengths with the increase of the Cu precursor and the decrease of Zn and In precursors. The dopant emission wavelength can be easily tuned in the whole visible region ranging from 465 nm to 700 nm by changing the molar ratio of Cu/Zn/In/S. On the basis of experimental results, it was testified that the emission of CZIS QDs was the trap state emission rather than the excitonic emission. The emission mechanisms of CZIS QDs were attributed to three kinds of approaches: (i) photogenerated holes efficiently move to trap states induced by Cu defects and recombine with the electrons in the energy level of sulfur vacancies; (ii) the holes in Cu trap states recombine with the electrons in the surface defect state; (iii) the electrons in the conduction band recombine with the holes in levels caused by Zn vacancies. After coating the ZnS shell around the CZIS core, the fluorescence quantum yield of CZIS QDs can reach 25–35%. CZIS/ZnS QDs conjugated with antibodies were successfully applied for labeling Hep-G2 liver cancer cells. The cytotoxicity studies revealed that the viabilities of the cells incubated with different concentrations of CZIS/ZnS QDs and at different times all remained at a high level of more than 90%. Hence, the CZIS/ZnS nanoparticle is a promising material as the fluorescent probe for biological applications.

We present a hydrothermal approach for the preparation of biocompatible and high-quality Zn

Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI50 values of 30–80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell...

There is still a great demand in the clinic for the drugs which can overcome a variety of imatinib resistant ABL mutants. Starting from a type I inhibitor axitinib, which has been reported to overcome ABL-T315I mutant induced resistance, through a structure guided drug design approach and binding mode switch strategy, we have discovered a novel type II ABL inhibitor 24 (CHMFL-ABL-121), which significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant T315I. 24 exhibited IC50 values of 2 nM and 0.2 nM against purified inactive ABL wt and T315I kinase protein respectively and inhibited the proliferation of the established CML cell lines with GI50 at single digit nM. In cellular context, 24 strongly affected BCR-ABL mediated signaling pathways and induced apoptosis as well as arrested cell cycle at G0/G1 phase. In the in vivo study, 50 mg/kg/day dosage of 24 displayed TGI of 52% in the TEL-ABLT315I-BaF3 cell inoculated allograft mouse model without obvious toxicity.

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg-1 day-1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.

We prepared novel photoanodes structured as FTO/ZnO nanoflowers/ZnTiO3/CdS/CdTeS/ZnS quantum dots (QDs) with highly exposed large specific area and energy coupling. The design of the photoanode expressed significant enhanced photoelectrochemical (PEC) performance such as improved absorption efficiency, reduced recombination rate, and enhanced charge transportation state, resulting in a significant increase in photoelectron current. The multinanoheterostructures photoanode provides a high photocatalytic activity and a maximum photocurrent density up to 9.41 mA/cm2 under AM 1.5 G illumination. The novel cosensitized multinanoheterostructures photoanodes lead to a remarkable and promising application in photoelectrochemical and water splitting reactions.

As a two dimensional material with extraordinary optoelectronic properties, graphene has been persistently focused and studied. Inspired by the effects of prominent near-field enhancement and tight field confinement of graphene surface plasmons, tunable perfect absorber constituted by square graphene-dielectric arrays is proposed in this work and investigated with numerical simulation. Complete monolayer graphene is utilized in the arrays, without demand of manufacture process to cut graphene layer into periodic patterns. Within a wide range of specific geometric parameters, the arrays achieve two absorption peaks with near unity absorbance at near-infrared wavelengths. The absorption performance of the arrays is also independent of polarization. It's discovered that surface plasmonic modes are simultaneously excited on graphene and gold-dielectric interface, and there is a strong coupling between such two modes. Moreover, both of the two peaks can be dynamically tuned by adjusting chemical potential of graphene, without salient absorption reduction. With these excellent features, the arrays may provide prospects in development of new sensors and switches. Keywords: Graphene, Surface plasmons, Perfect absorption, Tunable absorption

Hematological toxicity is a common adverse effect of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML). We retrospectively investigated the incidence of hematological toxicity after TKI administration in 143 CML patients and parameters associated with hematological toxicity. Severe hematological toxicity (grade 3-4) existed in 26 (18.2%) patients. Marrow fibrosis (MF), age, Sokal score, and spleen enlargement were associated with severe hematological toxicity. Further multivariate analysis showed that only MF was an independent predictor. Complete cytogenetic response(CCyR) rates and major molecular response (MMR) rates with grade 3-4 hematological toxicity were 42.3% and 26.9%, respectively, significantly lower than patients with grade 1-2 and without hematological toxicity (

Cutaneous T-cell lymphoma (CTCL) is associated with the downregulation of miR-337 expression, although the exact underlying mechanism is unknown. In the present work, we investigated the molecular mechanism and function of miR-337 in regulating CTCL cell viability and invasion. We observed that miR-337 expression was downregulated in both CTCL tumors and cell lines. Furthermore, CCK assay, BrdU incorporation assay, and flow cytometry revealed that transfection with the miR-337 mimic resulted in decreased proliferation and increased apoptotic levels in CTCL cells. Results of the Transwell migration assay indicated that the miR-337 mimic decreased CTCL cell invasion in vitro. Both bioinformatics prediction and the dual-luciferase reporter assay revealed that miR-337 targets the 3'-UTR of STAT3 for silencing. Overexpression of STAT3 counteracted the pro-apoptotic influence of miR-337 in CTCL cell lines and restored their invasion properties. The results thus indicate that the miR-337-STAT3 axis inhibits the proliferation of malignant T cells and that miR-337 may serve as a promising therapeutic target for CTCL.

In this work, we prepared ultrathin MoS2 nanosheets with exposed active edge sites and high electric conductivity that can sufficiently absorb light in the visible region to enable solar energy conversion. The gold nanocrystal-decorated MoS2 nanosheets facilitate sufficiently enhanced photoelectrochemical water splitting in the UV-visible region. Different Au nanostructures, such as Au nanoparticles and nanorods, were modified on the surface of MoS2 nanosheets to promote photoelectrochemical water decomposition. By spin-coating a synthetic gold-modified MoS2 hybrid photoanode on a FTO substrate, the efficiency of photoelectrochemical water oxidation was significantly enhanced, by 2 times (nanorods) and 3.5 times (nanoparticles) in the visible-infrared region; furthermore, the average optical resistance was reduced by a factor of two compared to the MoS2 photoanode without Au, and the photocurrent increases exponentially when the system bias was greater than 0.7 volts. The Au-MoS2 metal-semiconductor interface plays an important role in studying the surface plasmon interactions, charge transfer mechanism, and electric field amplification. This rational design for such a unique hybrid nanostructure explains the plasmon-enhanced photoelectrochemical water splitting. This current contribution provides a new path for using the plasmonic metal/semiconductor heterostructure to effectively harvest UV-visible light for solar fuel generation.

Long non-coding RNA CRNDE and DNA methylation play a vital role in the occurrence and development of chronic lymphocytic leukemia (CLL). This study attempted to investigate the biological role of CRNDE methylation in CLL. The expression and methylation levels of CRNDE in CLL cell lines (MEC-1 and HG3) before or after methylation inhibitor (5-Aza-2'-deoxycytidine, 5-Aza-CdR) treatment was detected by quantitative real-time PCR or methylation-Specific PCR. The relationship among CRNDE, miR-28 and NDRG2 was verified by luciferase reporter assay. The effect of CRNDE overexpression and 5-Aza-CdR treatment on cell proliferation and apoptosis of MEC-1 and HG3 cells were assessed by CCK8 and flow cytomery. Compared with normal B lymphocytes, CRNDE was down-regulated and the methylation level of CRNDE was increased in MEC-1 and HG3 cells. Then, 5-Aza-CdR treatment caused an increase of CRNDE expression in MEC-1 and HG3 cells by demethylation. The overexpression or demethylation of CRNDE inhibited cell proliferation and promoted apoptosis in MEC-1 and HG3 cells by up-regulating CRNDE expression. Moreover, CRNDE functioned as a competing endogenous RNA to repress miR-28, which controlled its down-stream target NDRG2. CRNDE overexpression inhibited cell proliferation and promoted apoptosis via miR-28/NDRG2 axis in CLL. In conclusion, our data elaborated that CRNDE expression was regulated by DNA methylation, and the protective effect of CRNDE on CLL was attributed to the inhibition of proliferation in CLL via miR-28/NDRG2 axis. Thus, this work highlights a novel competing endogenous RNA circuitry involving key regulators of CLL.

Attention on semiconductor nanocrystals have been largely focused because of their unique optical and electrical properties, which can be applied as light absorber and luminophore. However, the band gap and structure engineering of nanomaterials is not so easy because of their finite size. Here we demonstrate an approach for preparing ternary AgInS2 (AIS), quaternary AgZnInS (AZIS), AgInS2/ZnS and AgZnInS/ZnS nanocompounds based on cation exchange. First, pristine Ag2S quantum dots (QDs) with different sizes were synthesized in one-pot, followed by the partial cation exchange between In(3+) and Ag(+). Changing the initial ratio of In(3+) to Ag(+), reaction time and temperature can control the components of the obtained AIS QDs. Under the optimized conditions, AIS QDs were obtained for the first time with a cation disordered cubic phase and high photoluminescence (PL) quantum yield (QY) up to 32% in aqueous solution, demonstrating the great potential of cation exchange in the synthesis for nanocrystals with excellent optical properties. Sequentially, Zn(2+) ions were incorporated in situ through a second exchange of Zn(2+) to Ag(+)/In(3+), leading to distinct results under different reaction temperature. Addition of Zn(2+) precursor at room temperature produced AIS/ZnS core/shell NCs with successively enhancement of QY, while subsequent heating could obtain AZIS homogeneous alloy QDs with a successively blue-shift of PL emission. This allow us to tune the PL emission of the products from 483 to 675 nm and fabricate the chemically stable QDs core/ZnS shell structure. Based on the above results, a mechanism about the cation exchange for the ternary nanocrystals of different structures was proposed that the balance between cation exchange and diffusion is the key factor of controlling the band gap and structure of the final products. Furthermore, photostability and in vitro experiment demonstrated quite low cytotoxicity and remarkably promising applications in the field of clinical diagnosis.

Acute myeloid leukemia (AML) is one of the most common, complex, and heterogeneous hematological malignancies in adults. Despite progresses in understanding the pathology of AML, the 5-year survival rates still remain low compared with CML, CLL, etc. The relationship between genomic features and drug responses is critical for precision medication. Herein, we depicted a picture for response of 145 drugs against 33 primary cell samples derived from AML patients with full spectrum of genomic features assessed by whole exon sequencing and RNA sequencing. In general, most of the samples were much more sensitive to the combinatorial chemotherapy regimens than the single chemotherapy drugs. Overall, these samples were moderately sensitive to the Traditional Chinese Medicine (TCM) and the targeted drugs. In the weighted gene coexpression network analysis (WGCNA), the TCM and targeted therapies displayed similar genetic signatures in the gene module correlation. Meanwhile, the expression of miRNAs, lncRNAs, and mRNAs did not display apparent gene module correlations among those different types of therapies. In addition, the combinatorial chemotherapy bear more module correlations than the single drugs. Interestingly, we found that the gene mutations and drug response were not enriched in any WGCNA module analysis. Most of the sensitive drug response biomarkers were enriched in the ribosome, endocytosis, cell cycle, and p53 associated signaling pathways. This study showed that gene expression modules might show better correlation than gene mutations for drug efficacy predictions.

BCR fused ABL kinase is the critical driving oncogene for chronic myeloid leukemia (CML) and has been extensively studied as the drug discovery target in the past decade. The successful introduction of tyrosine kinase inhibitors (TKI) such as Imatinib, Dasatinib and Bosutinib has greatly improved the CML patient survival rate. However, upon the chronic treatment, a variety of TKI resistant mutants, such as the V299L mutant which has been found in more and more patients with the high-throughput sequencing technology, are observed, although the incidence is still considered rare compared to the more prevalent gatekeeper T315I mutant. However, with the progress of the precision medicine concept, the rare mutation (or the orphan drug target) has attracted more and more attention. Here we report a novel type II BCR-ABL kinase inhibitor, CHMFL-ABL-039, which not only displayed great potency (IC(50): 7.9 nM) and selectivity (S score (1) = 0.02) against native ABL kinase among other kinases in the kinome, but also exhibited great potency (IC(50): 27.9 nM) and selectivity against Imatinib-resistant V299L mutant among other frequently observed ABL kinase mutants. CHMFL-ABL-039 has demonstrated greater efficacies than Imatinib regarding to the anti-proliferation, inhibition of the signaling pathway, arrest of cell cycle progression, induction of apoptosis in vitro and suppression of the tumor progression in vivo in the native and V299L mutated BCR-ABL kinase-driven cells/xenograft models. It would be a useful pharmacological tool to study the TKI resistant ABL V299L mutant-mediated pathology and provide a potential precise treatment approach for this orphan CML subtype in the precision medicine era.

Circular RNA (circRNA) belongs to the non-coding RNA family and is involved in various human cancers, such as lung cancer and colorectal cancer. Nevertheless, whether circRNA expression is related to chronic lymphocytic leukemia (CLL) progression remains largely unclear. In our study, we investigated the role of circ-CBFB in CLL. We found that circ-CBFB was markedly overexpressed in CLL cells compared to normal controls. Furthermore, we found that circ-CBFB could serve as a diagnostic and prognostic biomarker for CLL patients. We also explored the physiological function of circ-CBFB. We found that circ-CBFB knockdown significantly suppressed CLL cell proliferation, arrested cell cycle progression, and induced cellular apoptosis. In terms of its mechanism, we identified circ-CBFB as a sponge of miR-607, which targeted FZD3. By inhibiting miR-607 availability, circ-CBFB promoted FZD3 expression, leading to the activation of the Wnt/β-catenin pathway and consequent CLL progression. Taken together, our findings revealed that the circ-CBFB/miR-607/FZD3/Wnt/β-catenin regulatory signaling cascade contributes to CLL progression.

The Snail family transcriptional repressor 1 gene (Snail1) was screened in multiple myeloma cells (MMCs) from bortezomib-resistant MM patients and was found to be significantly associated with the development of drug-resistance mechanisms. In the present study, we first confirmed that the protein expression of Snail1 in bortezomib-resistant MMCs was significantly higher than that in MMCs without bortezomib resistance. The mechanistic studies confirmed that the enhancement of Snail1 expression in bortezomib-resistant MMCs directly upregulated transcription of the intracellular MDR1 gene to immediately develop multiple drug resistance mechanisms and inhibited P53 protein expression through the Snail1/hsa-miRNA-22-3p/P53 pathway to inhibit tumor cell apoptosis. By upregulating MDR1 and downregulating P53, Snail1 induced the drug resistance of MMCs to bortezomib, while Snail1 gene silencing effectively improved the drug sensitivity of MMCs to bortezomib chemotherapy. The present study further elucidated the drug resistance mechanisms of MMCs and provides evidence for increased clinical efficacy of bortezomib in MM patients.

We present a hydrothermal approach for the preparation of biocompatible and high-quality Zn3In2S6 (ZIS) quantum dots (QDs) in the presence of glutathione (GSH) as a stabilizer at different reaction temperatures. The as-prepared QDs exhibited small particle diameters (from 3.3 to 7.5 nm) with a hexagonal structure and size-dependent optical properties. The combination of the pH value and the amount of GSH played a crucial role in the enhancement of PL intensity. After the incorporation of Ag via cation exchange, the obtained Ag–Zn–In–S (AZIS) QDs demonstrated both red-shifted photo-luminescence (PL) emission and higher quantum yield. Furthermore, based on the investigations of PL lifetimes and excitation intensity-dependent PL spectra, we concluded that PL emission of ZIS QDs originated from shallow donor–acceptor (D–A) pair recombination, and intrinsic trap state-related deep D–A pair transition dominated the main emission of AZIS QDs. Furthermore, the biocompatible AZIS QDs with high quantum yield were applied to targeted labeling and imaging in the cytoplasm of hepatocellular carcinoma cells, indicating their promising applications in single-cell monitoring.

Here we demonstrate a novel and facile strategy of highly luminescent water-soluble Zn-doped AgIn5S8 (ZAIS) nanocrystals and ZAIS/ZnS core/shell structures, which were based on hydrothermal reaction between the acetate salts of the corresponding metals and sulfide precursor in the presence of l-cysteine at 110 °C in a Teflon-lined autoclave. The photoluminescent (PL) emission wavelength can be conveniently tuned from 560 to 650 nm by tailoring the stoichiometric ratio of [Ag]/[Zn]. The as prepared nanocrystals were characterized systematically and exhibit long PL lifetimes more than 100 ns. The influence of experimental conditions, including concentration of l-cysteine and reaction temperature, was investigated. In addition, we performed a coating procedure with the ZnS shell outside the ZAIS core and showed excellent PL quantum yields up to 35%. The in vitro experiment exhibited quite low cytotoxicity and marvelous biocompatibility, revealing their promising prospect in bioscience. Furthermore, the obtained ZAIS/ZnS nanocompounds (NCs) were covalently conjugated to alpha-fetoprotein antibodies and targeted fluorescent imaging for hepatocellular carcinoma cells was realized.