Molten Guest-Mediated Metal-Organic Frameworks Featuring Multi-Modal Supramolecular Interaction Sites for Flame-Retardant Superionic Conductor in All-Solid-State Batteries.

The development of solid-state electrolytes (SSEs) with outstanding comprehensive performance is currently a critical challenge for achieving high energy density and safer solid-state batteries (SSBs). In this study, a strategy of nano-confined in situ solidification is proposed to create a novel category of molten guest-mediated metal-organic frameworks, named MGM-MOFs. By embedding the newly developed molten crystalline organic electrolyte (ML20) into the nanocages of anionic MOF-OH, MGM-MOF-OH, characterized by multi-modal supramolecular interaction sites and continuous negative electrostatic environments within nano-channels, is achieved. These nanochannels promote ion transport through the successive hopping of Li+ between neighbored negative electrostatic environments and suppress anion movement through the chemical constraint of the hydroxyl-functionalized pore wall. This results in remarkable Li+ conductivity of 7.1 × 10-4 S cm-1 and high Li+ transference number of 0.81. Leveraging these advantages, the SSBs assembled with MGM-MOF-OH exhibit impressive cycle stability and a high specific energy density of 410.5 Wh kganode + cathode + electrolyte -1 under constrained conditions and various working temperatures. Unlike flammable traditional MOFs, MGM-MOF-OH demonstrates high robustness under various harsh conditions, including ignition, high voltage, and extended to humidity.

VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.

The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.

Event-related brain potentials reveal enhancing and compensatory mechanisms during dual neurocognitive and cycling tasks.

BACKGROUND: Various neurocognitive tests have shown that cycling enhances cognitive performance compared to resting. Event-related potentials (ERPs) elicited by an oddball or flanker task have clarified the impact of dual-task cycling on perception and attention. In this study, we investigate the effect of cycling on cognitive recruitment during tasks that involve not only stimulus identification but also semantic processing and memory retention. METHODS: We recruited 24 healthy young adults (12 males, 12 females; mean age = 22.71, SD = 1.97 years) to perform three neurocognitive tasks (namely color-word matching, arithmetic calculation, and spatial working memory) at rest and while cycling, employing a within-subject design with rest/cycling counterbalancing. RESULTS: The reaction time on the spatial working memory task was faster while cycling than at rest at a level approaching statistical significance. The commission error percentage on the color-word matching task was significantly lower at rest than while cycling. Dual-task cycling while responding to neurocognitive tests elicited the following results: (a) a greater ERP P1 amplitude, delayed P3a latency, less negative N4, and less positivity in the late slow wave (LSW) during color-word matching; (b) a greater P1 amplitude during memory encoding and smaller posterior negativity during memory retention on the spatial working memory task; and (c) a smaller P3 amplitude, followed by a more negative N4 and less LSW positivity during arithmetic calculation. CONCLUSION: The encoding of color-word and spatial information while cycling may have resulted in compensatory visual processing and attention allocation to cope with the additional cycling task load. The dual-task cycling and cognitive performance reduced the demands of semantic processing for color-word matching and the cognitive load associated with temporarily suspending spatial information. While dual-tasking may have required enhanced semantic processing to initiate mental arithmetic, a compensatory decrement was noted during arithmetic calculation. These significant neurocognitive findings demonstrate the effect of cycling on semantic-demand and memory retention-demand tasks.

Bilayer Zwitterionic Metal-Organic Framework for Selective All-Solid-State Superionic Conduction in Lithium Metal Batteries.

Solid-state batteries (SSBs) hold immense potential for improved energy density and safety compared to traditional batteries. However, existing solid-state electrolytes (SSEs) face challenges in meeting the complex operational requirements of SSBs. This study introduces a novel approach to address this issue by developing a metal-organic framework (MOF) with customized bilayer zwitterionic nanochannels (MOF-BZN) as high-performance SSEs. The BZN consist of a rigid anionic MOF channel with chemically grafted soft multicationic oligomers (MCOs) on the pore wall. This design enables selective superionic conduction, with MCOs restricting the movement of anions while coulombic interaction between MCOs and anionic framework promoting the dissociation of Li+ . MOF-BZN exhibits remarkable Li+ conductivity (8.76 × 10-4 S cm-1 ), high Li+ transference number (0.75), and a wide electrochemical window of up to 4.9 V at 30 °C. Ultimately, the SSB utilizing flame retarded MOF-BZN achieves an impressive specific energy of 419.6 Wh kganode+cathode+electrolyte -1 under constrained conditions of high cathode loading (20.1 mg cm-2 ) and limited lithium metal source. The constructed bilayer zwitterionic MOFs present a pioneering strategy for developing advanced SSEs for highly efficient SSBs.

Covalent Organic Framework with Multi-Cationic Molecular Chains for Gate Mechanism Controlled Superionic Conduction in All-Solid-State Batteries.

Although solid-state batteries (SSBs) are high potential in achieving better safety and higher energy density, current solid-state electrolytes (SSEs) cannot fully satisfy the complicated requirements of SSBs. Herein, a covalent organic framework (COF) with multi-cationic molecular chains (COF-MCMC) was developed as an efficient SSE. The MCMCs chemically anchored on COF channels were generated by nano-confined copolymerization of cationic ionic liquid monomers, which can function as Li+ selective gates. The coulombic interaction between MCMCs and anions leads to easier dissociation of Li+ from coordinated states, and thus Li+ transport is accelerated. While the movement of anions is restrained due to the charge interaction, resulting in a high Li+ conductivity of 4.9×10-4  S cm-1 and Li+ transference number of 0.71 at 30 °C. The SSBs with COF-MCMC demonstrate an excellent specific energy density of 403.4 Wh kg-1 with high cathode loading and limited Li metal source.

Circular RNA circ_0000212 accelerates cervical cancer progression by acting as a miR-625-5p sponge to upregulate PTP4A1.

Cervical cancer is one of the most common malignant tumors in women. Circular RNA (circRNA) has been shown to play a crucial role in cervical cancer. Here, the aim of this study was to explore the functions and a novel miRNA/mRNA network underlying circ_0000212 in cervical cancer regulation. The expression of circ_000212, miR-625-5p and Protein Tyrosine Phosphatase 4A1 (PTP4A1) mRNA was measured by quantitative real-time PCR (qRT-PCR). 5-ethynyl-2'-deoxyuridine assay was conducted to detect the proliferation of cervical cancer cells. Wound healing and transwell assays were employed to assess cell migration and invasion. The angiogenesis abilities of cervical cancer cells were evaluated by tube formation assay. Flow cytometry was performed for analyzing cell apoptosis. The expression of PTP4A1 protein and apoptosis-relative protein were detected via western blot. The dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were employed to clarify the interaction between circ_0000212 or PTP4A1 and miR-625-5p. The impact of circ_0000212 on cervical cancer growth in vivo was detected by xenograft assay. Circ_0000212 and PTP4A1 were highly expressed and miR-625-5p expression level was decreased in cervical cancer. Circ_0000212 silencing suppressed cervical cancer cell proliferation, migration, invasion and angiogenesis while promoting apoptosis. MiR-625-5p was targeted by circ_0000212, and miR-625-5p inhibition reversed the effects of circ_0000212 knockdown. MiR-625-5p directly targeted PTP4A1, and the inhibitory effect of miR-625-5p on the malignant progression of cervical cancer was reversed after PTP4A1 overexpression. In-vivo assays validated that circ_0000212 promoted cervical cancer tumor growth in vivo . circ_0000212 acted as an oncogene in cervical cancer progression, and knockdown of circ_0000212 repressed cervical cancer development by increasing miR-625-5p and decreasing PTP4A1.

Deep Neural Network for the Detections of Fall and Physical Activities Using Foot Pressures and Inertial Sensing.

Fall detection and physical activity (PA) classification are important health maintenance issues for the elderly and people with mobility dysfunctions. The literature review showed that most studies concerning fall detection and PA classification addressed these issues individually, and many were based on inertial sensing from the trunk and upper extremities. While shoes are common footwear in daily off-bed activities, most of the aforementioned studies did not focus much on shoe-based measurements. In this paper, we propose a novel footwear approach to detect falls and classify various types of PAs based on a convolutional neural network and recurrent neural network hybrid. The footwear-based detections using deep-learning technology were demonstrated to be efficient based on the data collected from 32 participants, each performing simulated falls and various types of PAs: fall detection with inertial measures had a higher F1-score than detection using foot pressures; the detections of dynamic PAs (jump, jog, walks) had higher F1-scores while using inertial measures, whereas the detections of static PAs (sit, stand) had higher F1-scores while using foot pressures; the combination of foot pressures and inertial measures was most efficient in detecting fall, static, and dynamic PAs.

Serum CHI3L1 as a Biomarker for Non-invasive Diagnosis of Liver Fibrosis.

BACKGROUND: Liver fibrosis is the early pathological manifestation of various chronic liver diseases (including schistosomiasis, alcoholic, viral, nonalcoholic, fatty liver, etc.), which can progress to cirrhosis and even liver cancer. Out of the 7.7 billion world population, approximately 2 billion individuals have evidence of hepatitis B virus (HBV) infection; of these, 350 to 400 million suffer from chronic HBV infection, accounting for about 5% of the global population. The global prevalence of hepatitis C is 3%. These figures indicate that liver fibrosis is quite common. METHODS: 98 patients with liver fibrosis were included in this study. The serum chitinase-3 Like Protein-1 (CHI3L1) level was measured by the double antibody Sandwich ELISA method. RESULTS: Serum levels of CHI3L1 were significantly different between no-fibrosis and fibrosis groups (P < 0.01). There was a strong correlation between the levels of CHI3L1, elastometry, hyaluronan, CIV (P < 0.01) and age and sex, TBIL, DBIL, ALB, AST, ALT, GGT, ALP, PLT, LN, PIINP, FIB-4, and APRI (P < 0.05). The expression of CHI3L1 was different from fibrosis grades S1, S3, and S4 (P < 0.05, P < 0.001). The expression of CHI3L1 was significantly different between F1 and F4 (P < 0.05). Serum CHI3L1 expression level can be a valuable metric for diagnosing liver fibrosis, with an AUC value of 0.812. Out of the 98 patients who had undergone liver puncture, 79 patients (30.38%) had ALT ≤ 2ULN. CONCLUSIONS: The expression level of serum CHI3L1 was significantly higher in patients with liver fibrosis than that in patients without liver fibrosis. The expression levels of serum CHI3L1 were different in different grades of liver fibrosis and increased with the severity of liver fibrosis. Serum CHI3L1 can distinguish early stage (S1) of liver fibrosis from late stage (S3-4) of liver fibrosis. Serum CHI3L1 combined with HA is even more effective in the diagnosis of S2-4 hepatic fibrosis. The diagnostic efficacy of serum CHI3L1 in patients with ALT ≤ 2ULN was better than that of the other non-invasive diagnostic models.

Icaritin Inhibits Migration and Invasion of Human Ovarian Cancer Cells via the Akt/mTOR Signaling Pathway.

Ovarian cancer (OC) is the most lethal of all gynecologic malignancies with poor survival rates. Although surgical treatment and chemotherapy had advanced to improve survival, platinum-based chemoresistance remains a major hurdle in the clinical treatment of OC. The search for novel active ingredients for the treatment of drug-resistant OC is urgently needed. Here, we demonstrated that icaritin, the main active ingredient derived from the traditional Chinese herb Epimedium genus, significantly suppressed the proliferation, migration, and invasion of both drug-susceptible and cisplatin-resistant OC cells in vitro. Mechanistically, icaritin at 20 µM significantly inhibited the phosphorylation of Akt and mTOR, as well as decreased the expression of vimentin and increased the expression of E-cadherin. Our data indicate that icaritin, a prenylated flavonoid natural product, could serve as a potential inhibitor of cisplatin-resistant OC by inhibiting the Akt/mTOR signaling pathway.

Constructing Heterogeneous Structure in Metal-Organic Framework-Derived Hierarchical Sulfur Hosts for Capturing Polysulfides and Promoting Conversion Kinetics.

Lithium-sulfur batteries (LSBs) are still severely blocked by the shuttle of polysulfides (LiPSs), resulting in low sulfur utilization and decreased lifetime. The optimal design of hosts with tailored porous structures and catalytic sites is expected to address this issue. Herein, a Bi/Bi2O3 heterostructure within the metal-organic framework (MOF)-derived sulfur host with a hierarchical structure was elaborated for both serving as sulfur hosts and promoting the redox reaction kinetics of LiPSs. The shuttle effects of LiPSs can be mitigated by the dual functional Bi/Bi2O3 heterostructure enriched in the outer layer of CAU-17-derived carbonic rods, i.e., the effective redox conversion of LiPSs can be realized at the Bi/Bi2O3 heterointerface by the adsorption of LiPSs over Bi2O3 and subsequently catalytic conversion over Bi. Benefiting from these merits, the fabricated LSBs realized a significantly optimized performance, including a high discharge capacity of 740.8 mAh g-1 after 1000 cycles with an ultralow decay rate of 0.022% per cycle at 1 C, a high areal capacity of 6.6 mAh cm-2 after 100 cycles with a sulfur loading of 8.1 mg cm-2, and good performance in pouch cells as well.

Two Carboxyl-Decorated Anionic Metal-Organic Frameworks as Solid-State Electrolytes Exhibiting High Li+ and Zn2+ Conductivity.

A highly electronegative carboxyl-decorated anionic metal-organic framework (MOF), (Me2NH2)2[In2(THBA)2](CH3CN)9(H2O)21 (InOF; H4THBA = [1,1':4',1″-terphenyl]-2',3,3″,5,5',5″-hexacarboxylic acid), with high-density electronegative functional sites was designed and constructed. One unit cell of InOF possesses 12 negative sites that originate from the negatively charged secondary building unit [In(COO)4]- and exposed carboxyl groups on the ligand. The abundant electronegative sites can facilitate the hopping of ions in channels and thus result in highly efficient ion conductivities for various metal ions. Our results show that Li+-loaded materials have a remarkably high ion conductivity of 1.49 × 10-3 S/cm, an ion transference number of 0.78, and a relatively low activation energy of 0.19 eV. The Na+, K+, and Zn2+ ion conductivities of InOF are 7.97 × 10-4, 7.69 × 10-4, and 1.22 × 10-3 S/cm at 25 °C, respectively.

Resistance-induced brain activity changes during cycle ergometer exercises.

BACKGROUND: EEGs are frequently employed to measure cerebral activations during physical exercise or in response to specific physical tasks. However, few studies have attempted to understand how exercise-state brain activity is modulated by exercise intensity. METHODS: Ten healthy subjects were recruited for sustained cycle ergometer exercises at low and high resistance, performed on two separate days a week apart. Exercise-state EEG spectral power and phase-locking values (PLV) are analyzed to assess brain activity modulated by exercise intensity. RESULTS: The high-resistance exercise produced significant changes in beta-band PLV from early to late pedal stages for electrode pairs F3-Cz, P3-Pz, and P3-P4, and in alpha-band PLV for P3-P4, as well as the significant change rate in alpha-band power for electrodes C3 and P3. On the contrary, the evidence for changes in brain activity during the low-resistance exercise was not found. CONCLUSION: These results show that the cortical activation and cortico-cortical coupling are enhanced to take on more workload, maintaining high-resistance pedaling at the required speed, during the late stage of the exercise period.

Design of thiol-lithium ion interaction in metal-organic framework for high-performance quasi-solid lithium metal batteries.

Metal-organic frameworks (MOFs) have recently emerged as promising solid electrolytes (SEs) for solid-state batteries (SSBs). Developing MOFs with high-density functional groups may improve the spatial density of hopping sites and facilitate ion transport. Herein we synthesized a new series of ion conductive MOFs, Zr-MA-M (M = Li+, Na+, K+, Zn2+), with high density -SH groups functionalized in small pores and metal ions adsorbed on the thiol groups. Taking advantage of the interaction between S and metal ions, such ion conductors show high ionic conductivity, low interfacial resistance, high lithium ion (Li+) transference number (0.63) and wide electrochemical window up (4.6 V). Moreover, the SSBs assembled with Zr-MA-Li+ based SE exhibit excellent rate performance (106 mA h g-1 at 2C) and remarkable cyclic stability (low decay rate of 0.21‰ per cycle for 700 cycles at 2C). Thus, this study provides a new route for developing high-performance MOF-based SEs via the application of host-guest interaction.

Therapeutic effects of dental pulp stem cells on vascular dementia in rat models.

Dental pulp stem cells are a type of adult stem cells with strong proliferative ability and multi-differentiation potential. There are no studies on treatment of vascular dementia with dental pulp stem cells. In the present study, rat models of vascular dementia were established by two-vessel occlusion, and 30 days later, rats were injected with 2 × 107 dental pulp stem cells via the tail vein. At 70 days after vascular dementia induction, dental pulp stem cells had migrated to the brain tissue of rat vascular dementia models and differentiated into neuron-like cells. At the same time, doublecortin, neurofilament 200, and NeuN mRNA and protein expression levels in the brain tissue were increased, and glial fibrillary acidic protein mRNA and protein expression levels were decreased. Behavioral testing also revealed that dental pulp stem cell transplantation improved the cognitive function of rat vascular dementia models. These findings suggest that dental pulp stem cell transplantation is effective in treating vascular dementia possibly through a paracrine mechanism. The study was approved by the Animal Ethics Committee of Harbin Medical University (approval No. KY2017-132) in 2017.

Therapeutic potential of dental pulp stem cell transplantation in a rat model of Alzheimer's disease.

Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest. They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors. Few studies have reported Alzheimer's disease treatment using dental pulp stem cells. Rat models of Alzheimer's disease were established by injecting amyloid-ß1-42 into the hippocampus. Fourteen days later, 5 × 106 dental pulp stem cells were injected into the hippocampus. Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin, NeuN, and neurofilament 200 in the hippocampus, while the expression of amyloid-ß was decreased. Moreover, cognitive and behavioral abilities were improved. These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins, which indicates a potential therapeutic effect for Alzheimer's disease. This study was approved by the Animal Ethics Committee of Harbin Medical University, China (approval No. KY2017-132) on February 21, 2017.

Icaritin induces ovarian cancer cell apoptosis through activation of p53 and inhibition of Akt/mTOR pathway.

AIMS: Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers. Currently, the first-line OC treatment consists of cytoreductive surgery and platinum-based chemotherapy. However, most patients develop chemoresistance after the first-line treatment limits the success of treatment. Therefore, there is an urgent need to identify effective therapeutic agents. MAIN METHODS: Cell viabilities were detected by MTS assay; Annexin V-FITC/PI assay and western blotting assay were performed to analyze the apoptotic cells in vitro; An immunofluorescence assay was performed to analyze the TUNEL+ apoptotic cells in vivo; Patient-derived xenografts were established to test the in vivo antitumor effects; The key proteins of p53, caspase-mediated apoptotic pathway and Akt/mTOR pathway were detected by Western blotting. KEY FINDINGS: Icaritin, a prenylflavonoid derivative from Epimedium Genus, inhibited the proliferation of drug-sensitive OC cells (OV2008 and C13*) and cisplatin resistant OC cells A2780cp. Icaritin induced OC cell apoptosis in vitro, as indicated by the increase of Annexin V+/PI+ apoptotic cells analyzed with flow cytometry, and the cleavage of caspase 9, caspase 3 and poly-ADP-ribose polymerase (PARP) detected with western blotting. Icaritin also inhibited tumor growth and induced OC cells apoptosis in patient-derived xenografts, as indicated by the tumor growth delay and increase of TUNEL-positive cells in tumor tissues. The icaritin-induced OC cell apoptosis may be associated with the activation of p53 and the suppression of Akt/mTOR pathway. SIGNIFICANCE: This study sheds light on the underlying mechanisms of antitumor effect of icaritin, and warrants clinical trial for treatment of OC.

Lentivirus-mediated microRNA-124 gene-modified bone marrow mesenchymal stem cell transplantation promotes the repair of spinal cord injury in rats.

Our study aims to explore the effects of lentivirus-mediated microRNA-124 (miR-124) gene-modified bone marrow mesenchymal stem cell (BMSC) transplantation on the repair of spinal cord injury (SCI) in rats. BMSCs were isolated from the bone marrow of rats. The target gene miR-124 was identified using a luciferase-reporter gene assay. Seventy-two rats were selected for construction of the SCI model, and the rats were randomly divided into the blank group, sham group, SCI group, negative control (NC) group, overexpressed miR-124 group and si-PDXK group. The mRNA expression of miR-124 and the mRNA and protein expression of pyridoxal kinase (PDXK) were detected by quantitative real-time polymerase chain reaction and western blotting. The locomotor capacity of the rats was evaluated using the Basso, Beattie and Bresnahan (BBB) scale. Brdu, neuron-specific enolase (NSE), neurofilament (NF) and microtubule-associated protein 2 (MAP2) were detected using immunohistochemistry. The expression levels of thyrotropin-releasing hormone (TRH), prostacyclin (PGI2) and gangliosides (GM) were measured using an enzyme-linked immunosorbent assay. PDXK was identified as the target gene of miR-124. The overexpressed miR-124 group exhibited higher miR-124 expression than the SCI, NC and si-PDXK groups. Compared with the SCI and NC groups, the PDXK expression was downregulated in the overexpressed miR-124 and si-PDXK groups, and the BBB scores were significantly increased 7, 21 and 35 days after transplantation. The double-labeled positive cell densities (Brdu+NSE/NF/MAP2) and the expression levels of TRH, PGI2 and GM in the overexpressed miR-124 group were significantly higher than those in the NC and SCI groups. These results indicated that miR-124 targeted PDXK to accelerate the differentiation of BMSCs into neurocytes and promote SCI repair.

Clinical significance of CSF3R, SRSF2 and SETBP1 mutations in chronic neutrophilic leukemia and chronic myelomonocytic leukemia.

Chronic neutrophilic leukemia (CNL) and chronic myelomonocytic leukemia (CMML) are rare hematologic neoplasms. We performed CSF3R, SRSF2 and SETBP1 mutational analyses in 10 CNL and 56 CMML patients. In this sample cohort, 80% of CNL patients harbored CSF3R mutations, of which the CSF3R T618I mutation was dominant. Mutations in CSF3R and SETBP1 were found in 7.1% and 5.3% CMML patients respectively, while 25% of CMML patients carried SRSF2 mutations. Strikingly, we identified that all of the CSF3R mutations detected in CMML patients were represented by a P733T mutation. The CSF3R P733T mutation represents a novel CSF3R mutation. In addition, none of the four CSF3R P733T mutated patients carried SRSF2 mutations [0/14 (0%) patients with combined CSF3R P733T and SRSF2 mutations vs. 4/42 (9.5%) with CSF3R P733T and wt SRSF2, P < 0.001]. Both mut SRSF2 and mut SETBP1 patients had shorter overall survival (OS) and progression-free survival (PFS) compared to patients with wt SRSF2 (P < 0.001 both) and wt SETBP1 (P < 0.001 and P = 0.02, respectively). While we found no significant differences in OS and PFS as a consequence of CSF3R mutation status, our work suggest that the CSF3R T618I mutation is a diagnostic marker with good specificity and sensitivity for CNL. In conclusion, our study highlights effective diagnostic and prognostic markers of CNL and CMML patients in the Chinese population.

Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma.

BACKGROUND: Activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) presents aggressive clinical courses and poor prognosis. Targeting key pathways may raise the possibility of improving clinical outcomes. METHODS: The synergetic effects were assessed by CCK-8 assay and measured by isobologram analysis. The NVP-Bez235 and lenalidomide cytotoxicity were measured by flow cytometry, Western Blot and si-RNA transfection. The combined treatment inducing tumor regression in vivo was performed in nude mice of OCI-Ly10 xenograft mouse model. RESULTS: Low dose of two agents represented significant inhibition of proliferation with CI value < 1. NVP-Bez235 combined with lenalidomide remarkably increased apoptosis through intrinsic pathway by upregulating Bim, Bax and downregulating Bcl-xL. Akt, especially NF-κB, played an important role in the synergetic effects. Cotreatment also induced the cell cycle to be arrested in G0/G1 phase, and decreased S phase by increasing p21 expression, downregulating cyclinA and diminishing CDK2 phosphorylation in Su-DHL2 and OCI-Ly3 but not in OCI-Ly10. Mice treated with NVP-Bez235/lenalidomide represented obvious tumor growth regression and prolonged overall survival. CONCLUSIONS: Our findings demonstrated the synergistic effect of low dose of NVP-Bez235 and lenalidomide in ABC-DLBCL, the underlying mechanism may be multifunctional, involving apoptosis, Akt and NF-κB inactivation and cell cycle arrest. Cotreatment was also effective in vivo. These data pave the way for potential treatment of ABC-DLBCL with combination of NVP-Bez235 and lenalidomide.

[Analysis of CALR, JAK2 and MPL gene mutations in BCR-ABL negative myeloproliferative neoplasms].

OBJECTIVE: To explore the mutational status of CALR, JAK2 and MPL genes in BCR-ABL negative myeloproliferative neoplasms (MPN) patients and the clinical features of MPN patients with these mutations. METHODS: A total of 246 patients with a definite diagnosis of BCR-ABL negative MPN were enrolled from January 2009 to January 2014 into this study. Among them, there were 48 cases of polycythemia vera (PV) patients, 171 cases of essential thrombocythemia (ET) patients and 27 cases of primary myelofibrosis (PMF) patients. And CALR, JAK2 V617F, 12 exons of JAK2 and MPL W515L/K genes were amplified by PCR and sequenced directly. Clinical features were also analyzed in patients. RESULTS: Among 246 cases of BCR-ABL-negative MPN patients, 52 cases (21.1%) had CALR mutation, 121 cases (49.2%) JAK2 V617F mutation, 0 case (0) 12 exons of JAK2 mutation, and 2 cases (0.8%) MPL W515L/K mutation, respectively. These mutations were found existing exclusively. In PV patients, the white blood cell and platelet counts in JAK2 V617F mutated group were higher than those in wild-type JAK2 V617F group, while the level of hemoglobin was higher in wild-type JAK2 V617F group (all P<0.05). In ET patients, the white blood cell count, the level of hemoglobin, the frequency of thromboembolic events and risk stratification in JAK2 V617F mutated group were higher than those in CALR mutated group (all P<0.05). In PMF patients, the level of hemoglobin in JAK2 V617F mutated group were significantly higher than those in CALR mutated group (P<0.05). CONCLUSIONS: The proliferative level of bone marrow, risk of thromboembolic events and stratification are lower in CALR mutated patients than those in JAK2 V617F mutated patients. The pathogenic mechanism of mutated gene should be further investigated in future.