Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities.

Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient-derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation-dependent manner. Mechanistic studies identify that AML cell-derived exosomes play a vital role during the AML cell-mediated MSCs education/reprogramming process. Pre-administration of mice BM microenvironment with AML-derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML-derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome-based AML cells-MSCs communication. Collectively, the data show that AML-educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.

Is cardia cancer a special type of gastric cancer? A differential analysis of early cardia cancer and non-cardia cancer.

Background: The prognosis of early cardia cancer and non-cardia cancer is still controversial. It is difficult to collect a large number of cases with complete information in clinical practice. Our study was aimed to identify the differences in clinicopathological characteristics and outcomes of early cardia gastric cancer and non-cardia gastric cancer. Methods: All cases analyzed were from Surveillance, Epidemiology, and End Results database. The data of the patients with early gastric cancer from 2004 to 2010 was retrospectively analyzed. Patients were distributed to cardia cancer group and non-cardia cancer group. Univariate and multivariate analyses were performed to examine differences between groups. The competitive risk model was made to compare the association with cardia cancer and non-cardia cancer about the causes of death. Propensity score matching (PSM) was performed to reduce the bias. Results: We found that cardia cancer was more common in male patients and the White than that in non-cardia cancer at early stage, signet ring cell carcinoma was more common in non-cardia cancer, and the differentiation of non-cardia cancer was worse. Univariate analysis showed that age, marital status, race, tumor location, histology, grade, stage, and operation or not can determine the prognosis. And the prognosis of patients with cardia cancer was worse than that of non-cardia cancer, according to lymph node metastasis and the depth of tumor invasion. Multivariate analysis showed cardia cancer was an independent prognostic factor for poor prognosis. After PSM, cardia cancer still exhibited poor prognosis. Conclusions: At early stage, cardia cancer had a poor prognosis compared with non-cardia cancer. The prevention and treatment of early cardia cancer need to be seriously treated.

Exponential damping key to successful containment of COVID-19 outbreak

Due to its excessively high capacity for human-to-human transmission, the 2019 novel coronavirus disease (COVID-19), first reported in Wuhan in China, spread rapidly to the entire nation and beyond, and has now been declared a global public health emergency. Understanding the transmission pattern of the virus and the efficacy of transmission control measures is crucial to ensuring regional and global disease control. Here we propose a simple model based on exponential infectious growth, but with a time-varying, largely damping, transmission rate. This model provides an excellent fit to the existing data from the 102 countries and regions which have reported cases for more than 6 days, and, we think, has largely captured the transmission patterns of the COVID-19 outbreak under a variety of intervention and control measures. We found that the damping rate, defined as the rate of the exponential decline in transmission rate, ranged from -0.125 to 0.513 d-1 globally (a negative damping rate represents acceleration in spread). The estimated peak time (when the fastest spread occurs) and the final number of infections were found to be greatly affected by the damping rate. Successful control measures, such as those implemented in China and South Korea, have resulted in a clear pattern of exponential damping in the viral spread (also shown during the 2003 outbreak of Severe Acute Respiratory Syndrome, SARS). The damping rate, therefore, could be used as an indicator for the efficacy of implemented control measures. Our model suggests that the COVID-19 outbreak is currently accelerating worldwide, especially rapidly in certain countries (e.g. USA and Australia) where exponential damping is yet to emerge. Consistent with the message from the World Health Organisation (WHO), we thus strongly suggest all countries to take active measures to contain this global pandemic. Slight increments in the damping rate from additional control efforts, especially in countries showing weak or no exponential damping in COVID-19 transmission, could lead to a radically more positive outcome in the fight to contain the pandemic.

A simple ecological model captures the transmission pattern of the coronavirus COVID-19 outbreak in China

The rapid spread of the 2019 novel coronavirus (COVID-19), initially reported in the city of Wuhan in China, and quickly transmitted to the entire nation and beyond, has become an international public health emergency. Estimating the final number of infection cases and the turning point (time with the fastest spreading rate) is crucial to assessing and improving the national and international control measures currently being applied. In this paper we develop a simple model based on infectious growth with a time-varying infection rate, and estimate the final number of infections and the turning point using data updated daily from 3 February 2020, when China escalated its initial public health measures, to 10 February. Our model provides an extremely good fit to the existing data and therefore a reasonable estimate of the time-varying infection rate that has largely captured the transmission pattern of this epidemic outbreak. Our estimation suggests that (i) the final number of infections in China could reach 78,000 with an upper 95% confidence limit of 88,880; (ii) the turning point of the fastest spread was on the 4th or the 5th of February; and (iii) the projected period for the end of the outbreak (i.e., when 95% of the final predicted number of infection is reached) will be the 24th of February, with an upper 95% confidence limit on the 19th of March. This suggests that the current control measures in China are excellent, and more than sufficient to contain the spread of this highly infectious novel coronavirus, and that the application of such measures could be considered internationally for the global control of this outbreak.

pH-sensitive prodrug conjugated polydopamine for NIR-triggered synergistic chemo-photothermal therapy.

Combination of chemotherapy with photothermal therapy (PTT) demonstrate highly desirable for efficient medical treatment of tumor. At present works, camptothecin (CPT)-containing polymeric prodrug (PCPT) were fabricated by polymerization of a pH-sensitive camptothecin (CPT) prodrug monomer and MPC using reversible addition-fragmentation transfer (RAFT) strategy. The pH-sensitive polymeric prodrug was tethered onto surface of polydopamine (PDA) nanoparticles by amidation chemistry for combination of chemotherapy with photothermal therapy. Specifically, the active CPT quickly released from the multifunctional nanoparticles in acidic microenvironment ascribe to the cleavage of bifunctional silyl ether linkage. Meanwhile, the PDA could convert the near infrared (NIR) light energy into heat with high efficiency, which makes the resulted nanoparticles an effective platform for photothermal therapy. In vitro analysis confirmed that the PDA@PCPT nanoparticles could be efficiently uptaked by HeLa cells and deliver CPT into the nuclei of cancer cells. The cell viability assays indicated an evident in vitro cytotoxicity to HeLa cancer cells under 808 nm light irradiation. Significant tumor regression was also observed in the tumor-bearing mice model with the combinational therapy provided from the PDA@PCPT nanoparticles. The PDA@PCPT multifunctional system which was achieved by a facile route should be a potential candidate in the anti-cancer field due to the synergistic therapeutic effect, which is superior to any single approach.

Hyperbranched Polyglycerol Functionalized Silica Stationary Phase for Hydrophilic Interaction Liquid Chromatography.

Surface-initiated anionic-ring-opening multibranching polymerization was employed to prepare a hyperbranched polyglycerol (HPG) functionalized silica stationary phase for hydrophilic interaction liquid chromatography (HILIC). The obtained stationary phase was characterized by Fourier-transform infrared spectrometry (FT-IR) and thermogravimetric analysis (TGA). The chromatographic properties of the prepared stationary phase were systematically investigated. The abundance and multitude distribution of hydroxyl groups in HPG endowed the stationary phase with improved hydrophilicity and enhanced separation performance compared with the stationary phase functionalized with monolayer of hydroxyl groups. The stationary phase showed excellent retention of various polar compounds, such as nucleosides, necleobases, phenols and sulfanilamides, indicating great potential in the separation of complex biosamples.

Plasma-treated Ce/TiO2-SiO2 catalyst for the NH3-SCR of NOx.

Ce/TiO2-SiO2 catalysts with different Ti/Si molar ratios are prepared by the incipient impregnation method and their NH3-SCR activities are evaluated at 100-500°C on a fixed reactor. The Ce/TiO2-SiO2 (3/1) catalyst, modified by non-thermal plasma (NTP) treatment and then activated by thermal treatment at 500°C for 4 h, exhibits best performance. Comprehensive deNOx performance of the catalyst is evidently improved and its efficiency reaches up to 99.21% at 350°C. NO conversion efficiency of the treated catalyst doped with K remains about 90.23% at 300°C and the catalyst also shows improved activity at lower temperatures. Various characterization methods show that the activity enhancement is correlated only with NTP treatment, as it increases the number of Ce3+ species, which generates more chemisorbed oxygen, leads to improved dispersion of Brønsted and Lewis acidic sites and finally has an inherent etching effect.

Two Equilibria of (N-Methyl-3-pyridinium)chlorocarbene, a Cationic Carbene.

Equilibrium constants and the associated thermodynamic parameters are reported for the equilibria established between the cationic carbene (N-methyl-3-pyridinium)chlorocarbene tetrafluoroborate (MePyr(+)CCl BF4(-), 3) and 1,3,5-trimethoxybenzene (TMB) to form a carbene-TMB complex, as well as between carbene 3 and chloride ion to form the zwitterion, N-methyl-3-pyridinium dichloromethide (10). These equilibrium constants and thermodynamic parameters are contrasted with analogous data for several related carbenes, and the influence of the pyridinium unit in carbene 3 is thereby highlighted. Computational studies augment and elucidate the experimental results.

Molecularly Imprinted Polymers Based Electrochemical Sensor for 2,4-Dichlorophenol Determination.

A molecularly imprinted polymers based electrochemical sensor was fabricated by electropolymerizing pyrrole on a Fe3O4 nanoparticle modified glassy carbon electrode. The sensor showed highly catalytic ability for the oxidation of 2,4-dichlorophenol (2,4-DCP). Square wave voltammetry was used for the determination of 2,4-DCP. The oxidation peak currents were proportional to the concentrations of 2,4-DCP in the range of 0.04 to 2.0 µM, with a detection limit of 0.01 µM. The proposed sensor was successfully applied for the determination of 2,4-DCP in water samples giving satisfactory recoveries.

Absolute reactivity of (N-methyl-3-pyridinium)chlorocarbene.

(N-Methyl-3-pyridinium)chlorocarbene tetrafluoroborate (MePyr(+)CCl BF4(-), 4) is generated by laser flash photolysis (LFP) of the corresponding diazirine (5) and reacted with tetramethylethylene, cyclohexene, 1-hexene, 2-ethyl-1-butene, methyl acrylate, and acrylonitrile. Absolute rate constants are measured for these carbene-alkene addition reactions, and activation parameters are obtained for additions of MePyr(+)CCl BF4(-) to tetramethylethylene, cyclohexene, and 1-hexene. MePyr(+)CCl BF4(-) is computed to be a highly reactive, electrophilic, singlet carbene, and experiments are in accord with expectations. Its activation parameters are compared with those of CF3CCl, CCl2, CClF, and CF2. In all cases, enthalpy-entropy compensation is observed, with ΔH(‡) and ΔS(‡) decreasing in tandem as carbenic stability decreases. A qualitative explanation is offered for this phenomenon.

Nucleophilic intermolecular chemistry and reactivity of dimethylcarbene.

Experimental and computational studies find that dimethylcarbene (DMC), the parent dialkylcarbene, is both predicted to be and functions as a very reactive nucleophilic carbene in addition reactions with five simple alkenes. Activation energies and enthalpies for DMC additions to 2-ethyl-1-butene and methyl acrylate are computed and observed to be negative.

Graphene oxide-coumarin derivative conjugate as activatable nanoprobe for intracellular imaging with one- or two-photon excitation.

An interesting activatable fluorescent imaging probe based on a graphene oxide-coumarin derivative conjugate with high sensitivity in cancer cell visualization was proposed. The nanoprobe has a fluorescence off-on response for intracellular imaging via covalently linking coumarin derivatives to graphene oxide (GO) through disulfide bonds. The obtained nanoprobe shows no or weak fluorescence (OFF) most likely due to the fluorescence resonance energy transfer from the coumarin moiety to GO. It becomes activated (ON) inside the cells by glutathione initiated dissociation, showing remarkably enhanced fluorescence. More significantly, the present activatable nanoprobe can be efficiently taken up by cells. Two-photon induced fluorescence imaging of the proposed nanoprobe was also clearly observed by utilizing femtosecond pulse laser excitation, and affords a powerful alternative candidate for near-infrared (NIR) fluorescence imaging of tumors. Similar fluorescence was visualized in a tumor-bearing mouse model using this probe. These results demonstrate the potential of using this activatable nanoprobe for the detection of cancer.

The biphasic redox sensing of SENP3 accounts for the HIF-1 transcriptional activity shift by oxidative stress.

AIM: To investigate the mechanisms underlying the biphasic redox regulation of hypoxia-inducible factor-1 (HIF-1) transcriptional activity under different levels of oxidative stress caused by reactive oxidative species (ROS). METHODS: HeLa cells were exposed to different concentrations of H(2)O(2) as a simple model for mild and severe oxidative stress. Luciferase reporter assay and/or quantitative real-time PCR were used to investigate the transcriptional activity. Immunoblot was used to detect protein expression. Chromatin immunoprecipitation assay was used to detect HIF-1/DNA binding. The interaction of p300 with HIF-1α or with SENP3, and the SUMO2/3 conjugation states of p300 were examined by coimmunoprecipitation. RESULTS: HIF-1 transcriptional activity in HeLa cells was enhanced by low doses (0.05-0.5 mmol/L) of H(2)O(2), but suppressed by high doses (0.75-8.0 mmol/L) of H(2)O(2). The amount of co-activator p300 bound to HIF-1α in HeLa cells was increased under mild oxidative stress, but decreased under severe oxidative stress. The ROS levels differentially modified cysteines 243 and 532 in the cysteine protease SENP3, regulating the interaction of SENP3 with p300 to cause different SUMOylation of p300, thus shifting HIF-1 transcriptional activity. CONCLUSION: The shift of HIF-1 transactivation by ROS is correlated with and dependent on the biphasic redox sensing of SENP3 that leads to the differential SENP3/p300 interaction and the consequent fluctuation in the p300 SUMOylation status.

SUMO2 and SUMO3 transcription is differentially regulated by oxidative stress in an Sp1-dependent manner.

Protein SUMOylation (SUMO is small ubiquitin-related modifier) is a dynamic process that is strictly regulated under physiological and pathological conditions. However, little is known about how various intra- or extra-cellular stimuli regulate expression levels of components in the SUMO system. SUMO isoforms SUMO2 and SUMO3 can rapidly convert to be conjugated in response to a variety of cellular stresses. Owing to the limitations of sequence homology, SUMO2 and SUMO3 cannot be differentiated between and are thus referred to as SUMO2/3. Whether these two isoforms are regulated in distinct manners has never been addressed. In the present paper we report that the expression of SUMO3, but not SUMO2, can be down-regulated at the transcription level by cellular oxidative stress. In the present study, we checked SUMO2 and SUMO3 mRNA levels in cells exposed to various doses of H2O2 and in cells bearing different levels of ROS (reactive oxygen species). We found an inverse relationship between SUMO3 transcription and ROS levels. We characterized a promoter region specific for the mouse Sumo3 gene that is bound by the redox-sensitive transcription factor Sp1 (specificity protein 1) and demonstrated oxidation of Sp1, as well as suppression of Sp1-DNA binding upon oxidative stress. This revealed for the first time that the expression of SUMO2 and SUMO3 is regulated differently by ROS. These findings may enhance our understanding about the regulation of SUMOylation and also shed light on the functions of Sp1.

Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90.

The molecular chaperone heat shock protein 90 (Hsp90) and the co-chaperone/ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) control the turnover of client proteins. How this system decides to stabilize or degrade the client proteins under particular physiological or pathological conditions is unclear. We report here a novel client protein, the SUMO2/3 protease SENP3, that is sophisticatedly regulated by CHIP and Hsp90. SENP3 is maintained at a low basal level under non-stress condition due to Hsp90-independent CHIP-mediated ubiquitination. Upon mild oxidative stress, SENP3 undergoes thiol modification, which recruits Hsp90. Hsp90/SENP3 association protects SENP3 from CHIP-mediated ubiquitination and subsequent degradation, but this effect of Hsp90 requires the presence of CHIP. Our data demonstrate for the first time that CHIP and Hsp90 interplay with a client alternately under non-stress and stress conditions, and the choice between stabilization and degradation is made by the redox state of the client. In addition, enhanced SENP3/Hsp90 association is found in cancer. These findings provide new mechanistic insight into how cells regulate the SUMO protease in response to oxidative stress.

SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.

Small ubiquitin-like modifier (SUMO) 2/3 is known to conjugate to substrates in response to a variety of cellular stresses. However, whether and how SUMO2/3-specific proteases are involved in de-conjugation under cell stress is unclear. Here, we show that low doses of hydrogen peroxide (H(2)O(2)) induce an increase of the SENP3 protein, which removes SUMO2/3 from promyelocytic leukemia (PML). Low dose H(2)O(2) causes SENP3 to co-localize with PML bodies and reduces the number of PML bodies in a SENP3-dependent manner. Furthermore, de-conjugation of SUMO2/3 from PML is responsible for the accelerated cell proliferation caused by low dose H(2)O(2). Knocking down PML promotes basal cell proliferation as expected. This can be reversed by reconstitution with wild-type PML but not its mutant lacking SUMOylation, indicating that only the SUMOylated PML can play an inhibitory role for cell proliferation. Thus, SENP3 appears to be a key mediator in mild oxidative stress-induced cell proliferation via regulation of the SUMOylation status of PML. Furthermore, SENP3 is over-accumulated in a variety of primary human cancers including colon adenocarcinoma in which PML is hypo-SUMOylated. These results reveal an important role of SENP3 and the SUMOylation status of PML in the regulation of cell proliferation under oxidative stress.

4,5-Diaza-9H-fluoren-9-imine.

In the title compound, C(11)H(7)N(3), the diaza-fluorene rings are almost coplanar with an r.m.s. deviation of 0.0160 Å. In the crystal structure, C-H⋯N hydrogen bonds link mol-ecules into sheets parallel to the ab plane. Mol-ecules are also stacked regularly along the c axis by a variety of π-π inter-actions with centroid-centroid distances in the range 3.527 (2)-3.908 (2) Å.

N-(4,5-Diaza-9H-fluoren-9-yl-idene)-4-meth-oxy-aniline.

In the title compound, C(18)H(13)N(3)O, the diaza-fluorene ring system is almost coplanar (r.m.s. deviation = 0.0640 Å) and subtends an angle of 61.5 (4)° with the plane of the meth-oxy-substituted benzene ring. In the crystal structure, pairs of C-H⋯O hydrogen bonds link mol-ecules into centrosymmetric dimers parallel to the ab plane. Mol-ecules are also stacked in an obverse fashion along the c axis by a variety of π-π inter-actions with centroid-centroid distances in the range 3.557 (2)-3.921 (2) Å.

SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation.

The physiological function of Sentrin/SUMO-specific proteases (SENPs) remains largely unexplored, and little is known about the regulation of SENPs themselves. Here, we show that a modest increase of reactive oxygen species (ROS) regulates SENP3 stability and localization. We found that SENP3 is continuously degraded through the ubiquitin-proteasome pathway under basal condition and that ROS inhibit this degradation. Furthermore, ROS causes SENP3 to redistribute from the nucleoli to the nucleoplasm, allowing it to regulate nuclear events. The stabilization and redistribution of SENP3 correlate with an increase in the transcriptional activity of the hypoxia-inducing factor-1 (HIF-1) under mild oxidative stress. ROS-enhanced HIF-1 transactivation is blocked by SENP3 knockdown. The de-SUMOylating activity of SENP3 is required for ROS-induced increase of HIF-1 transactivation, but the true substrate of SENP3 is the co-activator of HIF-1 alpha, p300, rather than HIF-1 alpha itself. Removing SUMO2/3 from p300 enhances its binding to HIF-1 alpha. In vivo nude mouse xenografts overexpressing SENP3 are more angiogenic. Taken together, our results identify SENP3 as a redox sensor that regulates HIF-1 transcriptional activity under oxidative stress through the de-SUMOylation of p300.

Oxidative modification of caspase-9 facilitates its activation via disulfide-mediated interaction with Apaf-1.

Intracellular reactive oxygen species (ROS) are known to regulate apoptosis. Activation of caspase-9, the initial caspase in the mitochondrial apoptotic cascade, is closely associated with ROS, but it is unclear whether ROS regulate caspase-9 via direct oxidative modification. The present study aims to elucidate the molecular mechanisms by which ROS mediate caspase-9 activation. Our results show that the cellular oxidative state facilitates caspase-9 activation. Hydrogen peroxide treatment causes the activation of caspase-9 and apoptosis, and promotes an interaction between caspase-9 and apoptotic protease-activating factor 1 (Apaf-1) via disulfide formation. In addition, in an in vitro mitochondria-free system, the thiol-oxidant diamide promotes auto-cleavage of caspase-9 and the caspase-9/Apaf-1 interaction by facilitating the formation of disulfide-linked complexes. Finally, a point mutation at C403 of caspase-9 impairs both H(2)O(2)-promoted caspase-9 activation and interaction with Apaf-1 through the abolition of disulfide formation. The association between cytochrome c and the C403S mutant is significantly weaker than that between cytochrome c and wild-type caspase-9, indicating that oxidative modification of caspase-9 contributes to apoptosome formation under oxidative stress. Taken together, oxidative modification of caspase-9 by ROS can mediate its interaction with Apaf-1, and can thus promote its auto-cleavage and activation. This mechanism may facilitate apoptosome formation and caspase-9 activation under oxidative stress.