Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

FtsA acts through FtsW to promote cell wall synthesis during cell division in Escherichia coli.

In Escherichia coli, FtsQLB is required to recruit the essential septal peptidoglycan (sPG) synthase FtsWI to FtsA, which tethers FtsZ filaments to the membrane. The arrival of FtsN switches FtsQLB in the periplasm and FtsA in the cytoplasm from a recruitment role to active forms that synergize to activate FtsWI. Genetic evidence indicates that the active form of FtsQLB has an altered conformation with an exposed domain of FtsL that acts on FtsI to activate FtsW. However, how FtsA contributes to the activation of FtsW is not clear, as it could promote the conformational change in FtsQLB or act directly on FtsW. Here, we show that the overexpression of an activated FtsA (FtsA*) bypasses FtsQ, indicating it can compensate for FtsQ's recruitment function. Consistent with this, FtsA* also rescued FtsL and FtsB mutants deficient in FtsW recruitment. FtsA* also rescued an FtsL mutant unable to deliver the periplasmic signal from FtsN, consistent with FtsA* acting on FtsW. In support of this, an FtsW mutant was isolated that was rescued by an activated FtsQLB but not by FtsA*, indicating it was specifically defective in activation by FtsA. Our results suggest that in response to FtsN, the active form of FtsA acts on FtsW in the cytoplasm and synergizes with the active form of FtsQLB acting on FtsI in the periplasm to activate FtsWI to carry out sPG synthesis.

Nanostructured Inorganic Chalcogenide-Carbon Nanotube Yarn having a High Thermoelectric Power Factor at Low Temperature.

As power-conversion devices, flexible thermoelectrics that enable conformal contact with heat sources of arbitrary shape are attractive. However, the low performance of flexible thermoelectric materials, which does not exceed those of brittle inorganic counterparts, hampers their practical applications. Herein, we propose inorganic chalcogenide-nanostructured carbon nanotube (CNT) yarns with outstanding power factor at a low temperature using electrochemical deposition. The inorganic chalcogenide-nanostructured CNT yarns exhibit the power factors of 3425 and 2730 µW/(m·K2) at 298 K for the p- and n-type, respectively, which is higher than those of previously reported flexible TE materials. On the basis of excellent performance and geometry advantage of the nanostructured CNT yarn for modular design, all-CNT based thermoelectric generators have been easily fabricated, showing the maximum power densities of 24 and 380 mW/m2 at ΔT = 5 and 20 K, respectively. These results provide a promising strategy for the realization of high-performance flexible thermoelectric materials and devices for flexible/or wearable self-powering systems.

Genetic analysis of the septal peptidoglycan synthase FtsWI complex supports a conserved activation mechanism for SEDS-bPBP complexes.

SEDS family peptidoglycan (PG) glycosyltransferases, RodA and FtsW, require their cognate transpeptidases PBP2 and FtsI (class B penicillin binding proteins) to synthesize PG along the cell cylinder and at the septum, respectively. The activities of these SEDS-bPBPs complexes are tightly regulated to ensure proper cell elongation and division. In Escherichia coli FtsN switches FtsA and FtsQLB to the active forms that synergize to stimulate FtsWI, but the exact mechanism is not well understood. Previously, we isolated an activation mutation in ftsW (M269I) that allows cell division with reduced FtsN function. To try to understand the basis for activation we isolated additional substitutions at this position and found that only the original substitution produced an active mutant whereas drastic changes resulted in an inactive mutant. In another approach we isolated suppressors of an inactive FtsL mutant and obtained FtsWE289G and FtsIK211I and found they bypassed FtsN. Epistatic analysis of these mutations and others confirmed that the FtsN-triggered activation signal goes from FtsQLB to FtsI to FtsW. Mapping these mutations, as well as others affecting the activity of FtsWI, on the RodA-PBP2 structure revealed they are located at the interaction interface between the extracellular loop 4 (ECL4) of FtsW and the pedestal domain of FtsI (PBP3). This supports a model in which the interaction between the ECL4 of SEDS proteins and the pedestal domain of their cognate bPBPs plays a critical role in the activation mechanism.

High-Performance Thermoelectric Fabric Based on a Stitched Carbon Nanotube Fiber.

With the continuous development of flexible and wearable thermoelectric generators (TEGs), high-performance materials and their integration into convenient wearable devices have to be considered. Herein, we have demonstrated highly aligned wet-spun carbon nanotube (CNT) fibers by optimizing the liquid crystalline (LC) phase via hydrochloric acid purification. The liquid crystalline phase facilitates better alignment of CNTs during fiber extrusion, resulting in the high power factor of 2619 µW m-1 K-2, which surpasses those of the dry-spun CNT yarns. A flexible all-carbon TEG was fabricated by stitching a single CNT fiber and doping selected segments into n-type by simple injection doping. The flexible TEG shows the maximum output power densities of 1.9 mW g-1 and 10.3 mW m-2 at ΔT = 30 K. Furthermore, the flexible TEG was developed into a prototype watch-strap TEG, demonstrating easy wearability and direct harvesting of body heat into electrical energy. Combining high-performance materials with scalable fabrication methods ensures the great potential for flexible/or wearable TEGs to be utilized as future power-conversion devices.

Essential Role for FtsL in Activation of Septal Peptidoglycan Synthesis.

Spatiotemporal regulation of septal peptidoglycan (PG) synthesis is achieved by coupling assembly and activation of the synthetic enzymes (FtsWI) to the Z ring, a cytoskeletal element that is required for division in most bacteria. In Escherichia coli, the recruitment of the FtsWI complex is dependent upon the cytoplasmic domain of FtsL, a component of the conserved FtsQLB complex. Once assembled, FtsWI is activated by the arrival of FtsN, which acts through FtsQLB and FtsA, which are also essential for their recruitment. However, the mechanism of activation of FtsWI by FtsN is not clear. Here, we identify a region of FtsL that plays a key role in the activation of FtsWI which we designate AWI (activation of FtsWI) and present evidence that FtsL acts through FtsI. Our results suggest that FtsN switches FtsQLB from a recruitment complex to an activator with FtsL interacting with FtsI to activate FtsW. Since FtsQLB and FtsWI are widely conserved in bacteria, this mechanism is likely to be also widely conserved.IMPORTANCE A critical step in bacterial cytokinesis is the activation of septal peptidoglycan synthesis at the Z ring. Although FtsN is the trigger and acts through FtsQLB and FtsA to activate FtsWI the mechanism is unclear. Here, we find an essential role for FtsL in activating septal peptidoglycan (PG) synthesis and find that it acts on FtsI. Our results suggest a model where FtsWI is recruited in an inactive form by FtsQLB, and upon the arrival of FtsN, FtsQLB undergoes a conformational change so that a region of FtsL, which we designate the AWI domain, becomes available to interact with FtsI and activate the FtsWI complex. This mechanism for activation of the divisome has similarities to the activation of the elongasome and is likely to be widely conserved in bacteria.

High-performance compliant thermoelectric generators with magnetically self-assembled soft heat conductors for self-powered wearable electronics.

Softening of thermoelectric generators facilitates conformal contact with arbitrary-shaped heat sources, which offers an opportunity to realize self-powered wearable applications. However, existing wearable thermoelectric devices inevitably exhibit reduced thermoelectric conversion efficiency due to the parasitic heat loss in high-thermal-impedance polymer substrates and poor thermal contact arising from rigid interconnects. Here, we propose compliant thermoelectric generators with intrinsically stretchable interconnects and soft heat conductors that achieve high thermoelectric performance and unprecedented conformability simultaneously. The silver-nanowire-based soft electrodes interconnect bismuth-telluride-based thermoelectric legs, effectively absorbing strain energy, which allows our thermoelectric generators to conform perfectly to curved surfaces. Metal particles magnetically self-assembled in elastomeric substrates form soft heat conductors that significantly enhance the heat transfer to the thermoelectric legs, thereby maximizing energy conversion efficiency on three-dimensional heat sources. Moreover, automated additive manufacturing paves the way for realizing self-powered wearable applications comprising hundreds of thermoelectric legs with high customizability under ambient conditions.

Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study.

Fluorine is a unique atom that imparts distinct properties to bioactive molecules upon incorporation. Herein, we prepare and study fluorinated derivatives of the nanomolar affine peripherally restricted dual CB1R/CB2R agonist; CRA13 and its analogs. Binding affinity evaluation relative to CRA13 proved the stronger binding affinity of compound 7c to CB1R and CB2R by 6.95 and 5.64 folds. Physicochemical properties evaluation proved compound 7c improved lipophilicity profile suggesting some enhanced BBB penetration relative to CRA13. Radiosynthesis of 18F-labeled compound 7c was conducted conveniently affording pure hot ligand. In vivo PET study investigation demonstrated efficient distribution of 18F-labeled compound 7c in peripheral tissues visualizing peripheral CB1R/CB2R generating time-activity-curves showing good standard uptake values. Despite enhanced BBB penetration and increased cannabinoid receptors binding affinity, low brain uptake of 7c was observed. In silico docking study explained the measured binding affinities of compounds 7a-d to CB1R. While most of previous efforts aimed to develop central cannabinoid PET imaging agents, 18F-labeled compound 7c might be a promising agent serving as a universal CB1R/CB2R PET imaging agents for diagnosis and therapy of various diseases correlated with peripheral cannabinoid system. It might also serve as a lead compound for development of PET imaging of peripheral and central cannabinoid systems.

Carbon nanotube fibers with enhanced longitudinal carrier mobility for high-performance all-carbon thermoelectric generators.

With the increase in practical interest in flexible thermoelectric (TE) generators, the demand for high-performance alternatives to brittle TE materials is growing. Herein, we have demonstrated wet-spun CNT fibers with high TE performance by systematically controlling the longitudinal carrier mobility without a significant change in the carrier concentration. The carrier mobility optimized by CNT alignment increases the electrical conductivity without decreasing the thermopower, thus improving the power factor. On further adjusting the charge carriers via mild annealing, the CNT fibers exhibit a high power factor of 432 µW m-1 K-2. Based on the excellent TE performance and shape advantages for modular design of the CNT fiber, the all-carbon based flexible TE generator without an additional metal electrode has been fabricated. The flexible TE generator based on 40 pairs of p- and n-type CNT fibers shows the maximum power density of 15.4 and 259 µW g-1 at temperature differences (ΔT) of 5 and 20 K, respectively, currently one of the highest values reported for TE generators based on flexible materials. The strategy proposed here can improve the performance of flexible TE fibers by optimizing the carrier mobility without a change in the carrier concentration, and shows great potential for flexible TE generators.

Stretchable Conductive Adhesives with Superior Electrical Stability as Printable Interconnects in Washable Textile Electronics.

As practical interest in stretchable electronics increases for future applications in wearables, healthcare, and robotics, the demand for electrical interconnects with high electrical conductivity, durability, printability, and adhesion is growing. Despite the high electrical conductivity and stretchability of most previous interconnects, they lack stable conductivity against strain and adhesion to stretchable substrates, leading to a limitation for their practical applications. Herein, we propose a stretchable conductive adhesive consisting of silver particles with carbon nanotube as an auxiliary filler in silicone adhesives. The conductive adhesive exhibits a high initial conductivity of 6450 S cm-1. They show little change in conductivity over 3000 stretching cycles at 50% strain, currently the highest stability reported for elastic conductors. Based on strong adhesion to stretchable substrates, the gel-free, dry adhesives printed on an elastic bandage for electrocardiography monitoring exhibit an extremely stable performance upon movement of the subject, even after several cycles of detachment-reattachment and machine washing.

1H-NMR and 13C-NMR dataset for some oxidative metabolites of CRA13 and their analogs.

CRA13 (CB-13; SAB-378) is a dual CB1R/CB2R agonist cannabinoid agent developed by Novartis Pharma. Upon administration, it undergoes metabolism to oxidative metabolites. Herein, the 1H-NMR and 13C-NMR dataset of some oxidative metabolites and analogs thereof are presented for further analysis and comparison purposes, for whom may be interested.

Coaxial struts and microfractured structures of compressible thermoelectric foams for self-powered pressure sensors.

Long-term operation of wearable pressure sensors to detect body movement requires self-powered human-based energy sources to minimize the need for recharging. Recently, pressure sensors with thermoelectric properties based on conducting polymers have been reported; however, these devices are limited in their ability to simultaneously achieve sufficient power generation and sensitivity of the sensor. In this article, we suggest a coaxial strut structure of poly(styrene-ethylene/butylene-styrene)(SEBS)-poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)(PEDOT:PSS)-melamine foam (MF) with a fractured microstructure for a highly sensitive, efficient self-powered pressure sensor. In the coaxial struts, the MF core provides a compressible and elastic framework; the intermediate PEDOT:PSS acts as a conductor and a thermoelectric material; and the SEBS shell ensures mechanical stability and resilience to stabilize the brittle PEDOT:PSS layer under high loading conditions. Additionally, by compressing the coaxial foam to 1/20, partial microfracture of PEDOT:PSS occurs only in the SEBS shell; thus, the pressure sensitivity increases significantly while maintaining high conductivity and thermoelectric performance. The coaxial foam was assembled into a wearable TEG to generate 338 nW from the forearms and demonstrate the high sensitivity of pressure sensors without an external power supply.

Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity.

CRA13; a peripheral dual CB1R/CB2R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1R and CB2R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2R ligand with attenuated CB1R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB2R affinity and reduced CB1R affinity. The CB2R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.

MinC and FtsZ mutant analysis provides insight into MinC/MinD-mediated Z ring disassembly.

The Min system negatively regulates the position of the Z ring, which serves as a scaffold for the divisome that mediates bacterial cytokinesis. In Escherichia coli, this system consists of MinC, which antagonizes assembly of the tubulin homologue FtsZ. MinC is recruited to the membrane by MinD and induced by MinE to oscillate between the cell poles. MinC is a dimer with each monomer consisting of functionally distinct MinCN and MinCC domains, both of which contact FtsZ. According to one model, MinCC/MinD binding to the FtsZ tail positions MinCN at the junction of two GDP-containing subunits in the filament, leading to filament breakage. Others posit that MinC sequesters FtsZ-GDP monomers or that MinCN caps the minus end of FtsZ polymers and that MinCC interferes with lateral interactions between FtsZ filaments. Here, we isolated minC mutations that impair MinCN function and analyzed FtsZ mutants resistant to MinC/MinD. Surprisingly, we found mutations in both minC and ftsZ that differentiate inhibition by MinC from inhibition by MinC/MinD. Analysis of these mutations suggests that inhibition of the Z ring by MinC alone is due to sequestration, whereas inhibition by MinC/MinD is not. In conclusion, our genetic and biochemical data support the model that MinC/MinD fragments FtsZ filaments.

MinE conformational dynamics regulate membrane binding, MinD interaction, and Min oscillation.

In Escherichia coli MinE induces MinC/MinD to oscillate between the ends of the cell, contributing to the precise placement of the Z ring at midcell. To do this, MinE undergoes a remarkable conformational change from a latent 6ß-stranded form that diffuses in the cytoplasm to an active 4ß-stranded form bound to the membrane and MinD. How this conformational switch occurs is not known. Here, using hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) we rule out a model in which the two forms are in rapid equilibrium. Furthermore, HDX-MS revealed that a MinE mutant (D45A/V49A), previously shown to produce an aberrant oscillation and unable to assemble a MinE ring, is more rigid than WT MinE. This mutant has a defect in interaction with MinD, suggesting it has difficulty in switching to the active form. Analysis of intragenic suppressors of this mutant suggests it has difficulty in releasing the N-terminal membrane targeting sequences (MTS). These results indicate that the dynamic association of the MTS with the ß-sheet is fine-tuned to balance MinE's need to sense MinD on the membrane with its need to diffuse in the cytoplasm, both of which are necessary for the oscillation. The results lead to models for MinE activation and MinE ring formation.

2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms.

Mouse embryonic stem cells (ESCs) are maintained in serum with leukemia inhibitory factor (LIF) to maintain self-renewal and pluripotency. Recently, a 2i culture method was reported using a combination of MEK inhibition (MEKi) and GSK3 inhibition (GSK3i) with LIF to maintain ESCs in a naive ground state. How 2i maintains a ground state of ESCs remains elusive. Here we show that MEKi and GSK3i maintain the ESC ground state by downregulating global DNA methylation through two distinct mechanisms. MEK1 phosphorylates JMJD2C for ubiquitin-mediated protein degradation. Therefore, MEKi increased JMJD2C protein levels but decreased DNMT3 expression. JMJD2C promotes TET1 activity to increase 5-hydroxymethylcytosine (5hmC) levels. GSK3i suppressed DNMT3 expression, thereby decreasing DNA methylation without affecting 5hmC levels. Furthermore, 2i increased PRDM14 expression to inhibit DNMT3A/B protein expression by promoting G9a-mediated DNMT3A/B protein degradation. Collectively, 2i allows ESCs to maintain a naive ground state through JMJD2C-dependent TET1 activation and PRDM14/G9a-mediated DNMT3A/B protein degradation.

The Abuse Potential of α-Piperidinopropiophenone (PIPP) and α-Piperidinopentiothiophenone (PIVT), Two New Synthetic Cathinones with Piperidine Ring Substituent.

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) α-piperidinopropiophenone (PIPP) and (2) α-piperidinopentiothiophenone (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.

The abuse potential of two novel synthetic cathinones with modification on the alpha-carbon position, 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP) and 2-(methylamino)-1-phenyloctan-1-one (MAOP), and their effects on dopaminergic activity.

The recreational use of synthetic cathinones has dramatically increased in recent years, which is partly due to easy accessibility and ability of synthetic cathinones to exert rewarding effects similar to cocaine and methamphetamine. Many synthetic cathinones have already been scheduled in several countries; however, novel and diverse synthetic cathinones are emerging at an unprecedented rate, often outpacing regulatory processes. Recently, designer modifications of the basic cathinone molecule are usually performed on the alpha-carbon position. In this study, we designed and synthesized two novel synthetic cathinones with substituents on alpha-carbon position, [1] 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP), and [2] 2-(methylamino)-1-phenyloctan-1-one (MAOP). Then, we evaluated their rewarding and reinforcing effects through the conditioned place preference (CPP) in mice and self-administration (SA) test in rats. Locomotor activity was also assessed in mice during daily MACHP or MAOP treatment for 7days and drug challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. MACHP and MAOP produced CPP at 10 and 30mg/kg. In the SA test, MACHP (1mg/kg/infusion), but not MAOP, was self-administered. Both MACHP and MAOP induced locomotor sensitization in mice. qRT-PCR analyses showed that MACHP and MAOP reduced dopamine transporter gene expression in the striatum. These data indicate that MACHP and MAOP may have rewarding properties, which might be attributed to their ability to affect the dopaminergic activity. These findings may be useful in predicting the abuse potential and hasten the regulation of future cathinone entities with similar modifications.

A novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), produced rewarding effects and altered striatal dopamine-related gene expression in mice.

The recreational use of synthetic cathinones has grown rapidly which prompted concerns from legal authorities and health care providers. However, in response to legislative regulations, synthesis of novel synthetic cathinones by introducing substituents in cathinone molecule has dramatically increased the diversity of these substances. Based on current trends, the aromatic ring is one of the popular sites in cathinone molecule being explored by designer-type modifications. In this study, we designed and synthesized a novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), which has a naphthalene substituent on the aromatic ring. Thereafter, we determined whether BMAPN has rewarding and reinforcing effects through the conditioned place preference (CPP) test in mice and self-administration (SA) paradigm in rats. Locomotor sensitization was also assessed in mice during daily BMAPN treatment for 7days and drug challenge. Furthermore, we investigated the effects on BMAPN on dopamine-related genes in the striatum of mice using quantitative real-time polymerase chain reaction (qRT-PCR). BMAPN induced CPP at 10 and 30mg/kg and was modestly self-administered at 0.3mg/kg/infusion. Repeated BMAPN (30mg/kg) administration also produced locomotor sensitization. qRT-PCR analyses revealed decreased dopamine transporter and increased dopamine receptor D2 gene expression in the striatum of the BMAPN-treated mice. These data indicate that BMAPN has rewarding and reinforcing properties, which might be due to its effects on dopamine-related genes. The present study suggests that these findings may be useful in predicting abuse potential of future cathinone entities with aromatic ring substitutions.