Heat-triggered shape recovery, EMI shielding and flame retardant: A novel cellulose/M(OH)(OCH3)@dopamine@Ag (M=Co, Ni) nanopaper for early fire alarm.

Fire alarm systems are essential for protecting lives and properties from fire hazards. However, most of the existing fire alarm nanopapers rely on the resistance reduction after heating, which requires direct contact with the flame. In this study, we present a novel fire alarm nanopaper (CMPA) based on heat-triggered shape recovery. The CMPA is composed of hydroxypropyl methyl cellulose (HPMC) as the matrix and 2D nanomaterials M(OH)(OCH3) as fillers. When the temperature of CMPA exceeded the glass transition, the thrice-folded CMPA-1.0 flattened in 30s and connected to the alarm circuit based on its conductive surface. According to the results, the CMPA-1.0 with a thickness of about 0.2 mm had an efficient electromagnetic shielding of 42.1 dB. Moreover, the CMPA-1.0 self-extinguished rapidly after being ignited with its original shape preserved. The peak heat release rate of CMPA-1.0 was 108.9 W/g, which was 61.9 % lower than that of HPMC. Furthermore, the thermal conductivity of CMPA-1.0 reached to 0.317 W m-1 K-1, which was 40.8 % higher than that of HPMC, reducing the heat accumulation effectively. This work shows that CMPA is an ideal material for sensitive and safe early fire alarm, and the strategy based on heat-triggered shape recovery is promising in fire alarm application.

Development of a biaxial apparatus for jamming profiles of photoelastic granular media.

We describe a two-dimensional biaxial apparatus that is used to conduct the experimental study of the jamming of granular media. The setup is designed based on the photoelastic imaging technique, which allows us to detect force-bearing contacts among particles, calculate the pressure on each particle according to the mean squared intensity gradient method, and compute contact forces on each particle [T. S. Majmudar and R. P. Behringer, Nature 435, 1079-1082 (2005)]. Particles float in a density-matched solution to avoid basal friction during experiments. We can compress (uniaxially or biaxially) or shear the granular system by an entangled comb geometry by moving the paired boundary walls independently. A novel design for the corner of each pair of perpendicular walls is described, which allows for independent motion. We control the system using a Raspberry Pi with Python code. Three typical experiments are described briefly. Furthermore, more complicated experiment protocols can be implemented to achieve specific granular materials research goals.

DA-ActNN-YOLOV5: Hybrid YOLO v5 Model with Data Augmentation and Activation of Compression Mechanism for Potato Disease Identification.

To solve the problems of weak generalization of potato early and late blight recognition models in real complex scenarios, susceptibility to interference from crop varieties, colour characteristics, leaf spot shapes, disease cycles and environmental factors, and strong dependence on storage and computational resources, an improved YOLO v5 model (DA-ActNN-YOLOV5) is proposed to study potato diseases of different cycles in multiple regional scenarios. Thirteen data augmentation techniques were used to expand the data to improve model generalization and prevent overfitting; potato leaves were extracted by YOLO v5 image segmentation and labelled with LabelMe for building data samples; the component modules of the YOLO v5 network were replaced using model compression technology (ActNN) for potato disease detection when the device is low on memory. Based on this, the features extracted from all network layers are visualized, and the extraction of features from each network layer can be distinguished, from which an understanding of the feature learning behavior of the deep model can be obtained. The results show that in the scenario of multiple complex factors interacting, the identification accuracy of early and late potato blight in this study reached 99.81%. The introduced data augmentation technique improved the average accuracy by 9.22%. Compared with the uncompressed YOLO v5 model, the integrated ActNN runs more efficiently, the accuracy loss due to compressed parameters is less than 0.65%, and the time consumption does not exceed 30 min, which saves a lot of computational cost and time. In summary, this research method can accurately identify potato early and late blight in various scenarios.

An Industrial-Grade Solution for Crop Disease Image Detection Tasks.

Crop leaf diseases can reflect the current health status of the crop, and the rapid and automatic detection of field diseases has become one of the difficulties in the process of industrialization of agriculture. In the widespread application of various machine learning techniques, recognition time consumption and accuracy remain the main challenges in moving agriculture toward industrialization. This article proposes a novel network architecture called YOLO V5-CAcT to identify crop diseases. The fast and efficient lightweight YOLO V5 is chosen as the base network. Repeated Augmentation, FocalLoss, and SmoothBCE strategies improve the model robustness and combat the positive and negative sample ratio imbalance problem. Early Stopping is used to improve the convergence of the model. We use two technical routes of model pruning, knowledge distillation and memory activation parameter compression ActNN for model training and identification under different hardware conditions. Finally, we use simplified operators with INT8 quantization for further optimization and deployment in the deep learning inference platform NCNN to form an industrial-grade solution. In addition, some samples from the Plant Village and AI Challenger datasets were applied to build our dataset. The average recognition accuracy of 94.24% was achieved in images of 59 crop disease categories for 10 crop species, with an average inference time of 1.563 ms per sample and model size of only 2 MB, reducing the model size by 88% and the inference time by 72% compared with the original model, with significant performance advantages. Therefore, this study can provide a solid theoretical basis for solving the common problems in current agricultural disease image detection. At the same time, the advantages in terms of accuracy and computational cost can meet the needs of agricultural industrialization.

rs10865710 polymorphism in PPARG promoter is associated with the severity of type 2 diabetes mellitus and coronary artery disease in a Chinese population.

BACKGROUND: Relationship between polymorphisms in peroxisome proliferator-activated receptor gamma (PPARG) and progression of type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) remains to be clarified. METHODS: 635 subjects were divided into T2DM, CAD, T2DM complicated with CAD (T2DM/CAD) and control groups according to diagnostic criteria. The rs10865710 and rs3856806 polymorphisms were genotyped, and the severity of T2DM and CAD was evaluated for all subjects. RESULTS: In patients with T2DM, G allele carriers of rs10865710 polymorphism had significantly higher levels of glucose, triglycerides, apolipoprotein B (ApoB) and lipoprotein (a) (Lp(a)) than non-carriers, T allele carriers of rs3856806 polymorphism had significantly higher levels of glucose, low-density lipoprotein cholesterol (LDL-C), ApoB and Lp(a) than non-carriers. In patients with CAD, G allele carriers of rs10865710 polymorphism had significantly higher levels of total cholesterol (TC), ApoB and Lp(a) than non-carriers, T allele carriers of rs3856806 polymorphism had significantly higher levels of body mass index, blood pressure, TC, LDL-C and ApoB than non-carriers. Patients with one or two G alleles of rs10865710 polymorphism had significantly higher levels of Gensini scores and more diseased coronary branches than those patients without CAD. The rs3856806 polymorphism was not associated with CAD severity, but it was found to be significantly associated with T2DM/CAD, T allele frequency was significantly higher in T2DM/CAD group than that in T2DM/CAD-free group. CONCLUSIONS: The rs10865710 and rs3856806 polymorphisms in PPARG are significantly associated with glucose levels in patients with T2DM. The rs10865710 polymorphism is significantly associated with the severity of CAD, which is possibly mediated by hyperlipidaemia and hyperglycaemia.

General adverse response to cyclophosphamide in Chinese patients with systemic autoimmune diseases in recent decade­a single-center retrospective study.

This study was conducted to investigate the adverse reaction to cyclophosphamide (CYC) in Chinese patients with systemic autoimmune diseases. Patients with systemic autoimmune diseases who were exposed to CYC and followed up regularly for at least 2 years in Rheumatology Department during June 2003 to June 2013 were enrolled into this study. Participants were divided into per oral (PO) group and intravenous (IV) group. The adverse effects to CYC were recorded and analyzed. A total of 419 patients were enrolled in this study. The occurrence rates of gastrointestinal discomfort, alopecia, myelosuppression, secondary infection, abnormal liver function, dizziness/headache, menstrual disturbance and reversal to normal menstruation after discontinuation of CYC were 21.5%, 12.4%, 7.4 %, 3.6%, 3.1%, 3.1%, 30.3% and 31.0%, respectively. None of the patients had hemorrhagic cystitis. The significant risk factors for gastrointestinal discomfort were female, exposure to CYC for a long time and intravenous route. Risk factors for mylosuppression were female and combination with other immunosuppressants. Risk factors were female gender for alopecia and older age for menstrual disturbance. Female patients were much more likely to have gastrointestinal discomfort, mylosuppression and alopecia when CYC was administrated intravenously. Risk factors were older age for menstrual disturbance and the combination with other immunosuppressants for myelosuppression. Hemorrhagic cystitis did not appear in our series for the possible reason of prophylactic hydration before intravenous injection and maybe racial difference.

Importance of characterizing determinants of variability in exposure: application to dasatinib in subjects with chronic myeloid leukemia.

Characterizing the key determinants of variability in the exposure of orally administered drugs may be important in understanding the implications of exposure variability on clinical responses. In particular, partitioning overall variability into interoccasion variability (IOV) and interindividual variability (IIV) allows a better assessment of the clinical importance of exposure variability. The IOV characterizes the dose-to-dose variability in exposure within a subject and is likely to be less clinically relevant than IIV for chronically administered drugs as the effect of IOV averages out over repeated dosing. The main aims of this model-based analysis were (1) to characterize the IOV and IIV of dasatinib, a novel, orally administered, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases that is indicated for the treatment of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia and (2) to demonstrate using simulated data that it is possible to estimate IIV and IOV in relative bioavailability (F(R)) of an orally administered drug, given an adequate sampling scheme. Variability in dasatinib exposure was estimated to be mainly due to IOV in F(R) (44% coefficient of variation [CV]) and, to a lesser extent, due to IIV in F(R) and IIV in clearance (32% and 25% CV, respectively). The IIV is expected to be more clinically relevant than IOV for chronically administered oral drugs such as dasatinib, as the overall variability in cumulative exposure will be mainly due to IIV. The analysis of simulated data demonstrated that models ignoring either IIV or IOV in F(R) resulted in upwardly biased estimates of interindividual or residual variability. Thus, it may be important to account for both IIV and IOV in F(R), particularly for orally administered agents that exhibit absorption-related variability in exposure.

Enzyme kinetics of GTI-2040, a phosphorothioate oligonucleotide targeting ribonucleotide reductase.

Enzyme kinetics of GTI-2040 (5'-GGC TAA ATC GCT CCA CCA AG-3'), a phosphorothioate ribonucleotide reductase antisense, were investigated for the first time in 3' exonuclease solution and human liver microsomes (HLMs), using the ion-pair high-performance liquid chromatogram method for quantification of the parent drug and two major 3'N-1 and 3'N-2 metabolites. Enzyme kinetics of GTI-2040 in 3'-exonuclease solution were found to be well characterized by the Michaelis-Menten model, using the sum of formation rates of 3'N-1 and 3'N-2 (approximately total metabolism) because of sequential metabolism. In HLMs, a biphasic binding was observed for GTI-2040 with high- and low-affinity constants (K(d)s) of 0.03 and 3.8 microM, respectively. Enzyme kinetics of GTI-2040 in HLMs were found to deviate from Michaelis-Menten kinetics when the total GTI-2040 substrate was used. However, after correction for the unbound fractions, the formation rate of total metabolites could be described by Michaelis-Menten kinetics. Using the free substrate fraction, the K(m) and V(max) of GTI-2040 were determined to be 6.33 +/- 3.2 microM and 16.5 +/- 8.4 nmol/mg/h, respectively. Using these values, in vitro hepatic intrinsic clearance (CL(int)) in HLM was estimated to be 2.61 +/- 0.56 ml/h. The CL(int) was then used to predict GTI-2040's in vivo intrinsic clearance in humans by a microsomal protein scaling factor, which gave a mean value of 182.7 l/h, representing 24.1% of the observed in vivo mean scaled hepatic intrinsic clearance of 758.7 l/h in patients with acute myeloid leukemia. We concluded that the saturable nonspecific binding of GTI-2040 in HLMs complicated the interpretation of its enzyme kinetics, and scaled intrinsic clearance from HLMs only partially predicted the in vivo intrinsic clearance.

Application of LC-MS for quantitative analysis and metabolite identification of therapeutic oligonucleotides.

Therapeutic oligonucleotides (OGNs) have been studied extensively in the recent years as novel agents designed to selectively and specifically inhibit target gene expression in cell culture, in animal disease models and in human. This review summarizes applications of liquid chromatography coupled with mass spectrometry or tandem mass spectrometry (LC-MS or LC-MS/MS) for quantitative analysis of therapeutic OGNs and characterization of their metabolism in vitro and in vivo described in the literature over the past 10 years. Although the applications of LC-MS or LC-MS/MS to the molecular mass measurement, sequence determination, DNA adducts identification, detection of mutations and characterization of covalent and/or noncovalent DNA/RNA complexes have been comprehensively reviewed in a few excellent review papers. The quantitative bioanalysis and metabolite identification of therapeutic OGNs using LC-MS or LC-MS/MS have not been covered. This review covers technical issues, current approaches and applications of LC-MS or LC-MS/MS for quantitative analysis of OGNs in biological matrices and characterization of their in vitro and in vivo metabolism. Finally, some conclusions are drawn and prospects of LC-MS in quantitative analysis and metabolism characterization of therapeutic OGNs are discussed.

A specific picomolar hybridization-based ELISA assay for the determination of phosphorothioate oligonucleotides in plasma and cellular matrices.

PURPOSE: To develop and validate an ultrasensitive and specific hybridization-based enzyme-linked immunosorbent assay method for quantification of two phosphorothioate oligonucleotides (PS ODNs) (G3139 and GTI-2040) in biological fluids. METHODS: This assay was based on hybridization of analytes to the biotin-labeled capture ODNs followed by ligation with digoxigenin-labeled detection ODN. The bound duplex was then detected by anti-digoxigenin-alkaline phosphatase using Attophos (Promega, Madison, WI, USA) as substrate. S1 nuclease and major factors such as the hybridization temperature, concentration of capture probe, and the use of detergent were evaluated toward assay sensitivity, selectivity, and accuracy. RESULTS: The method is selective to the parent drugs with minimal cross-reactivity (<6%) with 3'-end deletion oligomers for both G3139 and GTI-2040. A linear range of 0.05 to 10 nM (r2 > 0.99) was observed for GTI-2040 in a variety of biological matrices. For both G3139 and GTI-2040, the within-day precision and accuracy values were found to be <20% and 90-110%, respectively; the between-day precision and accuracy were determined to be <20% and 90-120%. Addition of S1 nuclease combined with washing step greatly improved the assay linearity and selectivity. The utility of this assay was demonstrated by simultaneous determination of GTI-2040 in plasma and its intracellular levels in treated acute myeloid leukemia patients. CONCLUSIONS: The validated hybridization enzyme-linked immunosorbent assay method is specific for quantitation of PS ODNs in biological samples to picomolar level. This method provides a powerful technique to evaluate plasma pharmacokinetics and intracellular uptake of PS ODNs in patients and shows its utility in clinical evaluations.

High performance liquid chromatographic analysis and preclinical pharmacokinetics of the heteroarotinoid antitumor agent, SHetA2.

BACKGROUND: SHetA2 {[(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl)amino]methane-thione], NSC 726189} is a sulfur-containing heteroarotinoid, which selectively inhibits cancer cell growth and induces apoptosis without activation of nuclear retinoic acid receptors (RARs). The objective was to develop and validate a HPLC/UV method for the determination of SHetA2, and study the pharmacokinetics of SHetA2 in the mouse. METHODS: SHetA2 and the internal standard, methylated XK469 (MeXK469) were isolated from 0.2 ml of mouse plasma by solid phase extraction. The analytes were separated on a narrow-bore C18 column, with the mobile phase consisting of 60% acetonitrile in water at a flow rate of 0.2 ml/min. UV detection was set at 341 nm. Pharmacokinetic studies of SHetA2 were carried out in mice following i.v. bolus dose at 20 mg/kg and oral administrations at 20 and 60 mg/kg. RESULTS: The standard curves were linear between 25 and 2,500 nM and the lower limit of quantification (LLOQ) was 25 nM. The within-run coefficients of variation (CVs) were 11.1% at 10, 9.4% at 100, and 5.2% at 2,500 nM and the respective between-run CVs were 10.9, 3.1, and 1.5% (all n=5). The recovery was 85.8% for SHetA2 and 80.6% for MeXK469. Following i.v. bolus dose, plasma concentrations of approximately 10 microM were achieved at 5 min in mice and declined biexponentially with detectable levels at 60 h. The data were fitted with a two-compartment model, which gave a mean initial t1/2 of 40 min and terminal t1/2 of 11.4 h (n=6). The total body clearance was approximately 1.81 l/h/kg. The volume of distribution at steady state (Vdss) was 20.8 l/kg. Plasma protein binding was found to be 99.3-99.5% at low micromolar concentrations. Plasma concentration data for the i.v. and p.o. doses were also fitted interactively to a two-compartment deconvolution model. From this result, oral bioavailability values of 15% at 20 mg/kg and 19% at 60 mg/kg were obtained. CONCLUSIONS: A highly sensitive HPLC/UV method for the quantification of SHetA2 in plasma has been developed to support pharmacokinetics of SHetA2 in the mouse. Pharmacokinetic behaviors of this drug appear to be favorable for future development.

Metabolism of GTI-2040, a phosphorothioate oligonucleotide antisense, using ion-pair reversed phase high performance liquid chromatography (HPLC) coupled with electrospray ion-trap mass spectrometry.

GTI-2040 is a 20-mer phosphorothioate oligonucleotide, which is complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase. This study characterized both the in vivo and in vitro metabolism of GTI-2040. A highly specific ion-pair reversed-phase electrospray ionization (IP-RP-ESI) liquid chromatography-mass spectrometry (LC-MS) method was used for the identification of GTI-2040 and metabolites from a variety of biological samples including exonuclease enzyme solutions, plasma, urine, mouse liver/kidney homogenates, and human liver microsomes. Progressively chain-shortened metabolites truncated from the 3' terminal of GTI-2040 were detected in all of the evaluated biological samples. GTI-2040 was found to be a good substrate for 3' but not 5' exonuclease. While the pattern of n-1 chain-shortened 3'-exonucleolytic degradation was similar in the mouse liver and kidney homogenates, the latter was found to contain a larger number of shortenmers, the kidneys appeared to possess higher enzymatic reactivity toward GTI-2040. Thus, metabolism of GTI-2040 was found to occur in a variety of biological samples, mainly mediated by the 3' exonuclease.

Characterization and quantification of Bcl-2 antisense G3139 and metabolites in plasma and urine by ion-pair reversed phase HPLC coupled with electrospray ion-trap mass spectrometry.

A novel ion-pair reversed phase electrospray ionization (IP-RP-ESI) liquid chromatography-mass spectrometry (LC-MS) method has been developed for identification and quantification of Bcl-2 antisense phosphorothioate oligonucleotides G3139 and metabolites in plasma. This method utilized solid phase extraction for desalting and matrix removal and detection by an ion trap mass spectrometer. Resolution was accomplished on a micro C18 column eluted with a mobile phase consisting of hexafluoro-2-propanol and triethylamine in methanol at 50 degrees C. Five G3139 metabolites were identified in plasma and urine from treated patients and rats. A cassette HPLC-MS/MS quantification method for G3139 and three metabolites was developed and validated with a limit of quantification (LOQ) of 17.6 nM in human and rat plasma with acceptable precision and accuracy. Plasma pharmacokinetics of G3139 and metabolites in these species were described.

Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity.

PURPOSES: Pharmacologic downregulation of Bcl-2, an antiapoptotic protein overexpressed in cancer, might increase chemosensitivity in acute myeloid leukemia (AML). Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments. PATIENTS AND METHODS: Untreated patients with primary or secondary AML (stratified to cohort 1 or 2, respectively) who were > or = 60 years received induction with G3139, cytarabine, and daunorubicin at one of two different dose levels (45 and 60 mg/m2) and, on achievement of complete remission (CR), consolidation with G3139 and high-dose cytarabine. An enzyme-linked immunosorbent assay (ELISA)-based assay was used to measure plasma and intracellular concentrations (IC) of G3139. Bcl-2 mRNA and protein levels were quantified by real-time reverse transcriptase polymerase chain reaction and ELISA, respectively, in bone marrow samples collected before induction treatment and after 72 hours of G3139 infusion, prior to initiation of chemotherapy. RESULTS: Of the 29 treated patients, 14 achieved CR. With a median follow-up of 12.6 months, seven patients had relapsed. Side effects of this combination were similar to those expected with chemotherapy alone and were not dose limiting at both dose levels. After 72-hour G3139 infusion, Bcl-2/ABL mRNA copies were decreased compared with baseline (P = .03) in CR patients and increased in nonresponders (NRs; P = .05). Changes in Bcl-2 protein showed a similar trend. Although plasma pharmacokinetics did not correlate with disease response, the median IC of the antisense was higher in the CR patients compared with NRs (17.0 v 4.4 pmol/mg protein, respectively; P = .05). CONCLUSION: G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.

Cellular uptake and intracellular levels of the bcl-2 antisense g3139 in cultured cells and treated patients with acute myeloid leukemia.

PURPOSE: Down-regulation of Bcl-2 by the antisense G3139, currently under clinical evaluations, could restore chemosensitivity in otherwise resistant malignant cells. To date, the mechanism of intracellular accumulation of G3139 following in vivo administration remains to be elucidated. This study aimed to assess whether detectable intracellular concentrations of G3139 are achievable in vivo and how these relate to Bcl-2 down-regulation. EXPERIMENTAL DESIGN: Cellular uptake of G3139 was studied in leukemia myeloid cell lines and blasts collected from treated patients using a newly developed, novel, and highly sensitive ELISA-based assay. Real-time reverse transcription-PCR was used to quantify Bcl-2 mRNA changes in treated cells. RESULTS: The assay was fully validated and showed a limit of quantification of 50 pmol/L. When exposed to 0.33 to 10 mumol/L G3139, K562 cells exhibited intracellular concentrations in the range of 2.1 to 11.4 pmol/mg protein. When G3139 was delivered with cationic lipids, a 10- to 25-fold increase of the intracellular concentrations was observed. There was an accumulation of G3139 in the nuclei, and the ratio of nucleus to cytoplasm was increased 7-fold by cationic lipids. Intracellular concentrations of G3139 were correlated with Bcl-2 mRNA down-regulation. Robust intracellular concentrations of G3139 were achieved in vivo in bone marrow (range, 3.4-40.6 pmol/mg protein) and peripheral blood mononuclear cells (range, 0.47-19.4 pmol/mg protein) from acute myeloid leukemia patients treated with G3139. CONCLUSIONS: This is the first evidence that measurable intracellular levels of G3139 are achievable in vivo in acute myeloid leukemia patients and that Bcl-2 down-regulation is likely to depend on the achievable intracellular concentrations rather than on plasma concentrations.

Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.

Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).

[The role of mitogen-activated protein kinase (MAPK) pathway in the action mechanism of PYM-induced KB cells apoptosis].

OBJECTIVE: To study the role of mitogen-activated protein kinase (MAPK) pathway in the action mechanism of PYM-induced KB cell apoptosis. METHODS: Western blot analysis was used to investigate the expression of the mitogen-activated protein kinase. RESULTS: When treated with PYM in cultured KB cells, the extracellular signal-regulated kinase (ERKl/2) showed a dose-and time-dependent decreasing in phosphorylation status of these proteins through a western blot analysis, whereas protein levels of p38 MAPK remained unchanged. CONCLUSIONS: The mitogen-activated protein kinase (MAPK) pathway may play an important ro1e in PYM-induced apoptosis of KB cells.