4th Ones Research Articles

Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 in AML

Focal adhesion kinase (FAK), activated by integrins and cytokines, promotes cell growth, migration and metastasis. We previously reported that a selective FAK inhibitor, VS-4718, inhibited cell growth and induced cell death in leukemia cell lines in vitro, effectively reduced leukemia burden in peripheral blood and tissues including bone marrow, spleen, liver and lung, and significantly prolonged survival time in a human xenograft murine model (Carter BZ et al., MCT, 2017), 16(6):1133).Although BCL-2 inhibition by the BCL-2 inhibitor ABT-199 (Venetoclax) has demonstrated antileukemia activities, an acquired drug resistance frequently ensues. When combined with ABT-199, VS-4718 significantly potentiated ABT-199-induced apoptosis in AML cell lines and primary AML cells. VS-4718 treatment of Molm14 AML cells decreased levels of p-STAT5, MCL-1, and BCL-XL (Wang et al., ASH 2016) that play important roles in the acquired resistance to ABT-199.To further examine the effect of VS-4718 as a single agent and in combination with ABT-199 on primary AML cells in vivo, we generated patient-derived xenografts (PDX) from AML patient bone marrow cells expanded in NSGS (NOD-SCID IL2Rgnull-3/GM/SF, NSG-SGM3) mice. The xenograft used AML cells from a patient who had failed multiple chemotherapies and had NPM1, FLT3-ITD, TET2, DNMT3A, and WT1 gene mutations and a complex karyotype. The combination of VS-4718 and ABT-199 synergistically killed the PDX cells in vitro even under MSC co-culture conditions. Once PDX cells were engrafted into NSGS mice, animals were randomized into 4 groups (N=10/group) and treated with vehicle, VS-4718 (75 mg/kg, twice daily), ABT-199 (100 mg/kg, once per day), or the combination via oral gavage for 29 days. We observed that ABT-199 had a stronger anti-leukemic effect on peripheral blood than on tissue-resident cells, while VS-4718 was more effective in tissues. At the end of the treatments, VS-4718 significantly reduced circulating human CD45+ cells (P=0.0003), and ABT-199 alone (P=5.90E-07) and the ABT-199/VS-4718 combination (P=5.38E-07) were ever more effective. VS-4718 alone or in combination with ABT-199 reduced leukemia burden in spleen and liver and effectively reduced splenomegaly, while ABT-199 alone did not. VS-4718-treated mice survived significantly longer than the untreated controls (median survival 72 vs. 36 days, P=0.0002), while ABT-199 did not prolong survival (median survival 35 days). Also, the combination of VS-4718 with ABT-199 significantly prolonged survival (median survival 65.5 days, P=0.011 vs. control and P=0.0072 vs. ABT-199). No statistical difference in survival was found between VS-4718 and the combination treatment groups (P=0.33) (Fig. 1). All the mice had large spleen at death except the combination group: the 1st dead mouse had small and the 2nd to 4th ones had slightly enlarged spleen and only the last two had large spleen as others suggesting that additional reasons such as toxicity at the dose used may have contributed to the death of the 1st 4 mice in the combination group, hence shortened the median survival in this group.We determined expression of FAK and BCL-2 family proteins in cells from mouse spleens at the end of treatment and found that the combination of VS-4718 and ABT-199 decreased protein levels of FAK. Consistent with our in vitro results, the increased level of MCL-1 by ABT-199 was antagonized by the combination with VS-4718 in vivo suggesting the combination potentially be more effective.Conclusions: These results suggest a potential clinical benefit of combining a FAK inhibitor with Venetoclax for patients with AML. [Display omitted] DisclosuresPachter:Verastem, Inc.: Employment. Weaver:Verastem, Inc.: Employment. Carter:Daiichi Sankyo: Research Funding; novartis: Research Funding.

Construction and Experimental Verification of Novel Online Partial Discharge Monitoring System Using Power Line Communication

In this research, we aim to construct a completely new partial discharge (PD) monitoring system that applies inexpensive power line communication (PLC). We have proposed a PD detection method and monitoring system (PDMS-PLC) on the basis of PLC signal transfer rare is affected by an error due to disturbance. An attempt is made to identify PD source from the quadrant dependence of information transmission rate (hereinafter referred to PHY rate [Mbps]) by selecting a pair of quadrants of applied voltage phase; i.e. 1st and 3rd quadrants, or 2nd and 4th ones. It was found that the PHY (Abbreviation for the lowest physical layer in the OSI (open systems interconnection) hierarchical model.) rate number distribution reflects the PD characteristics obtained by the phase resolved PD (PRPD) pattern. Environmental noise level is also measured at an actual substation using PDMS-PLC. Consequently, the applicability of PDMS-PLC to PD signal detection and defect type identification is suggested.

Toxicological and Biochemical Effects of Jojoba, Simmondsia chinensis Extract on Cotton Leafworm, Spodoptera littoralis (Boisd.)

This study was conducted to evaluate the toxicity and biological effects of ethanolic leaf extract of Simmondsia chinensis on 2nd and 4th instar larvae of cotton leafworm, Spodoptera littoralis, as well as the effect on total protein content and the activity some enzymes of S. littoralis larvae after 48 and 72 hr of treatment. The obtained results indicated that the extract was more effective on the second instar larvae than the fourth one. The LC50 of the jojoba extract on the 2nd instar larvae was less than that on the 4th instar larvae , as well as it was decreased by increasing the period after treatment indicated that the larval mortality was higher on 2nd instars than 4th ones. Larval duration was shortened at all treatments of the 2nd instars compared with control. Pupae mortality was high on the 2nd instar treatments comparing with that of the 4th instars, also, the pupae duration was shortened at all treatments of the 2nd and 4th instars compared with control. The percentages of emerged moths were decreased by increasing the extract concentrations.There were significant differences in the egg laid per female between treatments and control. Total protein after 48 hr. of treating was decreased from 32 mg/ g b wt. in control to 31.8 mg/ g b wt. at treated larvae with – 0.36 % change, while it was 19.5 mg/g b wt. at control compared to 14 mg/ g b wt. after 72 hr. with –28.21 % change. As for the enzymes activity it was observed that nearly all enzyme activities were decreased in comparison with control except α-esterase activity which was decreased to 15.3µg-a-naphthal/min/mg protein after 48 hr. from treatment compared with control 27.7 µg-a-naphthal/min/mg protein and increased to 23.2 µg-a-naphthal/min/mg proteinafter72 hr. from treatment compared with control 19.5 µg-a-naphthal/min/mg protein. Also, AkP activity which increased to 20.5 U x 103/mg protein after 48hr. of treatment, compared with control7.9 U x 103/mg protein and decreased to 3.7U x 103/mg protein compared with control 5.8 U x 103/mg protein after72 hr. of treatment. Jojoba is suggested as a safe product with a potential for use as a bioinsecticide in integrated pest management especially in urban localities where use of chemical insecticides are discouraged.

Ultrasonographic measurements of the metacarpal and talar cartilage thicknesses in hemiplegic patients after stroke

Background: Immobilization of the extremities after stroke is known to be the foremost reason of articular cartilage degeneration and musculoskeletal ultrasound (US) has become increasingly important in the assessment of joint cartilage. To the best of our knowledge, US measurements of the metacarpal and talar cartilage thicknesses in hemiplegic patients after stroke have not been performed before.Objectives: The aim of the study was to explore whether metacarpal and talar cartilage thicknesses were affected after stroke using US.Methods: Fifty-eight patients (33 M and 25 F) with unilateral hemiplegia after stroke were enrolled between April and June 2015. Age, sex, body mass index, paretic side, and underlying etiology (ischemic or hemorrhagic) were noted. Modified Ashworth scale, Brunnstrom motor recovery stage (BMRS), motor functional independence measure and functional ambulation category were recorded. A 5–12 MHz linear array probe was used for ultrasonographic cartilage measurements at 2nd, 3rd, and 4th metacarpal heads and talus.Results: When compared with the non-paretic side, metacarpal (but not talar) cartilage thicknesses were found to be less on the paretic side (significant for the 3rd and 4th ones) (both p < 0.05). Subgroup analysis yielded thinner 3rd and 4th metacarpal cartilage thicknesses between the groups in patients with BMRS 1–3 (p = 0.009 and 0.054, respectively) but not in patients with BMRS 4–6 (p = 0.416 and 0.571, respectively).Conclusions: We may conclude that metacarpal (but not talar) cartilage is thinner on the paretic side of stroke patients that seems to be less with better motor functioning.

Miniaturized Quint-Band Bandpass Filter Based on Multi-Mode Resonator and Resonators With Mixed Electric and Magnetic Coupling

Based on multi-mode resonator (MMR) and $\lambda/4$ resonators, a miniaturized microstrip quint-band bandpass filter (BPF) with mixed electric and magnetic coupling (MEMC) has been presented. The proposed MMR is employed to generate the 1st, 2nd, and 5th passbands, while the 3rd and 4th ones of close band proximity are achieved by using four coupled $\lambda/4$ uniform impedance resonators (UIRs). Due to MEMC cancelling effect, virtual grounds in feed lines, and source-load cross coupling, multiple transmission zeros (TZs) can be yielded to obtain sharp passband roll-off skirts. To verify the validity of the design approach, a quint-band BPF centering at 2.1, 3.0, 4.0, 4.7, and 7.2 GHz (denoted as $f_{1}$ , $f_{2}$ , $f_{3}$ , $f_{4}$ , and $f_{5}$ ) with respective 3 dB fractional bandwidths of 13.7%, 5.6%, 10.5%, 5.1%, and 2.9% has been designed and fabricated, whose measured results show good consistence with the predicted frequency responses.

COMPARATIVE TOXIC ACTIVITY OF FOUR ALGAE, AGAINST THE 2ND AND 4TH LARVAL INSTARS OF BLACK CUTWORM, AGROTIS IPSILON (HUFNAGEL)

The dry biomass of four cyanobacterial microalgal strains Anabaena flos aquae, Anabanea laxa, Anabanea fertilissima and Nostoc muscorum was evaluated in invitro assay as a biopesticides against 2nd and 4th instars of Agrotis ipsilon. Larvae were fed on leaf discs painted with the algal solution for 24h. The 2ndinstar larvae were more susceptible than the 4th ones to the four tested algal treatments. N. muscorum treatment was the most toxic one against the 2nd and 4th larval instars. Where, its LC50values were 45 and 150 mg/ml, respectively while, A. fertilissima was the least one, its LC50 values were 250 and 660 mg/ ml, respectively. All the treated larvae were susceptible to four tested algal treatments and its resistance varied according to the larval instars and tested alga. Marked decrease in pupation for both 2nd and /or 4thinstar by the four algal treatments, whereas, the 2ndinstar treated with N. muscorum alga exhibited the most suppressive decrease to 44%, as compared to control (97%). Significant reduction for pupal weight, where, 4thinstar treated with A. flos aquae alga recorded the highest pupal weight decrease to average 290mg, as compared to 484mg of control. Besides prolonging pupal duration where, treatment for both instar with A. flos aquae and A. laxa algae induced the longest period and increased the pupal malformation percent where, 4thinstar treated with N. muscorum and A. flos aquae algae induced noticeable percent reached to21.3 and20% and increased adult malformation to30 and20% respectively, as respect to control. However, the larval treatment of 2nd instar with N. muscorum and A. fertilissima algae had the strongest effect in larval duration increase to average25 and 25.8day as compared to20.4day of control. In addition, the larval treatment of 4thinstar with the four algae decreased the adult fecundity and fertility. Moreover, N. muscorum and A. flos aquae algae inhibited the adult fecundity and eggs fertility to zero, as compared to505eggs/female of control. Marked declining of adult longevity with N. muscorum, A. flos aquae and A.laxa to average 7day, as compared to11day of control. Also, the treatment with the three algae disorder the sex ratio of males and females, as compared to that of control. While the larval treatment with A. fertilissima alga didn't affect the pupal malformation, eggs fertility, adult longevity and sex ratio.

Digital Median Filters

Several DSP algorithms need to remove high-frequency or impulsive noise while preserving edges, e.g., in speech and image processing applications: median filtering has been proved to be more effective for achieving this goal than other filtering techniques. Efficient architectural implementation for real-time applications involves a careful VLSI design, which takes into account modularity, regularity, adaptability, scalability, throughput, circuit complexity and fault tolerance. Four new architectural approaches are presented and evaluated in this paper to deal with different application and implementation constraints. They are: the serial-input polarizing median filter, the floating median filter, the pipelined polarizing median filter and the pipelined sorting median filter. The 1st and the 2nd architectures are based on majority voting, while the 3rd and the 4th ones are based on sorting techniques. All of them are designed so as to exhibit high scalability and to be easily pipelined for higher working frequencies.

Incorporation of radioactive zinc into the eggs of Japanese quails (Coturnix coturnix japonica).

The incorporation of 65Zn into the eggs was investigated after a single or daily intraperitoneal administration to the laying Japanese quails. After a single intraperitoneal administration, the 65Zn appeared first in the 2nd egg yolks, and reached the highest level in the 3rd and 4th ones, followed by a gradual decrease thereafter. The cumulative amount of 65Zn in the egg yolks over a period of 3 weeks accounted for about 40% of the dose. After daily intraperitoneal administration, the 6th-9th egg yolks contained the highest radioactivity among the eggs examined. In addition, the whole-body retention patterns were also observed in the both trials.

Studied on Branching Habits in Crop Plants : 3. Effects of leaf removal or addition of gibberellic acid throuth leaf blade on the growth of tillering buds in rice seedlings.

On the existence of any connection between the leaf blade and the tillering bud, studies were made by means of removal of leaf blade of different leaves or absorption of gibberellic acid (GA) through different leaves. In 1958, the leaf blade of the 4th (plot A) or the 3rd (plot B) leaf or both of them (plot C) were removed at seedling age 4. In 1959, the 5th (plot A) or the 4th (plot B) or both of them (plot C) were removed at age 5. GA was absorbed through the 4th or the 5th leaf blade at seedling age 5, in 1959. After the treatment, dry weight of plant, both growth in length and differentiation of leaves of each tillering buds were traced. The removal of leaf blade retarded the growth of each tillering bud as well as accumulation of dry weight of plant (fig. 1-fig. 4, table 3). When removed at seedling age 4 (fig. 3), the removal of the 3rd leaf or the 4th leaf or both of them caused similarly the retardation of the 2nd, 3rd and 4th tillering buds especially the 3rd and 4th ones. In the case of removal at seedling age 5, the removal of the 4th, or the 5th or both of these leaves retarded similarly the 3rd, 4th and 5th tillering buds especially the 4th and 5th ones. Moreover, the retardation in the growth of these tillering buds were nearly proportional to the inhibition in accumulation of dry matter in whole plant (table 4). That is, which tillering bud is retarded is recognized to be not due to which leaf is removed, but due to when leaf is removed. The absorption of GA through the 4th or the 5th leaf blade inhibited the growth of tillering buds. Also in this case, difference in leaf treated did not cause the difference in the situation of tillering bud inhibited (table 6). From these results, the growth of tillering bud is recognized to be not related to some particular leaf of main stem but related to all of leaves. In addition, when treated at seedling age n the n-th and (n-1)th tillering buds were affected sensitively.

Studies on Branching Habits in Crop Plants : 4. On the growth of tillering buds after enlargement of space by thinning in thick-sown rice seedlings.

This experiment was made for the purpose of studying the possibility of growth in tillering buds which have ceased to grow. Rice seeds were sown relatively thickly, i. e., one seed every 3 cm × 1.5 cm in 1959, and one seed every 3 cm × 1.5 cm or 6 cm × 3 cm in 1961. These rice seedlings were thinned alternatively so that the spaces among the seedlings were enlarged to 6 cm × 3 cm or to 12 cm × 6 cm. Thinning treatments were made at the seedling age 5, 6, 7 or 8 by means of clipping the seedlings with scissors. at the ground surface After that, the growth and the leaf formation of each tillering bud were observed at every seedling age. Moreover, the measurements of respiratory rates were made 2 days after thinning in 1961. During the two years of experiments, the tillering buds which grew surely after each age thinning were as follows: In 1959 (Fig. 2 and Table 3), the 2nd, 3rd, 4th, 5th and 6th tillering buds after the 5th age thinning, the 2nd, 4th, 5th and 6th ones after the 6th age thinning, the 6th, 7th and 8th ones after the 7th age thinning, and the 7th and 8th ones after the 8th age thinning; in 1961 (Fig. 3, Fig. 4 and Table 3), the 5th, 6th and 7th tillering buds after the 6th age thinning, and the 6th, 7th and 8th ones after the 7th and 8th age thinnings. The 2nd and 3rd buds grew after thinning of seedling age 5 or 6 in 1959, but did not grow after thinning of seedling age 6 in 1961. The difference between the results of two years' experiments is thought to be due to the facts that these buds were in the course of growth at seedling age 5 and 6 in 1959, although have ceased to grow at the same age in 1961. The differentiation of leaves on each tillering bud were observed at every seedling age with cross section (Table 1 and Fig. 5). In these observations the author could recognize the following facts; first, even in a bud which has ceased to grow, new leaves are being formed on the growing point though very slowly, second, leaf formation is accelerated by thinning not only in the tillering buds which grow after thinning (ex. the 6th bud in Fig. 5), but also in those which do not grow after thinning (ex. the 2nd and 4th ones in Fig. 5). As regards the respiratory rate, similarly, it was shown to be activated by thinning even in the buds which do not grow after thinning (Table 2). In a previous work, the author found that at the seedling age n in thick-sown rice seedlings, the nth and n-1th tillering buds are in the course of growth, the n-3th and lower ones have ceased to grow. In this experiment, the following facts were observed : If the spaces among seedlings are enlarged at seedling age n in the similar seedlings, the nth and n-1th buds grow surely and normally, the n-3th and lower ones do not grow, and the n-2th bud, which is in a critical stage, grow temporarily or very slightly with only a few exceptions. In those buds that do not grow, however, the formation of leaves are accelerated and the respiration activated. The main factors which inhibit the growth of these buds, in spite of activation of leaf formation and respiration, are going to be studied.