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1
Preobrazenski, Nicholas, Hashim Islam, Patrick J. Drouin, Jacob T. Bonafiglia, Michael E. Tschakovsky, and Brendon J. Gurd. "A novel gravity-induced blood flow restriction model augments ACC phosphorylation and PGC-1α mRNA in human skeletal muscle following aerobic exercise: a randomized crossover study." Applied Physiology, Nutrition, and Metabolism 45, no. 6 (June 2020): 641–49. http://dx.doi.org/10.1139/apnm-2019-0641.
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This study tested the hypothesis that a novel, gravity-induced blood flow restricted (BFR) aerobic exercise (AE) model will result in greater activation of the AMPK–PGC-1α pathway compared with work rate-matched non-BFR. Thirteen healthy males (age: 22.4 ± 3.0 years; peak oxygen uptake: 42.4 ± 7.3 mL/(kg·min)) completed two 30-min work rate-matched bouts of cycling performed with their legs below (CTL) and above their heart (BFR) at ∼2 weeks apart. Muscle biopsies were taken before, immediately, and 3 h after exercise. Blood was drawn before and immediately after exercise. Our novel gravity-induced BFR model led to less muscle oxygenation during BFR compared with CTL (O2Hb: p = 0.01; HHb: p < 0.01) and no difference in muscle activation (p = 0.53). Plasma epinephrine increased following both BFR and CTL (p < 0.01); however, only norepinephrine increased more following BFR (p < 0.01). PGC-1α messenger RNA (mRNA) increased more following BFR (∼6-fold) compared with CTL (∼4-fold; p = 0.036). VEGFA mRNA increased (p < 0.01) similarly following BFR and CTL (p = 0.21), and HIF-1α mRNA did not increase following either condition (p = 0.21). Phosphorylated acetyl-coenzyme A carboxylase (ACC) increased more following BFR (p < 0.035) whereas p-PKA substrates, p-p38 MAPK, and acetyl-p53 increased (p < 0.05) similarly following both conditions (p > 0.05). In conclusion, gravity-induced BFR is a viable BFR model that demonstrated an important role of AMPK signalling on augmenting PGC-1α mRNA. Novelty Gravity-induced BFR AE reduced muscle oxygenation without impacting muscle activation, advancing gravity-induced BFR as a simple, inexpensive BFR model. Gravity-induced BFR increased PGC-1α mRNA and ACC phosphorylation more than work rate-matched non-BFR AE. This is the first BFR AE study to concurrently measure blood catecholamines, muscle activation, and muscle oxygenation.
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Zhang, Yongshu, Yu Lei, Ali Khammanivong, and Mark C. Herzberg. "Identification of a Novel Two-Component System in Streptococcus gordonii V288 Involved in Biofilm Formation." Infection and Immunity 72, no. 6 (June 2004): 3489–94. http://dx.doi.org/10.1128/iai.72.6.3489-3494.2004.
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ABSTRACT Streptococcus gordonii is a pioneer colonizer of the teeth, contributing to the initiation of the oral biofilm called dental plaque. To identify genes that may be important in biofilm formation, a plasmid integration library of S. gordonii V288 was used. After screening for in vitro biofilm formation on polystyrene, a putative biofilm-defective mutant was isolated. In this mutant, pAK36 was inserted into a locus encoding a novel two-component system (bfr [biofilm formation related]) with two cotranscribed genes that form an operon. bfrA encodes a putative response regulator, while bfrB encodes a receptor histidine kinase. The bfr mutant and wild-type strain V288 showed similar growth rates in Todd-Hewitt broth (THB). A bfr-cat fusion strain was constructed. During growth in THB, the reporter activity (chloramphenicol acetyltransferase) was first detected in mid-log phase and reached a maximum in stationary phase, suggesting that transcription of bfr was growth stage dependent. After being harvested from THB, the bfr mutant adhered less effectively than did wild-type strain V288 to saliva-coated hydroxyapatite (sHA). To simulate pioneer colonization of teeth, S. gordonii V288 was incubated with sHA for 4 h in THB with 10% saliva to develop biofilms. RNA was isolated, and expression of bfrAB was estimated. In comparison to that of cells grown in suspension (free-growing cells), bfr mRNA expression by sessile cells on sHA was 1.8-fold greater and that by surrounding planktonic cells was 3.5-fold greater. Therefore, bfrAB is a novel two-component system regulated in association with S. gordonii biofilm formation in vitro.
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Amiri, Achour, Adrian I. Zuniga, Leandro G. Cordova, and Natalia A. Peres. "The Importance of Selecting Appropriate Rotation and Tank-Mix Partners for Novel SDHIs to Enhance Botrytis Fruit Rot Control in Strawberry." Plant Disease 103, no. 4 (April 2019): 729–36. http://dx.doi.org/10.1094/pdis-07-18-1276-re.
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Botrytis fruit rot (BFR), caused by the necrotrophic fungus Botrytis cinerea, is the most important disease of strawberry and is mainly controlled by applications of fungicides from multiple chemical groups. To develop more effective and sustainable BFR management programs, field trials were conducted to evaluate the efficacy of fluopyram and penthiopyrad, two newly registered succinate dehydrogenase inhibitors (SDHIs), rotated or tank mixed with the multisites thiram and captan or the single-sites fludioxonil and fenhexamid. The treatments were applied at two different strawberry fields during the 2013–14 and 2014–15 seasons. Overall, tank mixtures of fluopyram and penthiopyrad increased yield and reduced BFR better than rotations with the same fungicides. The multisite thiram tank mixed with fluopyram reduced BFR incidence by 63 to 86% versus 56 to 84% when the two fungicides were rotated. Thiram tank mixed with penthiopyrad reduced BFR incidence by 55 to 72% versus 42 to 66% when rotated. Captan rotated or tank mixed with fluopyram had a positive effect on yield and BFR incidence, whereas the combination of captan with penthiopyrad had negative impacts. Similarly, the single-site fenhexamid had significant positive impacts when rotated or tank mixed with fluopyram but resulted in poor BFR control when combined with penthiopyrad. The rotation of fludioxonil with both SDHIs had a significant positive effect, although its combination with fluopyram was more effective. The multirotation consisting of both SDHIs and different multi- and single-site fungicides did not provide a greater efficacy than the dual rotation or tank-mixture programs. Our findings suggest more scrutiny is needed when recommending tank-mixture or rotation partners for new fungicides to ensure compatibility and enhanced BFR management. Future recommendations should emphasize the importance of such selections at an early stage for delaying fungicide resistance development and extending the lifespan of at-risk fungicides.
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Fry, Christopher S., Erin L. Glynn, Micah J. Drummond, Kyle L. Timmerman, Satoshi Fujita, Takashi Abe, Shaheen Dhanani, Elena Volpi, and Blake B. Rasmussen. "Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men." Journal of Applied Physiology 108, no. 5 (May 2010): 1199–209. http://dx.doi.org/10.1152/japplphysiol.01266.2009.
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The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, low-intensity RE, combined with blood flow restriction (BFR), has been shown to stimulate mammalian target of rapamycin complex 1 (mTORC1) signaling and MPS in young men. We hypothesized that low-intensity RE with BFR would be able to activate mTORC1 signaling and stimulate MPS in older men. We measured MPS and mTORC1-associated signaling proteins in seven older men (age 70 ± 2 yr) before and after exercise. Subjects were studied identically on two occasions: during BFR exercise [bilateral leg extension exercise at 20% of 1-repetition maximum (1-RM) with pressure cuff placed proximally on both thighs and inflated at 200 mmHg] and during exercise without the pressure cuff (Ctrl). MPS and phosphorylation of signaling proteins were determined on successive muscle biopsies by stable isotopic techniques and immunoblotting, respectively. MPS increased 56% from baseline after BFR exercise ( P < 0.05), while no change was observed in the Ctrl group ( P > 0.05). Downstream of mTORC1, ribosomal S6 kinase 1 (S6K1) phosphorylation and ribosomal protein S6 (rpS6) phosphorylation increased only in the BFR group after exercise ( P < 0.05). We conclude that low-intensity RE in combination with BFR enhances mTORC1 signaling and MPS in older men. BFR exercise is a novel intervention that may enhance muscle rehabilitation to counteract sarcopenia.
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Mitchell, Emma A., Neil R. W. Martin, Mark C. Turner, Conor W. Taylor, and Richard A. Ferguson. "The combined effect of sprint interval training and postexercise blood flow restriction on critical power, capillary growth, and mitochondrial proteins in trained cyclists." Journal of Applied Physiology 126, no. 1 (January 1, 2019): 51–59. http://dx.doi.org/10.1152/japplphysiol.01082.2017.
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Sprint interval training (SIT) combined with postexercise blood flow restriction (BFR) is a novel method to increase maximal oxygen uptake (V̇o2max) in trained individuals and also provides a potent acute stimulus for angiogenesis and mitochondrial biogenesis. The efficacy to enhance endurance performance, however, has yet to be demonstrated. Trained male cyclists ( n = 21) (V̇o2max: 62.8 ± 3.7 ml·min−1·kg−1) undertook 4 wk of SIT (repeated 30-s maximal sprints) either alone (CON; n = 10) or with postexercise BFR ( n = 11). Before and after training V̇o2max, critical power (CP) and curvature constant ( Wʹ) were determined and muscle biopsies obtained for determination of skeletal muscle capillarity and mitochondrial protein content. CP increased ( P = 0.001) by a similar extent following CON (287 ± 39 W to 297 ± 43 W) and BFR (296 ± 40 W to 306 ± 36 W). V̇o2max increased following BFR by 5.9% ( P = 0.02) but was unchanged after CON ( P = 0.56). All markers of skeletal muscle capillarity and mitochondrial protein content were unchanged following either training intervention. In conclusion, 4 wk of SIT increased CP; however, this was not enhanced further with BFR. SIT was not sufficient to elicit changes in skeletal muscle capillarity and mitochondrial protein content with or without BFR. However, we further demonstrate the potency of combining BFR with SIT to enhance V̇o2max in trained individuals. NEW & NOTEWORTHY This investigation has demonstrated that 4 wk of sprint interval training (SIT) increased critical power in trained individuals; however, postexercise blood flow restriction (BFR) did not enhance this further. SIT, with or without BFR, did not induce any changes in skeletal muscle capillarity or mitochondrial protein content in our trained population. We do, however, confirm previous findings that SIT combined with BFR is a potent stimulus to enhance maximal oxygen uptake.
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Slysz, Joshua T., and Jamie F. Burr. "The Effects of Blood Flow Restricted Electrostimulation on Strength and Hypertrophy." Journal of Sport Rehabilitation 27, no. 3 (May 1, 2018): 257–62. http://dx.doi.org/10.1123/jsr.2017-0002.
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Context: The combined effect of neuromuscular electrical stimulation (NMES) and blood flow restriction (BFR) on muscle mass and strength has not been thoroughly investigated. Objective: To examine the effects of combined and independent BFR and a low-intensity NMES on skeletal muscle adaptation. Design: Exploratory study. Setting: Laboratory. Participants: Twenty recreationally active subjects. Main Outcome Measures: Subjects had each leg randomly allocated to 1 of 4 possible intervention groups: (1) cyclic BFR alone, (2) NMES alone, (3) BFR + NMES, or (4) control. Each leg was stimulated in its respective intervention group for 32 minutes, 4 days per week for 6 weeks. Mean differences in size (in grams) and isometric strength (in kilograms), between week 0 and week 6, were calculated for each group. Results: Leg strength increased 32 (19) kg in the BFR + NMES group, which differed from the 3 (11) kg change in the control group (P = .03). The isolated NMES and BFR groups revealed increases of 16 (28) kg and 18 (17) kg, respectively, but these did not statistically differ from the control, or one another. No alterations were statistically significant for leg size. Conclusion: Compared with a control that received no treatment, the novel combination of BFR and NMES led to increasing muscular strength of the knee extensors, but not muscle mass which had a large interindividual variability in response.
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Kipps, T. J., A. Österborg, J. Mayer, S. Stilgenbauer, A. Hellmann, C. D. Williams, R. Furman, G. Chan, C. Russell, and W. G. Wierda. "Clinical improvement with a novel CD20 mAb, ofatumumab, in fludarabine-refractory chronic lymphocytic leukemia (CLL) also refractory to alemtuzumab or with bulky lymphadenopathy." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 7043. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7043.
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7043 Background: Patients (pts) with CLL refractory tofludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (bulky fludarabine-refractory, BFR) have a poor prognosis. Ofatumumab is a human mAb specific for a distinctive small-loop epitope of CD20 that appears more potent than rituximab in eliciting complement-dependent lysis of B cells in vitro. We report, for the first time, results from the planned interim analysis of the clinical benefit observed in pts with DR or BFR CLL treated with ofatumumab in an international pivotal clinical study. Methods: Pts with DR or BFR CLL received 8 weekly then 4 monthly ofatumumab infusions (Dose 1, 300 mg; Doses 2–12, 2,000 mg). Primary endpoint was overall response rate (ORR; 1996 NCI-WG criteria), as assessed by an Independent Review Committee, over 24 wks. Results: Of 138 treated pts (DR: N = 59; BFR: N = 79; median age 64 and 62 yrs, respectively), 63% had Rai stage III/IV disease at screening. Pts had a median of 5 prior therapies. ORR (99% CI) was 58% (40, 74%) in the DR and 47% (32, 62%) in the BFR groups, and median overall survival (95% CI) was 13.7 mo (9.4, NR) and 15.4 mo (10.2, 20.2), respectively. Resolution of disease symptoms (maintained for ≥2 mo) were observed in a large proportion of pts (Table), including in pts considered nonresponders by NCI-WG criteria. Improvements in hematologic values were also observed in some pts with abnormal baseline values, particularly for platelet counts. Pts with thrombocytopenia at baseline (n = 73) experienced sustained increases in median platelet counts from 65 × 109/L to over 100 × 109/L by Wk 8; a similar pattern of rapid improvement was observed in Hgb values. Conclusions: Ofatumumab as single-agent achieves high ORR, and improves disease symptoms and hematologic parameters in heavily pretreated pts with DR and BFR disease who lack standard treatment options. [Table: see text] [Table: see text]
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Dai, Jianjian, Xiangyang Xu, Hao Yang, Chao Su, and Nan Ye. "Safety Risk Analysis of a New Design of Basalt Fiber Gabion Slope Based on Improved 3D Discrete Element Method and Monitoring Data." Sensors 22, no. 10 (May 10, 2022): 3645. http://dx.doi.org/10.3390/s22103645.
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Gabion has been extensively used in retaining walls and slope protection. This study carries out a safety risk analysis of a new structure combining basalt fiber reinforcement (BFR) and the traditional gabion structure. The micro-parameters of BFR and soil were calibrated by using the 3D discrete element method after the tensile test of BFR was completed. The mechanical property of the gabion unit was investigated by using a refined model and a numerical test of uniaxial compression. This work developed a simplified method to simulate the seepage effect. The stress condition and sliding displacement between gabions were also investigated. Deformation, stress, and porosity were all used to evaluate the stability of the new type of gabion slope. According to this study, BFR has a tensile strength of 68.22 MPa, and the safety factor increased by 25.68% after using these BFR gabions. The damage is mainly manifested by bending the BFRs and the dislocation of the gabion units, as the slope does not slip. It is indicated this novel gabion structure has a lower safety risk compared to traditional ones, and thus can be popularized and used in retaining walls and slope protection.
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Horiuchi, Masahiro, and Koichi Okita. "Blood Flow Restricted Exercise and Vascular Function." International Journal of Vascular Medicine 2012 (2012): 1–17. http://dx.doi.org/10.1155/2012/543218.
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It is established that regular aerobic training improves vascular function, for example, endothelium-dependent vasodilatation and arterial stiffness or compliance and thereby constitutes a preventative measure against cardiovascular disease. In contrast, high-intensity resistance training impairs vascular function, while the influence of moderate-intensity resistance training on vascular function is still controversial. However, aerobic training is insufficient to inhibit loss in muscular strength with advancing age; thus, resistance training is recommended to prevent sarcopenia. Recently, several lines of study have provided compelling data showing that exercise and training with blood flow restriction (BFR) leads to muscle hypertrophy and strength increase. As such, BFR training might be a novel means of overcoming the contradiction between aerobic and high-intensity resistance training. Although it is not enough evidence to obtain consensus about impact of BFR training on vascular function, available evidences suggested that BFR training did not change coagulation factors and arterial compliance though with inconsistence results in endothelial function. This paper is a review of the literature on the impact of BFR exercise and training on vascular function, such as endothelial function, arterial compliance, or other potential factors in comparison with those of aerobic and resistance training.
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Muyobela, Jackson, Christian W. W. Pirk, Abdullahi A. Yusuf, Njelembo J. Mbewe, and Catherine L. Sole. "A novel vehicle-mounted sticky trap; an effective sampling tool for savannah tsetse flies Glossina morsitans morsitans Westwood and Glossina morsitans centralis Machado." PLOS Neglected Tropical Diseases 15, no. 7 (July 19, 2021): e0009620. http://dx.doi.org/10.1371/journal.pntd.0009620.
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Background Black screen fly round (BFR) is a mobile sampling method for Glossina morsitans. This technique relies on the ability of operator(s) to capture flies landing on the screen with hand nets. In this study, we aimed to evaluate a vehicle-mounted sticky panel trap (VST) that is independent of the operator’s ability to capture flies against BFR, for effective and rapid sampling of G. m. morsitans Westwood and G. m. centralis Machado. We also determined the influence of the VST colour (all-blue, all-black or 1:1 blue-black), orientation and presence of odour attractants on tsetse catch. Methodology/Principal findings Using randomised block design experiments conducted in Zambia, we compared and modelled the number of tsetse flies caught in the treatment arms using negative binomial regression. There were no significant differences in the catch indices of the three colour designs and for in-line or transversely oriented panels for both subspecies (P > 0.05). When baited with butanone and 1-octen-3-ol, VST caught 1.38 (1.11–1.72; P < 0.01) times more G. m. centralis flies than the un-baited trap. Attractants did not significantly increase the VST catch index for G. m. morsitans (P > 0.05). Overall, the VST caught 2.42 (1.91–3.10; P < 0.001) and 2.60 (1.50–3.21; P < 0.001) times more G. m. centralis and G. m. morsitans respectively, than the BFR. The VST and BFR took 10 and 35 min respectively to cover a 1 km transect. Conclusion/Significance The VST is several times more effective for sampling G. m. morsitans and G. m. centralis than the BFR and we recommend its use as an alternative sampling tool.
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Ellefsen, Stian, Daniel Hammarström, Tor A. Strand, Erika Zacharoff, Jon E. Whist, Irene Rauk, Håvard Nygaard, et al. "Blood flow-restricted strength training displays high functional and biological efficacy in women: a within-subject comparison with high-load strength training." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 309, no. 7 (October 2015): R767—R779. http://dx.doi.org/10.1152/ajpregu.00497.2014.
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Limited data exist on the efficacy of low-load blood flow-restricted strength training (BFR), as compared directly to heavy-load strength training (HST). Here, we show that 12 wk of twice-a-week unilateral BFR [30% of one repetition maximum (1RM) to exhaustion] and HST (6-10RM) of knee extensors provide similar increases in 1RM knee extension and cross-sectional area of distal parts of musculus quadriceps femoris in nine untrained women (age 22 ± 1 yr). The two protocols resulted in similar acute increases in serum levels of human growth hormone. On the cellular level, 12 wk of BFR and HST resulted in similar shifts in muscle fiber composition in musculus vastus lateralis, evident as increased MyHC2A proportions and decreased MyHC2X proportions. They also resulted in similar changes of the expression of 29 genes involved in skeletal muscle function, measured both in a rested state following 12 wk of training and subsequent to singular training sessions. Training had no effect on myonuclei proportions. Of particular interest, 1) gross adaptations to BFR and HST were greater in individuals with higher proportions of type 2 fibers, 2) both BFR and HST resulted in approximately four-fold increases in the expression of the novel exercise-responsive gene Syndecan-4, and 3) BFR provided lesser hypertrophy than HST in the proximal half of musculus quadriceps femoris and also in CSApeak, potentially being a consequence of pressure from the tourniquet utilized to achieve blood flow restriction. In conclusion, BFR and HST of knee extensors resulted in similar adaptations in functional, physiological, and cell biological parameters in untrained women.
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Osterborg, Anders, Thomas J. Kipps, Jiri Mayer, Stephan Stilgenbauer, Catherine D. Williams, Andrzej Hellmen, Tadeusz Robak, et al. "Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of An International Pivotal Trial." Blood 112, no. 11 (November 16, 2008): 328. http://dx.doi.org/10.1182/blood.v112.11.328.328.
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Abstract Background: The prognosis for patients with CLL refractory to fludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5cm) lymphadenopathy (bulky fludarabine-refractory, BFR) is poor. The overall response rate (ORR) to salvage therapy for such patients is approximately 20% with a median survival of 9 mo (Tam et al, Leuk Lym, 2007). New effective treatments are needed for these patients. Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits potent in vitro complement-dependent cytotoxicity, even in malignant B cells with low CD20 expression levels. We report on a planned interim analysis of an international, multicenter, pivotal study of ofatumumab in patients with DR and BFR CLL. Methods: Patients with DR or BFR CLL received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2000 mg). Patients were premedicated with paracetamol, antihistamine and glucocorticoid. The primary end point was ORR (1996 NCI-WG response criteria) assessed by an Independent end points Review Committee (IRC) over a 24 wk period. Overall survival (OS) and safety were also evaluated. Results: This interim analysis included all 138 treated patients (DR, n=59; BFR, n=79: Table); 54% received all 12 infusions and 90% received □8 infusions. The ORR (99% CI) based upon IRC assessment was 51% (34, 68%) for the DR group and 44% (30, 59%) for the BFR group; 1 patient had CR. Additionally, a considerable number of patients had stable disease (Table). Median time to next CLL therapy was 9 mo for the DR group and 8 mo for the BFR group (Table); clinical progression was typically due to worsening lymphadenopathy. The median OS was about 14 mo for the DR group and 15 mo for the BFR group (Table); based upon a landmark analysis at wk 12, response was significantly correlated with longer survival for both groups. Updated efficacy results will be presented at the meeting. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of patients in the DR group and 38% in the BFR group, which were grade 3 (no grade 4) in 7% and 3%, respectively (only 1 grade 3 event was considered a serious adverse event). These events generally subsided with subsequent infusions. The most common grade 3 or 4 toxicities were infections (25% in DR; 27% in BFR group) and hematologic events including neutropenia (12% in DR; 10% in BFR group) and anemia (8% in DR; 4% in BFR group). Early death (within 8 wks from start of treatment) occurred in 2 patients (3%) in the DR group (sepsis, n=1; fungal pneumonia, n=1) and 3 patients (4%) in the BFR group (PD, n=1; sepsis, n=1; myocardial infarction, n=1). No patient tested developed antibodies to ofatumumab. Conclusions: These results demonstrate the effectiveness of ofatumumab in patients with double-refractory CLL or bulky fludarabine-refractory disease. Ofatumumab was well tolerated with no unexpected toxicities. This monoclonal antibody potentially represents an active treatment option with clinical benefit for patients with very poor prognosis who have exhausted standard treatment options. The encouraging single-agent activity in patients with refractory CLL warrants further investigation of ofatumumab in earlier disease settings, in combination with other agents, as maintenance, and in other B-cell malignancies. Table DR (n=59) BFR (n=79) CI=confidence interval; NR=not reached Characteristic Median(range) Age, yrs 64 (41–86) 62 (43–84) No. of prior treatments 5 (1–14) 4 (1–16) % of patients Rai Stage III/IV 54 70 Binet Stage C 51 65 ECOG performance status 0 44 30 1–2 53 67 Lymph node or CT lesion >5cm 93 100 Prior rituximab-containing regimen 59 54 ORR (%) (99% CI) 51 (34, 68) 44 (30, 59) Complete response 0 1 Partial response 51 43 Stable disease 39 43 Progressive disease 3 10 Median (95% CI) Time to next CLL therapy, mo 9.0 (7.3, 10.7) 7.9 (7.1, 9.3) Overall survival, mo 13.7 (9.4, NR) 15.4 (10.2, 20.2)
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Khouri, Issa F., Rima M. Saliba, Celina Ledesma, Elias J. Jabbour, Francesco Turturro, Gheath Alatrash, Sairah Ahmed, et al. "Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning Improves Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)." Blood 126, no. 23 (December 3, 2015): 2011. http://dx.doi.org/10.1182/blood.v126.23.2011.2011.
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Abstract Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab). Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily on days -5 to -3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant. Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin >3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR). Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P <0.001) and 21 (81%) vs 39 (63%), respectively, did not require platelet transfusions (P=0.08). Median follow-up times for BFR and FCR groups were 29 (range 19-60), and 104 (range, 34-195) months. The 3-year overall survival (OS) estimates in the BFR and FCR groups were 82% vs. 51% (P=0.03) and the 3-year progression-free survival estimates were 63% vs. 27% (P=0.001). The 3-year OS improvements were seen across the prognostic factors studied for BFR and FCR respectively: MUD (93% vs 30%), presence of 17p deletion (86% vs 50%), and age >50 years (79% vs 50%), β2-microglobulin >3 mg/L (73% vs 45%), >3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR. Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT. Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen. Disclosures No relevant conflicts of interest to declare.
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Alavi, Seyyed Yaser, and Shadmehr Mirdar. "The Comparison of Eight Weeks of HIIT and BFR on Mitochondrial Biogenesis and Angiogenesis Markers in Vastus Lateralis Muscle of Amateur Male Runners." Scientific Journal of Rehabilitation Medicine 10, no. 3 (July 1, 2021): 424–35. http://dx.doi.org/10.32598/sjrm.10.3.4.
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Background and Aims Post-exercise Blood Flow Restriction (BFR) is a novel training method that, through alterations to the haemodynamic, metabolic, and hypoxic stimulus, could augment skeletal muscle adaptation in endurance-trained individuals. This study aimed to compare the effect of eight weeks of High-Intensity Interval Training (HIIT) and BFR on PGC-1α and Vascular Endothelial Growth Factor (VEGF) as mitochondrial biogenesis and angiogenesis biomarkers, respectively, in amateur male runners. Methods In the current study, 15 runners (Meas±SD of age: 23±3 years; height: 172±5 cm; weight: 73±4 kg: BMI: 23±1.7 kg/m2) voluntarily participating in this study were divided into three groups: 1-Control 2-HIIT and 3-HIIT+BFR or BFR. The experimental groups performed three sessions a week (six trials each session) for eight weeks. The biopsy samples were collected from the vastus lateralis muscle at the first and end of eight weeks. The protein expression levels of the PGC-1α and VEGF were studied by immunohistochemical method. Data analysis was performed using the one-way Analysis of Covariance (ANCOVA), and a significance level of P<0.05 was considered. Results The findings showed that PGC-1α values were significantly increased in the HIIT and BFR groups (54.9% and 60.85%, respectively) compared to the control group, as well as VEGF levels were 51.31% and 57.52%, respectively (P<0.05). There were also significant differences between experimental groups in the protein expressions (P<0.05). Conclusion Given that activation of VEGF from the PGC-1 pathway is part of cellular-molecular mechanisms of high-intensity interval training, It seems that the combination of intense interval training and BFR can effectively affect the process of angiogenesis in the vastus lateralis muscle of amateur runners.
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Wierda, W. G., T. Kipps, J. Mayer, S. Stilgenbauer, T. Robak, C. D. Williams, R. Furman, G. Chan, C. Russell, and A. Österborg. "Activity of ofatumumab, a novel CD20 mAb, and prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulky fludarabine-refractory chronic lymphocytic leukemia (CLL)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 7044. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7044.
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7044^ Background: Salvage therapy has limited activity (20–26% overall response rate [ORR]) in patients (pts) with CLL refractory to fludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (bulky fludarabine-refractory, BFR). Ofatumumab (OFA) is a fully human mAb that targets a unique small-loop epitope of CD20 close to the cell surface and elicits more potent in vitro complement-dependent cytotoxicity of B-cell lines and tumor cells vs rituximab (RTX). To determine whether prior RTX exposure impacted activity of OFA in pts with DR or BFR CLL, an analysis was performed to assess efficacy by prior RTX exposure in pts treated with OFA in an international, pivotal study. Methods: Pts with DR or BFR CLL received 8 weekly infusions of OFA followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2,000 mg). Primary endpoint was ORR (1996 NCI-WG criteria) assessed by an Independent Review Committee over 24 weeks. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Results: Among 138 treated pts (DR, N=59; BFR, N=79) at the planned interim analysis, the ORR (99% CI) was 58% (40, 74%) in the DR group and 47% (32, 62%) in the BFR group. Median PFS (95% CI) was 5.7 mo (4.5, 8.0) and 5.9 mo (4.9, 6.4), and median OS (95% CI) was 13.7 mo (9.4, NYR) and 15.4 mo (10.2, 20.2), respectively. 59% and 54% of DR and BFR pts, respectively, previously received RTX-containing regimens. Both ORR and median PFS were similar in the prior RTX and no prior RTX subgroups (Table), and were comparable to efficacy data for the overall study population. ORR and median PFS were also similar in pts refractory to fludarabine in combination with RTX with or without cyclophosphamide. Conclusions: Single-agent therapy with OFA is effective in pts with DR or BFR CLL, irrespective of prior CD20 mAb therapy with RTX. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .
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Khouri, Issa F., Rima M. Saliba, Pramoda Challagundla, Celina Ledesma, Martin Korbling, Alison M. Gulbis, Maria Guillermo-Pacheco, et al. "Bfr (bendamustine, fludarabine, rituximab) Vs. FCR Nonmyeloablative Allogeneic Conditioning In Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): Outcome Results Including Minimal Residual Disease Analysis." Blood 122, no. 21 (November 15, 2013): 3349. http://dx.doi.org/10.1182/blood.v122.21.3349.3349.
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Abstract Background Bendamustine is a novel active agent in CLL with favorable safety profile. We have previously reported the outcomes of allogeneic stem cell transplantation (alloSCT) in CLL after FCR conditioning (Khouri et al. Cancer 2013). More recently, we initiated a trial with BFR. Herein, we compare outcomes in relapsed/refractory CLL patients following alloSCT according to the conditioning regimen received. Patients and Methods We studied 101 CLL patients treated on 3 consecutive trials at our center between 1999 and 2012. 75 (74%) received FCR and 26 (26%) received BFR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily x3) and rituximab (375 mg/m2 IV on day –13 and 1000 mg/m2 on days -6, +1, and +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant. Patients were staged with CT, PET (whenever indicated) scans and marrow biopsies, every 3 months for the first year, every 6 months x 5 years, then yearly thereafter. Minimal residual disease (MRD) by multicolor flow cytometry using an international standard approach was also assessed from bone marrow samples since 2004. Results Patients characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), β2-microglobulin >3 mg/L, refractory disease (38% in BFR vs. 46% in FCR, P=0.5), presence of 17p deletion [27% in BFR and 11/30 (37%) in FCR], and peripheral blood stem cell source (92% and 89%, respectively). More patients however received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 27%, respectively, P=0.01). Treatment-related mortality was similar within the 2 groups [4% and 7% at 6-months; 8% and 16% (P=0.3) at 1-year]. The incidence of acute grade 3 GVHD was 4% and 8% in the BFR and FCR groups, despite the higher % of unrelated transplants in BFR. None had acute grade 4 GVHD in either group. Median follow-up time for BFR and FCR groups were 14 (range 4-48), and 76 (range, 24-195) months, respectively. The 2-year progression rates in the BFR and FCR were 17% vs. 37%, respectively (P=0.04) (Figure), and the 2-year PFS rates were 75% vs. 40%, respectively (P=0.01). There was also a trend for a better 2-year OS rates (92% vs. 68%, P=0.1), favoring the BFR group. The conditioning regimen (P=0.04) and β2-microglobulin >3 mg/L (P=0.03) were the only predictors for progression by uni- and multivariate analysis undertaken in all 101 patients, whereas a number of prior therapies of > 3 was the only predictor for OS. Recent studies have suggested that MRD is an independent predictor of PFS and OS in CLL after conventional chemotherapy as well as after alloSCT. We assessed MRD in 61 patients following alloSCT. A 6-months landmark analysis showed that MRD-negativity was not a predictor for progression in these patients (P=0.6). Last MRD tests before clinical progression dates was available for 22 of 39 progressions in the FCR/BFR group. Last MRD test was found to be negative in 14/22 relapsed patients. Median duration between last MRD-negative test and clinical relapse was 92 days (range, 1-725). Median duration between last MRD-positive test and clinical relapse was 71 days (range, 21-330) Conclusion Our results show a lower rate of progression and improved survival after BFR when compared to FCR regimen in alloSCT for CLL. MRD by multicolor flow cytometry was not able to predict risk of progression in these patients whose disease was also assessed by CT imaging following transplantation. Disclosures: Khouri: Cephalon: Research Funding. Off Label Use: Bendamustine in transplantation.
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Khouri, Issa F., Wei Wei, Rosamar Valverde, Martin Korbling, Francesco Turturro, Alison M. Gulbis, Maria Guillermo-Pacheco, et al. "Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning: A Novel Regimen Inducing Immunosuppression Without Myelosuppression." Blood 122, no. 21 (November 15, 2013): 541. http://dx.doi.org/10.1182/blood.v122.21.541.541.
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Abstract Background We previously reported the use of BFR, with phase 1 escalating daily doses of 70, 90, 110, or 130 mg/m2 of bendamustine daily x 3 days prior to transplantation without dose-limiting toxicity (Khouri et al. ASH 2011, Abstract # 894). In this study, we report results of an expanded phase 2 trial. Methods Bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation , together with 30 mg/m2 IV of fludarabine given on the same days. Rituximab was given at a dose of 375 mg/m2 IV on day –13 and 1000 mg/m2 on days -6, +1, and +8, as previously described. Rituximab was omitted in patients with T-cell diseases. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant. Results The analysis included all 56 patients who received BFR (48 from the expanded phase 2 trial, and 8 from the phase 1 part). Histologies included: mantle cell (n=16), CLL (n=15) (3 with 17p- and 2 Richter’s), follicular (n=13), Diffuse large cell (n=9), peripheral T-cell lymphoma (n=3). Median age was 56 (range, 59-70) years. Median prior treatments was 3 (range, 1-7); 7 (12%) had failed a prior autotransplant. At study entry,27 (48%) patients were in CR/CRu, 23 (41%) in PR, and 6 (11%) had refractory disease. Thirty (54%) received their transplants from HLA-compatible siblings and 26 (46%) from unrelated donors. Median number of CD34-positive cells infused was 5.58 x 106/kg. Neutrophil counts recovered to > 0.5 x 109/L a median of 6 days after transplantation (range, 0-16 days). The median number of days on G-CSF was 1.5 days (range, 0-8 days). Thirteen patients (23%) did not require G-CSF as they never experienced an ANC < 0.5 x 109/L. Forty-nine patients (87.5%) did not require platelet transfusions. Platelet counts recovered to > 20 x 109/L in the remaining 7 patients after a median of 11 days (range, 10-19 days). All patients engrafted donor cells. By day 30, median donor myeloid and T-cells were 85% and 97%, respectively. Both increased to 100% by day 90. Recovery of donor cells was similar in both sibling and unrelated donor transplantation. Acute grade 2-4 GvHD and chronic extensive GvHD were observed in 7 (12.5%) and 8 (14%) of patients respectively. Treatment-related mortality at 1-year was 9%. Six patients died: 2 of progression, 2 of infection and 2 of GVHD complications. With a median follow-up time of 12 months (range, 2-37 months), the OS and PFS rates were 89% and 80%, respectively. Conclusions Our results show that the BFR regimen with bendamustine at a dose level of 130 mg/m2 daily x 3 days, constitutes a well-tolerated nonmyeloablative allogeneic conditioning for lymphoid malignancies. It allows engraftment of both sibling and unrelated donor cells with minimal myelosuppression. This regimen can be used as a platform for allogeneic transplantation in the outpatient setting. Disclosures: Khouri: Cephalon: Research Funding. Off Label Use: Bendamustine in transplantation.
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Chaine, Cecilia, Andrew S. Hursthouse, Bruce McLean, Iain McLellan, Brian McMahon, Jim McNulty, Jan Miller, and Evi Viza. "Recycling Plastics from WEEE: A Review of the Environmental and Human Health Challenges Associated with Brominated Flame Retardants." International Journal of Environmental Research and Public Health 19, no. 2 (January 11, 2022): 766. http://dx.doi.org/10.3390/ijerph19020766.
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Waste electrical and electronic equipment (WEEE) presents the dual characteristic of containing both hazardous substances and valuable recoverable materials. Mainly found in WEEE plastics, brominated flame retardants (BFRs) are a component of particular interest. Several actions have been taken worldwide to regulate their use and disposal, however, in countries where no regulation is in place, the recovery of highly valuable materials has promoted the development of informal treatment facilities, with serious consequences for the environment and the health of the workers and communities involved. Hence, in this review we examine a wide spectrum of aspects related to WEEE plastic management. A search of legislation and the literature was made to determine the current legal framework by region/country. Additionally, we focused on identifying the most relevant methods of existing industrial processes for determining BFRs and their challenges. BFR occurrence and substitution by novel BFRs (NBFRs) was reviewed. An emphasis was given to review the health and environmental impacts associated with BFR/NBFR presence in waste, consumer products, and WEEE recycling facilities. Knowledge and research gaps of this topic were highlighted. Finally, the discussion on current trends and proposals to attend to this relevant issue were outlined.
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Jatav, Minakshi. "Blood Flow Restriction (BFR) Therapy to Rehabilitate Muscle Injuries in Post-operative Knee Patient." Chettinad Health City Medical Journal 11, no. 02 (June 30, 2022): 51–61. http://dx.doi.org/10.24321/2278.2044.202216.
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KAATSU is a blood flow restriction training that was developed in Japan in the 1960s as a low-intensity strengthening exercise. It involves the wrapping of a tourniquet or pneumatic cuff over the muscle at a quick repetition rate during low-intensity muscle contractions. It is a muscle-strengthening technique used in physical therapy clinics to help patients regain muscle function following an injury or surgery. This is performed by temporarily cutting off blood flow to the muscles during the exercise. There were no linguistic or regional limitations in the literature searches for this article. This review contains a total of 25 records. Other resources were used to define additional elements. 4 records were duplicated and removed from the database. A total of 21 documents were found, with two being ruled out based on the title and abstract. Only 19 full-text items were authorised, and among these, 7 were eliminated because they were urgent research, case studies, and in a few studies, physical characteristics were not examined. This review article finally contained a total of 12 papers. Low-intensity exercise is used in blood flow restriction strengthening to achieve strength improvements similar to those seen in high-intensity training. BFR is a novel approach to physical therapy (PT). According to a preliminary study, this can result in adequate strength improvements during low-intensity exercise.
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Sprick, Justin D., and Caroline A. Rickards. "Combining remote ischemic preconditioning and aerobic exercise: a novel adaptation of blood flow restriction exercise." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 5 (November 1, 2017): R497—R506. http://dx.doi.org/10.1152/ajpregu.00111.2017.
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Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE) when performed at the same relative intensity. We also assessed the cerebrovascular responses due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65–70% maximal heart rate with and without intermittent BFR (4 × 5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher concentration NE compared with CE (1249 ± 170 vs. 962 ± 114 pg/ml; P = 0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P = 0.33), and MAP was 4–5 mmHg lower with BFRE versus CE during the reperfusion periods ( P ≤ 0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials ( P ≥ 0.22), suggesting equivalent cerebrometabolic demand. The exaggerated sympathoexcitatory response with BFRE was not accompanied by higher MAP, likely because of the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac or stroke rehabilitation, where exercising patients could benefit from the cardio and cerebro protection associated with RIPC.
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Torres, J. P., R. Hoto, J. Andrés, and J. A. García-Manrique. "Manufacture of Green-Composite Sandwich Structures with Basalt Fiber and Bioepoxy Resin." Advances in Materials Science and Engineering 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/214506.
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Nowadays, there is a growing interest for the use and development of materials synthesized from renewable sources in the polymer composites manufacturing industry; this applies for both matrix and reinforcement components. In the present research, a novel basalt fibre reinforced (BFR) bioepoxy green composite is proposed as an environmentally friendly alternative to traditional petroleum-derived composites. In addition, this material system was combined with cork as core material for the fabrication of fibre composite sandwich structures. Mechanical properties of both skin and core materials were assessed through flexural and tensile tests. Finite element (FEM) simulations for the mechanical stress analysis of the sandwich material were carried out, and a maximum allowable shear stress for material failure under bending loads was established. Permeability measurements of the basalt fabrics were carried out in order to perform numerical simulations of liquid composite moulding (LCM) processes on the PAM-RTM software. The proposed green-composite sandwich material was used for the fabrication of a longboard as a case study for a sports equipment application. Numerical simulations of the mould filling stage allowed the determination of an optimal mould filling strategy. Finally, the load-bearing capacity of the board was studied by means of FEM simulations, and the presented design proved to be acceptable for service.
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Li, Xuelin, Yu Wang, Wenbin Bai, Qiuyue Zhang, Leicheng Zhao, Zhipeng Cheng, Hongkai Zhu, and Hongwen Sun. "Novel Brominated Flame Retardants in Dust from E-Waste-Dismantling Workplace in Central China: Contamination Status and Human Exposure Assessment." Toxics 11, no. 1 (January 6, 2023): 58. http://dx.doi.org/10.3390/toxics11010058.
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Novel brominated flame retardants (NBFRs) have been widely used as alternatives to legacy BFRs. However, information on the contamination status and human exposure risks of electronic waste (e-waste)-derived NBFRs in the e-waste workplace is limited. In this study, six NBFRs and the legacy BFRs, hexabromocyclododecanes (HBCDs), were analyzed in 50 dust samples from an e-waste-dismantling workplace in Central China. The dust concentration of NBFRs in e-waste-dismantling workshops (median, 157–169 ng/g) was found to be significantly higher than those in an outdoor environment (17.3 ng/g) (p < 0.01). Differently, the highest median concentration of HBCDs was found in dust from the dismantling workshop for cellphones and computers (367 ng/g) among studied areas. The bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (BEHTBP) was the predominant compound, which contributed 66.0–88.0% of measured NBFR concentrations. NBFRs might originate from plastic and rubber materials in wastes based on the correlation and principal component analysis. Moreover, the total estimated daily intakes (average scenario) of NBFRs were calculated at 2.64 × 10−2 ng/kg bw/d and 2.91 × 10−2 ng/kg bw/d for the male and female dismantling workers, respectively, via dust ingestion, inhalation, and dermal contact pathways, which were lower than the reference dose values, and thus indicated a limited human exposure risk for NBFRs at the current level. Although the dust concentrations and daily intakes of NBFRs were still lower than those of other emerging pollutants (e.g., organophosphate and nitrogenous flame retardants) measured in the same sampling set, the elevated levels of NBFRs suggested the progressive BFR replacement process in China, which deserves more attention regarding their adverse effects on both the environment and human health.
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Zhao, Xuezhen, Tian Chen, Bin Yang, Dejun Wang, Wen Sun, Yuwei Wang, Xiaodi Yang, Sheng Wen, Jingguang Li, and Zhixiong Shi. "Serum levels of novel brominated flame retardants (NBFRs) in residents of a major BFR-producing region: Occurrence, impact factors and the relationship to thyroid and liver function." Ecotoxicology and Environmental Safety 208 (January 2021): 111467. http://dx.doi.org/10.1016/j.ecoenv.2020.111467.
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Irfan, Ali, Shah Faisal, Sajjad Ahmad, Sami A. Al-Hussain, Sadia Javed, Ameer Fawad Zahoor, Bushra Parveen, and Magdi E. A. Zaki. "Structure-Based Virtual Screening of Furan-1,3,4-Oxadiazole Tethered N-phenylacetamide Derivatives as Novel Class of hTYR and hTYRP1 Inhibitors." Pharmaceuticals 16, no. 3 (February 23, 2023): 344. http://dx.doi.org/10.3390/ph16030344.
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Human tyrosinase (hTYR) is a key and rate-limiting enzyme along with human tyrosinase-related protein-1 (hTYRP1), which are among the most prominent targets of inhibiting hyper pigmentation and melanoma skin cancer. In the current in-silico computer-aided drug design (CADD) study, the structure-based screening of sixteen furan-1,3,4-oxadiazole tethered N-phenylacetamide structural motifs BF1–BF16 was carried out to assess their potential as hTYR and hTYRP1 inhibitors. The results revealed that the structural motifs BF1–BF16 showed higher binding affinities towards hTYR and hTYRP1 than the standard inhibitor kojic acid. The most bioactive lead furan-1,3,4-oxadiazoles BF4 and BF5 displayed stronger binding in affinities (−11.50 kcal/mol and −13.30 kcal/mol) than the standard drug kojic acid against hTYRP1 and hTYR enzymes, respectively. These were further confirmed by MM-GBSA and MM-PBSA binding energy computations. The stability studies involving the molecular dynamics simulations also provided stability insights into the binding of these compounds with the target enzymes, wherein it was found that they remain stable in the active sites during the 100 ns virtual simulation time. Moreover, the ADMET, as well as the medicinal properties of these novel furan-1,3,4-oxadiazole tethered N-phenylacetamide structural hybrids, also showed a good prospect. The excellent in-silico profiling of furan-1,3,4--oxadiazole structural motifs BF4 and BF5 provide a hypothetical gateway to use these compounds as potential hTYRP1 and hTYR inhibitors against melanogenesis.
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Lindsey, Richard C., Catrina Godwin, and Subburaman Mohan. "Skeletal effects of nongenomic thyroid hormone receptor beta signaling." Journal of Endocrinology 242, no. 3 (September 2019): 173–83. http://dx.doi.org/10.1530/joe-19-0172.
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Thyroid hormone (TH) levels increase rapidly during the prepubertal growth period in mice, and this change is necessary for endochondral ossification of the epiphyses. This effect of TH on epiphyseal chondrocyte hypertrophy is mediated via TRβ1. In addition to its traditional genomic signaling role as a transcription factor, TRβ1 can also exert nongenomic effects by interacting with other signaling molecules such as PI3K. To investigate the role of nongenomic TRβ1 signaling in endochondral ossification, we evaluated the skeletal phenotype of TRβ147F mutant mice which exhibit a normal genomic response of TRβ1 to TH, but the nongenomic response through the PI3K pathway is impaired. Using microCT, we found that 13-week-old TRβ147F mice had significantly less trabecular bone mass at three sites. Histomorphometric analyses revealed that mineralizing surface to bone surface and BFR/BS were reduced in the mutant mice. Mechanistically, we found that activation of TRβ increased Alp and Osx expression in control but not TRβ147F osteoblasts. Since canonical β-catenin signaling has been implicated in mediating nongenomic TRβ–PI3K signaling, we evaluated the effect of TRβ1 activation on β-catenin target gene expression in MC3T3-E1 pre-osteoblasts. We found that β-catenin target genes were increased, suggesting that nongenomic TRβ1–PI3K pathway modulation of β-catenin signaling may mediate TRβ1 effects on osteoblast differentiation. Together, these results suggest that TH acting through TRβ1 regulates endochondral ossification in part via nongenomic signaling in mice. Further investigation of this nongenomic mechanism of TRβ1 signaling could lead to novel therapeutic targets for treatment and prevention of osteoporosis.
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Savard, Martin, Julie Labonté, Céléna Dubuc, Witold Neugebauer, Pedro D’Orléans-Juste, and Fernand Gobeil. "Further pharmacological evaluation of a novel synthetic peptide bradykinin B2 receptor agonist." Biological Chemistry 394, no. 3 (March 1, 2013): 353–60. http://dx.doi.org/10.1515/hsz-2012-0295.
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Abstract We recently identified a novel human B2 receptor (B2R) agonist [Hyp3,Thi5,NChg7,Thi8]-bradykinin (NG291) with greater in vitro and in vivo potency and duration of action than natural bradykinin (BK). Here, we further examined its stability and selectivity toward B2R. The hypotensive, antithrombotic, and profibrinolytic functions of NG291 relative to BK and its analogue ([Hyp3,Thi5,(4-Me)Tyr8(ΨCH2NH)Arg9]-BK) (RMP-7) were also tested. Contraction assays using isolated mouse stomachs (containing kinin B1R, B2R, and kininase I- and II-like activities) showed that NG291 is a more potent contractant than BK and is inhibited by HOE-140 (B2R antagonist) but unaffected by R954 (B1R antagonist), whereas both decreased the potency of BK. In stomach tissues from B2R knockout mice, BK maintained its activity via B1R, whereas NG291 had no contractile effect, indicating that it was selective for B2R. Unlike BK, NG291 was not degraded by rabbit lung ACE. Comparing intravenously administered BK and NG291 revealed that NG291 exhibited more potent and prolonged hypotensive action and greater antithrombotic and profibrinolytic activities. These effects were of comparable magnitude to RMP-7 and were absent in B2R knockout mice. We concluded that NG291 is a novel biostable B2R-selective agonist that may prove suitable for investigating the (pre)clinical cardioprotective efficacy of B2R activation.
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Lachenmeier, Dirk W., and Stephan G. Walch. "Evidence for adverse effects of cannabidiol (CBD) products and their non-conformity on the European food market – response to the European Industrial Hemp Association." F1000Research 9 (August 16, 2021): 1051. http://dx.doi.org/10.12688/f1000research.26045.2.
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An interesting and valuable discussion has arisen from our recent article (Lachenmeier et al., 2020) and we are pleased to have the opportunity to expand on the various points we made. Equally important, we wish to correct several important misunderstandings that were made by Kruse and Beitzke (2020) on behalf of the European Industrial Hemp Association (EIHA) that possibly contributed to their concerns about the validity of our data, toxicological assessment and conclusions regarding regulatory status of cannabidiol (CBD) products. First and foremost, our study did only assess the risk of psychotropic Δ9-tetrahydrocannabinol (THC) without inclusion of non-psychotropic Δ9-tetrahydrocannabinolic acid (THCA). Secondly, as this article will discuss in more detail, there is ample evidence for adverse effects of CBD products, not only in paediatric patients, but also in adult users of over-the-counter CBD products (including inadvertent “high” effects). Thirdly, the exposure and risk assessment was conducted using up-to-date guidelines according to the European Food Safety Authority (EFSA) and the German Federal Institute for Risk Assessment (BfR). And finally, the current legal situation in the European Union, without approval of any hemp extract-containing product according to the Novel Food regulation, actually allows blanket statements that all such products are illegal on the market, and this indeed would imply a general ban on the use and marketing of such products as food or food ingredients until such an approval has been granted. We hope that this reassures the F1000Research readership regarding the validity of our results and conclusions. We are pleased, though, that the EIHA has acknowledged the fact that there are non-compliant CBD products available, but according to our data these are a substantial fraction of the market.
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Lachenmeier, Dirk W., and Stephan G. Walch. "Evidence for side effects of cannabidiol (CBD) products and their non-conformity on the European food market – response to the European Industrial Hemp Association." F1000Research 9 (August 26, 2020): 1051. http://dx.doi.org/10.12688/f1000research.26045.1.
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An interesting and valuable discussion has arisen from our recent article (Lachenmeier et al., 2020) and we are pleased to have the opportunity to expand on the various points we made. Equally important, we wish to correct several important misunderstandings that were made by Kruse and Beitzke (2020) on behalf of the European Industrial Hemp Association (EIHA) that possibly contributed to their concerns about the validity of our data, toxicological assessment and conclusions regarding regulatory status of cannabidiol (CBD) products. First and foremost, our study did only assess the risk of psychotropic Δ9-tetrahydrocannabinol (THC) without inclusion of non-psychotropic Δ9-tetrahydrocannabinolic acid (THCA). Secondly, as this article will discuss in more detail, there is ample evidence for side effects of CBD products, not only in paediatric patients, but also in adult users of over-the-counter CBD products (including inadvertent “high” effects). Thirdly, the exposure and risk assessment was conducted using up-to-date guidelines according to the European Food Safety Authority (EFSA) and the German Federal Institute for Risk Assessment (BfR). And finally, the current legal situation in the European Union, without approval of any hemp extract-containing product according to the Novel Food regulation, actually allows blanket statements that all such products are illegal on the market, and this indeed would imply a general ban on the use and marketing of such products as food or food ingredients until such an approval has been granted. We hope that this reassures the F1000Research readership regarding the validity of our results and conclusions. We are pleased, though, that the EIHA has acknowledged the fact that there are non-compliant CBD products available, but according to our data these are a substantial fraction of the market.
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Albert-Weissenberger, Christiane, Christian Stetter, Sven G. Meuth, Kerstin Göbel, Michael Bader, Anna-Leena Sirén, and Christoph Kleinschnitz. "Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation." Journal of Cerebral Blood Flow & Metabolism 32, no. 9 (May 9, 2012): 1747–56. http://dx.doi.org/10.1038/jcbfm.2012.62.
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The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 ( P<0.05), whereas no significant induction could be observed for the B2R ( P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 ( P<0.001) and day 7 ( P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.
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Raslan, Furat, Tobias Schwarz, Sven G. Meuth, Madeleine Austinat, Michael Bader, Thomas Renné, Klaus Roosen, Guido Stoll, Anna-Leena Sirén, and Christoph Kleinschnitz. "Inhibition of Bradykinin Receptor B1 Protects Mice from Focal Brain Injury by Reducing Blood–Brain Barrier Leakage and Inflammation." Journal of Cerebral Blood Flow & Metabolism 30, no. 8 (March 3, 2010): 1477–86. http://dx.doi.org/10.1038/jcbfm.2010.28.
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Kinins are proinflammatory and vasoactive peptides that are released during tissue damage and may contribute to neuronal degeneration, inflammation, and edema formation after brain injury by acting on discrete bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on lesion size, blood–brain barrier (BBB) disruption, and inflammatory processes after a focal cryolesion of the right parietal cortex in mice. B1R and B2R gene transcripts were significantly induced in the lesioned hemispheres of wild-type mice ( P<0.05). The volume of the cortical lesions and neuronal damage at 24 h after injury in B1R −/− mice were significantly smaller than in wild-type controls (2.5±2.6 versus 11.5±3.9 mm3, P<0.001). Treatment with the B1R antagonist R-715 1 h after lesion induction likewise reduced lesion volume in wild-type mice (2.6±1.4 versus 12.2±6.1 mm3, P<0.001). This was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In contrast, genetic deletion or pharmacological inhibition of B2R had no significant impact on lesion formation or the development of brain edema. We conclude that B1R inhibition may offer a novel therapeutic strategy after acute brain injuries.
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Turhan, Ali G., Fanny Sarrazy, Marie Laure Bonnet, Angelina Bertrand, Marie Claude Meunier, Djamel Aggoune, Jean-Claude Chomel, et al. "A Novel DNA Repair Chip Assay Allows Rapid Identification of DNA Repair Abnormalities Induced By BCR-ABL." Blood 124, no. 21 (December 6, 2014): 4536. http://dx.doi.org/10.1182/blood.v124.21.4536.4536.
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Abstract BCR-ABL expression in leukemic cells is associated with several types of DNA repair abnormalities, involving homologous recombination (HR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), mismatch repair (MMR) and base-excision repair (BER) pathways. These defects, combined with the genetic instability inherent to chronic myeloid leukemia (CML), are thought lead to ABL-kinase domain mutations which remain poorly repaired and selected by tyrosine kinase inhibitor (TKI) therapies, leading to drug resistance. Currently, there is no functional, practical, single step assay to determine if BCR-ABL expression in a given leukemic cell is predominantly associated with a specific DNA repair pathway. For this purpose, we have used a novel DNA repair test based on biopchips evaluating the functional capacity of cells to achieve DNA repair through the use of a functional excision/synthesis repair assay that establish DNA Repair Enzyme Signatures. This assay allows monitoring the repair of a set of DNA lesions handled by BER (8oxoG, alkylated bases, glycols and Abasic sites) and NER (photoproducts, psoralen and cisplatin adducts). For modelling CML, we have used the UT7 cell line expressing BCR-ABL and T315I-mutated BCR-ABL. Parental (P)-UT7 cells were used as controls. We have tested the effects of BCR-ABL tyrosine kinase activity on the DNA repair assays using two strategies: The first was the evaluation of the effects of the nuclear extracts of UT7 cells expressing either native (N) BCR-ABL or T315I-mutated BCR-ABL before and after incubation of the cells in the presence of Imatinib (IM) or Nilotinib whereas the second tested the effects of BCR-ABL in an inducible system without the use of TKI. As expected, UT7 cells with N-BCR-ABL were sensitive to the inhibitory effects of these drugs whereas UT7 cells with T315I-mutated BCR-ABL were totally resistant. Using this system, we have found that the inhibition of BCR-ABL by IM stimulated the DNA repair capacity of the cells and specially BER (8oxoG, alkylated bases and glycols) and NER (photoproducts and psoralen adducts) after 4 or 8 hours of treatment, as compared to baseline repair capacities ( p< 0.05). No effect was detected for the repair of Abasic sites and Cisplatin adducts. When the cells were treated with Nilotinib in the same conditions, we have observed also the stimulation of DNA repair capacities for all lesions except for the Abasic sites ( p< 0.125). The fact of treating P-UT-7 cells or UT7-T315I cells with IM or Nilotinib had no effect and led conversely, to the inhibition of DNA repair activity via Abasic and Cisplat adducts pathways (p< 0.05) or Pso (p < 0.125). To confirm directly the effect of the BCR-ABL activity in the repair modifications observed, we have used UT7 cell lines expressing N-BCR-ABL or T315I-mutated BCR-ABL under the control of a Doxycycline-inducible promoter. In this TET-OFF system, BCR-ABL expression is inhibited upon Doxycycline addition to the culture and BCR-ABL protein becomes undetectable by Western blots at day 8. In this system, the analysis of DNA repair capacity demonstrated a statistically significant stimulation of repair of Alkylated bases, Glycols, Psoralen adducts and photoproducts ( p < 0.05) upon inhibition of N-BCR-ABL or that of T315I-mutated BCR-ABL. Interestingly, the fact of reducing BCR-ABL T315I in the DOX-inducible system stimulated DNA repair capacity whereas in the non-inducible UT7 cells expressing T315I, IM did not have a stimulatory effect, whereas Nilotinib induced a slight stimulation of both NER and BER pathways after 8 hours of treatment. Overall, these results demonstrate that the novel microarrays that we describe can be efficiently detect the DNA repair ability of the leukemic cells and the reversal of these abnormalities on TKI therapies. The preliminay results suggest clearly a differential effect of IM as compared to Nilotinib in terms of the stimulation of DNA repair capacity. This new methodology can now be used to quantify the abnormality of the DNA repair pathways in CML cells at diagnosis, allowing the monitoring of the tyrosine kinase inhibitor therapies and potentially predicting the occurrence of ABL-kinase mutations according to the preferential involvement of NER or BER pathways. Disclosures Turhan: Bristol Myers Squibb, Novartis: Honoraria, Research Funding. Sauvaigo:LXRepair: Employment, Equity Ownership.
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ZYCHMA, MARCIN J., JANUSZ GUMPRECHT, EWA ZUKOWSKA-SZCZECHOWSKA, and WLADYSLAW GRZESZCZAK. "Polymorphisms in the Genes Encoding for Human Kinin Receptors and the Risk of End-Stage Renal Failure." Journal of the American Society of Nephrology 10, no. 10 (October 1999): 2120–24. http://dx.doi.org/10.1681/asn.v10102120.
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Abstract. There is evidence that environmental factors and genetic predisposition affect the development of end-stage renal disease (ESRD). The role of kinin peptides in renal pathology has been also suggested, and a nephroprotective effect of kinins, mediated by B1and B2kinin receptors, has been postulated. Recently, two novel sequence differences in the B1R gene were identified, and the C allele of the G→C substitution at position -699 in the promoter region of the B1R gene was found to be less frequent among patients with ESRD compared with healthy control subjects. In this study, the association between B1R and B2R polymorphisms and ESRD was examined using a family-based study design: transmission/disequilibrium test. B1R gene G→C substitution at position -699 in the promoter region and B2R gene C→T transition at position 181 in exon 2 were genotyped in 247 family trios: offspring affected with ESRD and both parents. The less common alleles of both polymorphisms (B1R C allele and B2R T allele) were transmitted from heterozygous parents to offspring affected with ESRD less frequently than expected (37 and 36%, respectively;P< 0.05). In conclusion, results obtained in this study support a hypothesis of the protective role of bradykinin receptor gene polymorphisms in the development of ESRD.
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Morozova, Sofia M., Elena I. Lozinskaya, Haritz Sardon, Fabian Suárez-García, Petr S. Vlasov, Régis Vaudemont, Yakov S. Vygodskii, and Alexander S. Shaplov. "Ionic Polyureas—A Novel Subclass of Poly(Ionic Liquid)s for CO2 Capture." Membranes 10, no. 9 (September 18, 2020): 240. http://dx.doi.org/10.3390/membranes10090240.
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The growing concern for climate change and global warming has given rise to investigations in various research fields, including one particular area dedicated to the creation of solid sorbents for efficient CO2 capture. In this work, a new family of poly(ionic liquid)s (PILs) comprising cationic polyureas (PURs) with tetrafluoroborate (BF4) anions has been synthesized. Condensation of various diisocyanates with novel ionic diamines and subsequent ion metathesis reaction resulted in high molar mass ionic PURs (Mw = 12 ÷ 173 × 103 g/mol) with high thermal stability (up to 260 °C), glass transition temperatures in the range of 153–286 °C and remarkable CO2 capture (10.5–24.8 mg/g at 0 °C and 1 bar). The CO2 sorption was found to be dependent on the nature of the cation and structure of the diisocyanate. The highest sorption was demonstrated by tetrafluoroborate PUR based on 4,4′-methylene-bis(cyclohexyl isocyanate) diisocyanate and aromatic diamine bearing quinuclidinium cation (24.8 mg/g at 0 °C and 1 bar). It is hoped that the present study will inspire novel design strategies for improving the sorption properties of PILs and the creation of novel effective CO2 sorbents.
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Fukuoka, Yoshihiro, Michelle R. Hite, and Lawrence B. Schwartz. "Functional angiotensin and bradykinin receptors are expressed on primary human mast cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 126.19. http://dx.doi.org/10.4049/jimmunol.196.supp.126.19.
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Abstract Purpose The role of mast cells (MCs) has traditionally been recognized as an effector cell for IgE-mediated allergic diseases, involving ~20% of USA citizens. However, everyone has MCs, indicating their involvement in biologic and pathobiologic conditions beyond allergy. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor (AT1R) blockers are used to treat cardiovascular disorders such as hypertension, while a bradykinin type 2 receptor (B2R) inhibitor is used to treat attacks of hereditary angioedema. We examined the expression and biological function of AT1R, B2R and B1R on primary human MCs. Methods MCs were dispersed from fresh surgical human skin obtained from CHTN, and placed into culture with SCF (100 ng/ml) for 4–8 weeks. FACS analysis, western blotting, qRT-PCR, degranulation (β-hexosaminidase release), cytokine/chemokine secretion of IL-6, IL-8 and CCL5, nitric oxide (NO) production (DAF-AM diacetate) were measured. Results FACS analysis and western blotting showed the AT1R and B2R are expressed on MCs. Angiotensin II (0.1–10 μM) and bradykinin (BK, 0.1–2 μM) stimulated MCs to release cytokines (1–4 ng/ml) which was inhibited by specific inhibitors. BK also stimulated the production of NO. Both the B2R and B1R are up-regulated by TNFα (10 ng/ml for 3 days), leading to enhanced activation of MCs by BK (1 μM) and desArg-LysBK (1 μM). Exposure of MCs to angiotensin II (2 μM), angiotensin (1–7)(10 μM) or ACEI (ramipril 1 μM) also enhanced cytokine secretion triggered by low concentration of BK (0.03–0.25 μM). Conclusion These findings suggest functional interactions of AT1R, B2R, ACE and Mas on human MCs, providing novel roles for MCs in cardiovascular, inflammatory and allergic disorders.
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Smith, C. D., M. Williams, and M. Shaikh. "Novel psychoactive substances: a novel clinical challenge." Case Reports 2013, aug20 1 (August 20, 2013): bcr2013200663. http://dx.doi.org/10.1136/bcr-2013-200663.
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Jackson, Shawn S., Petr Ilyinskii, Valérie Philippon, Linda Gritz, Alicia Gómez Yafal, Kimberly Zinnack, Kristin R. Beaudry, et al. "Role of Genes That Modulate Host Immune Responses in the Immunogenicity and Pathogenicity of Vaccinia Virus." Journal of Virology 79, no. 10 (May 15, 2005): 6554–59. http://dx.doi.org/10.1128/jvi.79.10.6554-6559.2005.
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ABSTRACT Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.
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Kiernan, M. F., S. Palia, and G. Morris. "A novel nose piercing." Case Reports 2011, oct27 1 (October 28, 2011): bcr0920114787. http://dx.doi.org/10.1136/bcr.09.2011.4787.
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Kamble, Dr Sanjay Pandit. "Sujata Parashar’s The Temple Bar Woman: A Study in Revenge Tale." Journal of Language and Linguistics in Society, no. 22 (March 1, 2022): 1–4. http://dx.doi.org/10.55529/jlls.22.1.4.
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Sujata Parashar is a blooming Indian Writer in English. She has credited more than half dozen of novels. Her fictions are labeled as bollywood in book. Her novels are like a Hindi film. Romance, thrill and suspense are the core part of novel. The Temple Bar Woman is the best example of bollywood movies. The present novel is the picture of a girl who is victim of this unjust system. She is simple woman of character but due to the social system she enters in political filed to take revenge of her enemy. She is gang raped by the Vikram Singh the son of political leader. She is a daughter of headmaster and she herself is the teacher. With her friend she encounters with Vikram Singh. He misbehaves so she insults him in the village fair. Virkam takes the revenge of his insult by raping her. The story does not end here. She was in unconscious state and she was left in brothel. The place of prostitute and red light area, here she meets the Rkshit Singh a budding business tycoon and leading politician. He is unknown about her past life. With the help of Rakshit Singh and Habiba Bi she decides to take revenge and achieves success. Tit for tat is saying proved, reaction to action take place and she becomes the role model for the next coming generation. She stands as a model of rise, revolt and raise her voice.
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Ayyappan, T., D. Bharathiraja, and T. Vetrichelvan. "Formulation development and in-vitro/ex-vivo evaluation of novel buccoadhesive films of metoprolol tartrate using 23 factorial design techniques." Bangladesh Journal of Scientific and Industrial Research 49, no. 3 (February 11, 2015): 165–72. http://dx.doi.org/10.3329/bjsir.v49i3.22130.
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The aim of present investigation was to develop an optimized buccoadhesive film of metoprolol tartrate, a BCS class I drug, to provide unidirectional sustained drug delivery to the buccal mucosa that has potential to enhance the bioavailability. The films were prepared using HPMC K4M as film former, carbopol 934 P as buccoadhesive polymer and dimethyl sulfoxide as penetration enhancer, by solvent casting technique. The films were characterized for various pharmacotechnical parameters and 23 full factorial design was employed to study the effect of independent variables. The design was validated by extra design checkpoint formulation (BF9). The response of design was employed to study the effect of independent variables. The responses of design were analyzed using Design Expert 8.0.7.1 and the analytical tools of software were used to draw pareto charts. On the basis of software analysis, formulation BF4 with desirability factor of 0.698 was selected as optimized formulation and was evaluated for independent parameters. Optimized formulation showed 12.05 hr, ex-vivo residence time, and good permeation (42.68%) through goat buccal mucosa and 82.19% drug release after 8th hour. The release kinetics of optimized formulation best fitted the higuchi model. Histopathological studies revealed no buccal mucosal damage. Hence BF4 formulation can be concluded as promising drug delivery system to enhance the permeability limited absorption of metoprolol tartrate. DOI: http://dx.doi.org/10.3329/bjsir.v49i3.22130 Bangladesh J. Sci. Ind. Res. 49(3), 165-172, 2014
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Souza, Mateus Ventura, José Claudeni Oliveira Lima, Alexandre Magno Pinto Roque, and Douglas Bressan Riffel. "A Novel Algorithm to Detect Broken Bars in Induction Motors." Machines 9, no. 11 (October 26, 2021): 250. http://dx.doi.org/10.3390/machines9110250.
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A new algorithm is proposed in order to detect and quantify partially broken bars in induction motors during start-up without load. In the qualification process, no threshold is used. It uses the principle of the harmonic generated by the broken bar in the stator current, it should vary with the slip to confirm the failure and provide more security in the diagnosis. A severity index is also proposed, based on the maximum peaks of the Teager energy operator of the Gaussian filter applied in the stator current signal. Experimental data were used to validate the algorithm, comparing rotors manufactured with one partially bar, one failed bar, and two completely failed bars, arranged in a variety of ways. The results show that the algorithm qualifies correctly the faulty bar, even for a partially broken bar. In the quantification phase, the severity index of the fault shows the higher sensibility in comparison to the state-of-the-art. Its value for a 3 HP motor is: 8.837 × 10−10 for a healthy rotor, 2.553 × 10−8 for a partially broken bar, and 4.058 × 10−7 for one broken bar.
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GU, HO-GYUNG, BYUNG-GUL MIN, JI-YOUNG LEE, SEE-HAN PARK, MIN-SEOK LEE, CHANG-YOUNG LEE, and CHUL-HWAN KIM. "Mechanical modification of softwood pulp fibers using a novel lightweight vertical bar plate." April 2021 20, no. 4 (May 1, 2021): 241–51. http://dx.doi.org/10.32964/tj20.4.241.
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Refiner plates made using sand casting have a draft angle, which results in a trapezoidal bar shape. These trapezoidal bar plates have a limited throughput compared to the vertical bar plates, and eventually the edges of the bars become dull, resulting in longer time to reach the target freeness and shorter service life. The new light-weight refiner plate with a bar insertion method into a plate base was developed by selecting an aluminium-based alloy as the plate base material and a stainless steel alloy with high wear resistance as the bar material. The light-weight plate with sharp bar edges was very effective in reducing refining energy by reaching the target freeness faster than the sand-cast bar plate. Finally, the lightweight sharp bar plate, which weighed only about half the weight of the cast bar plate, was expected to significantly contribute to easy replacement, improved paper quality, and larger throughput without excessive loss of fiber length.
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Patel, Mahesh, and Annamalai A. "A Novel Uncoded Ser/Ber Estimation Method." International Journal of Wireless & Mobile Networks 7, no. 3 (June 30, 2015): 89–96. http://dx.doi.org/10.5121/ijwmn.2015.7307.
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Pappas, C., and F. Mezei. "The novel NSE spectrometer at BER II." Journal of Neutron Research 5, no. 1 (December 1, 1996): 35–39. http://dx.doi.org/10.1080/10238169608200207.
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Chaudhuri, Debangshu, and D. D. Sarma. "BF3-doped polyaniline: A novel conducting polymer." Pramana 67, no. 1 (July 2006): 135–39. http://dx.doi.org/10.1007/s12043-006-0044-7.
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Eshed, Iris, and Kay-Geert A. Hermann. "Novel imaging modalities in spondyloarthritis." Current Opinion in Rheumatology 27, no. 4 (July 2015): 333–42. http://dx.doi.org/10.1097/bor.0000000000000186.
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Shyu, Jenq Huey, Ching Kong Chen, Cheng Chi Yu, and Yi Jhong Luo. "Research and Development of an Adjustable Elliptical Exerciser." Advanced Materials Research 308-310 (August 2011): 2078–83. http://dx.doi.org/10.4028/www.scientific.net/amr.308-310.2078.
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This paper presents a novel design of adjustable elliptical exerciser, which can adjust both stride and inclined angle. Firstly, we use a selected coupler curve of four-bar linkage to design a six-bar linkage. From the six-bar linkage, we investigate the parameters which affect the corresponding elliptical path and its inclined angle. By considering the way of adjusting the inclined angle, the final design becomes a 2-DOF seven-bar-eight-joint linkage. We use SolidWorks software to design this novel elliptical exerciser, and use CAE software to check the stresses and strains to ensure the strength of the members of this design. The prototype of this novel design of adjustable elliptical exerciser has been fabricated, and its feasibility has been confirmed.
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Fang, Lei, Huaying Fan, Chunjing Guo, Linhan Cui, Peng Zhang, Hongjie Mu, Hui Xu, Feng Zhao, and Daquan Chen. "Novel Mitochondrial Targeting Multifunctional Surface Charge-Reversal Polymeric Nanoparticles for Cancer Treatment." Journal of Biomedical Nanotechnology 15, no. 11 (November 1, 2019): 2151–63. http://dx.doi.org/10.1166/jbn.2019.2854.
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Polymeric nanoparticles were widely used as delivery vehicles for targeted delivery of anticancer drugs, because of their targeting property and versatility. Mitochondria are one of the important organelles that regulate the apoptosis of cancer cells and can be considered as a pivotal target for cancer treatment. A pH-responsive charge-reversal and mitochondrial targeting nanoparticles, Vitamin B6-oligomeric hyaluronic acid-dithiodipropionic acid-berberine (B6-oHA-SS-Ber), were prepared in this study. Ber is a lipophilic cation that was conjugated with oHA through disulfide bonds to produce mitochondria-targeted conjugates (oHA-SS-Ber). B6 was conjugated to oHA to obtain B6-oHA-SS-Ber and the two types of Cur-loaded nanoparticles (Cur-NPs) were formulated by the dialysis method. Due to pKa of B6, the charge they carried in the tumor tissue acidic microenvironment can be transferred from negative charge to positive charge, further targeting mitochondria. In our study, we successfully synthesized B6-HA-SS-Ber and characterized the structure by 1H-NMR. According to the results of transmission electron microscopy (TEM), we found that the B6-oHA-SS-Ber/Cur micelles could self-assembled in water to form spherical nanoparticles, with a hydrodynamic diameter of 172.9±13 nm. Moreover, in vitro cytotoxicity, cellular uptake, lysosome escape and mitochondrial distribution researches revealed the better effect of B6-oHA-SS-Ber/Cur micelles in comparison to oHA-SS-Ber/Cur. In vivo anticancer activities indicated that the B6-oHA-SS-Ber/Cur micelles exhibited effective inhibition of tumor growth.
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Chang, Shinn Liang, Dai Jia Juan, and You Huang Syu. "Trajectories Generated by a Novel Cam Driven Five-Bar Mechanism." Applied Mechanics and Materials 799-800 (October 2015): 685–92. http://dx.doi.org/10.4028/www.scientific.net/amm.799-800.685.
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In industry, the special kind of trajectory is often designed to fit the desired motion required. In literature, four-bar mechanism is popularly applied and well studied in the trajectory generation. Different types of trajectories are generated by the choose of the ratio of links. The five-bar mechanism is another popular one to generate the desired trajectory and it is more flexible due to it has two degrees of freedom. The geared five-bar mechanism is then commonly used by reducing the degree of freedom of the mechanism into one by implied one pair of gear. In this study, the trajectories generated by a novel cam driven five-bar mechanism proposed by the authors are investigated. It could supply more choices in the application of trajectory generation.
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Maeda, Shintaro, Ken Morita, Kensho Suzuki, Hiroshi Sugiyama, Souichi Adachi, and Yasuhiko Kamikubo. "Targeting Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia with a Novel Transcriptional Inhibitor." Blood 128, no. 22 (December 2, 2016): 2737. http://dx.doi.org/10.1182/blood.v128.22.2737.2737.
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Abstract Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) is caused by reciprocal translocation between chromosome 9 (region q34) and chromosome 22 (region q11). This translocation results in oncogenic BCR-ABL fusion gene that encodes a chimeric BCR-ABL protein, continuously activated tyrosine kinase which causes unregulated cell division and leukemia. Although tyrosine kinase inhibitors (TKIs) are the most useful treatment against Ph+ALL patients, a part of them steadily become refractory to current therapy mainly through acquired mutations in ATP binding sites of BCR-ABL, necessitating a novel strategy to treat TKI resistant Ph+ALL. Here we show that our novel small molecule which targets specific transcriptional factor induces Ph+ALL cell death through directly controlling the expression of BCR-ABL gene. We have previously reported the fundamental requirement of transcription factor A (TFA) in the development of acute myeloid leukemia (AML), another form of acute leukemia originating from myeloid progenitor cells. Since previous reports suggest the involvement of TFA family genes in the development of lymphoid cells also, we first addressed the role of TFA in Ph+ALL cells using tetracycline-responsive short hairpin RNA (shRNA)-mediated gene knockdown system. Upon doxycycline treatment, shRNAs targeting TFA (sh_TFA)-transduced SU-Ph2 (Ph+ALL) and SU/SR (SU-Ph2 with BCR-ABL T315I mutation, therefore resistant to Imatinib) cells showed decreased proliferation rate with cell cycle arrest at G0/G1 phase and profound apoptosis. Intriguingly, TFA knockdown suppressed the expression of BCR-ABL fusion gene both at mRNA and protein levels. Concomitant down-regulation of BCR-ABL cytoplasmic gene targets such as mTOR-AKT, STAT and MEK-ERK pathways were also observed in sh_TFA-transduced ALL cells. These results indicate the possible interaction between BCR-ABL and TFA. Since expression of BCR-ABL fusion gene is tightly regulated by gene promoter of BCR andthere exists a TFA-consensus binding site in the proximal promoter region of BCR, we next addressed the TFA-mediated transcriptional regulation of BCR-ABL. In silico data analysis of gene expression array sets extracted from ALL patients revealed the positive correlation of BCR and TFA expressions. Analysis of chromatin immunoprecipitation and sequencing (ChIP-Seq) in mouse ES cells disclosed the potential TFA binding in the proximal regulatory region of BCR, which we have confirmed by ChIP assay in SU/SR cells. These findings suggest that TFA positively and directly controls BCR-ABLexpression through BCR promoter binding in ALL cells. We next sought to explore the effect of TFA inhibition in ALL cells in vivo. Immunodeficient NOG mice transplanted with SU/SR cells that are transduced with sh_TFA or control vector were followed for overall survival and chimerism of ALL cells in the peripheral blood. As expected, TFA inhibition decelerated the dissemination of leukemia and prolonged overall survival period in these mice. We next challenged this ALL-xenografted mice with newly synthesized small compound which irreversibly attenuates the function of TFA as a transcription factor. Existence of T315I mutation in BCR-ABL gene in SU/SR cells naturally provides TKI-therapy resistance to these mice, and oral Imatinib treatment at 100 mg/kg body weight did not prolonged their survivals actually. In contrast, our novel compound was highly effective in these mice at 375 microgram/kg body weight and significantly prolonged the overall survival period without serious side effects, overcoming TKIs resistance. These findings collectively underscore the importance of TFA in the maintenance of ALL cells with resistance to TKIs and is a druggable target in the leukemia therapy. Disclosures No relevant conflicts of interest to declare.
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Thillainathan, Mathura, and George C. J. Fernandez. "A Novel Approach to Plant Genotypic Classification in Multi-site Evaluation." HortScience 37, no. 5 (August 2002): 793–98. http://dx.doi.org/10.21273/hortsci.37.5.793.
Full textAbstract:
A user-friendly SAS statistical and graphical application to classify genotypes evaluated under multiple sites is presented. First, the test sites are classified into three environments, LOW [(\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}j}\) \end{document}) < Q1], MEDIUM [Q1< = (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}j}\) \end{document})< = Q3], and HIGH [(\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}j}\) \end{document}) >Q3] yielding environments, using the first (Q1) and third (Q3) quartile of the site mean yield (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}j}\) \end{document}) as the cutoff value. Then, in each environment, the genotypes are classified as low [L: (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{i{\cdot}}\) \end{document}) < (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}{\cdot}}\) \end{document})], medium [M: (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{i{\cdot}}\) \end{document}) = (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}{\cdot}}\) \end{document})], and high [H: (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{i{\cdot}}\) \end{document}) > (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}{\cdot}}\) \end{document})] yielding under each of the three environments, by comparing each genotype mean (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{i{\cdot}}\) \end{document}) with the overall genotypic mean (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\bar{Y}}_{{\cdot}{\cdot}}\) \end{document}) based on lsd0.01 statistic computed from a separate two-way ANOVA models for LOW, MED, and HIGH yielding environments. Using the user-friendly SAS MACRO, EXPLORGE horticulturists can effectively and quickly perform genotype classification under multi-site evaluation. The steps involved in downloading the necessary MACRO-CALL file from the author's home page [http://www.ag.unr.edu/gf] and the instructions for running the SAS MACRO are presented. The features of this graphical method and the graphics produced by the EXPLORGE MACRO are demonstrated and validated by published data.