Drug resistance to BCR-ABL1 tyrosine kinase inhibitor (TKI) and disease progression to blast crisis (BC) are major clinical problems in chronic myeloid leukemia (CML); however, underlying mechanisms ...governing this process remain to be elucidated. Here, we report Cordon-bleu protein-like 1 (Cobll1) as a distinct molecular marker associated with drug resistance as well as progression to BC. In detail, Cobll1 increases IKKγ stability, leading to NF-κB activation and reduction of nilotinib-dependent apoptosis, suggesting Cobll1-mediated NF-κB could be involved in drug resistance. Recently, NF-κB signalling has been highlighted as a core mechanism for chronic phase (CP)-BC progression, stem cell survival and tyrosine kinase inhibitor resistance. We also demonstrated that high expression of Cobll1 confers drug resistance to tyrosine kinase inhibitors in CML cell line as well as patient samples. The analysis of large sets of primary CML samples (n=90) shows that Cobll1 expression is dramatically increased in BC but not in CP, which is correlated with a poor survival rate (P=0.002). Moreover, our studies show that Cobll1 is highly expressed in CD34
primitive stem cell populations, and the zebrafish paralog Cobll1b is important for normal hematopoiesis during embryonic development. Based on these results, we propose that Cobll1 is a novel biomarker and potential therapeutic target for CML-BC.
We observed two types of reversible resistance switching (RS) effects in a NiO film: memory RS at low temperature and threshold RS at high temperature. We were able to control the type of RS effects ...by thermal cycling. These phenomena were explained using a new dynamic percolation model that can describe the rupture and formation of conducting filaments. We showed that the RS effects are governed by the thermal stability of the filaments, which arise from competition between Joule heating and thermal dissipation. This work provides us understandings on basic mechanism of the RS effects and their interrelation.
Quantum computing hardware technologies have advanced during the past two decades, with the goal of building systems that can solve problems that are intractable on classical computers. The ability ...to realize large-scale systems depends on major advances in materials science, materials engineering, and new fabrication techniques. We identify key materials challenges that currently limit progress in five quantum computing hardware platforms, propose how to tackle these problems, and discuss some new areas for exploration. Addressing these materials challenges will require scientists and engineers to work together to create new, interdisciplinary approaches beyond the current boundaries of the quantum computing field.
Artificial Muscles from Fishing Line and Sewing Thread Haines, Carter S.; Lima, Márcio D.; Li, Na ...
Science (American Association for the Advancement of Science),
02/2014, Letnik:
343, Številka:
6173
Journal Article
Recenzirano
The high cost of powerful, large-stroke, high-stress artificial muscles has combined with performance limitations such as low cycle life, hysteresis, and low efficiency to restrict applications. We ...demonstrated that inexpensive high-strength polymer fibers used for fishing line and sewing thread can be easily transformed by twist insertion to provide fast, scalable, nonhysteretic, long-life tensile and torsional muscles. Extreme twisting produces coiled muscles that can contract by 49%, lift loads over 100 times heavier than can human muscle of the same length and weight, and generate 5.3 kilowatts of mechanical work per kilogram of muscle weight, similar to that produced by a jet engine. Woven textiles that change porosity in response to temperature and actuating window shutters that could help conserve energy were also demonstrated. Large-stroke tensile actuation was theoretically and experimentally shown to result from torsional actuation.
Summary
To review the effect of teriparatide as an adjunctive modality for bisphosphonate-related osteonecrosis of the jaws (BRONJ), we describe a series of cases of teriparatide therapy for the ...treatment of BRONJ and serial changes of serum osteoclacin (s-OC) and serum C-terminal telopeptide cross-link of type I collagen (s-CTX).
Introduction
Management of BRONJ is quite challenging and the currently recommended modalities for BRONJ are still suboptimal. For the improvement of bony remodeling, some clinicians advocated bisphosphonate holiday although validity of this drug holiday has been debated so far. Recently, the use of teriparatide was introduced in several cases, but the number of the publication is limited and mostly anecdotal so far.
Method
Bisphosphonate was suspended and teriparatide was given to six patients diagnosed with BRONJ by single bone specialist. Medical record review and interviews were carried out. S-CTX and s-OC were measured at the baseline, 2 months and 3 months later teriparatide therapy. The outcome of the treatment and the change of biochemical markers were compared.
Result
In all six patients, s-OC values were significantly elevated within 2 months after teriparatide treatment and the BRONJ lesions were healed. S-CTX values were also elevated in four patients, whereas those of the rest two patients stayed within minimal change. The change was marginally significant at 3 months.
Conclusion
In terms of the multifactorial etiology of BRONJ, bone formation suppression was noticed in the patients. Based upon this finding, the short-term use of teriparatide might be beneficial to the resolution of BRONJ lesions by improving suppressed bone remodeling.
BACKGROUND AND PURPOSEData on adjunctive intra-arterial thrombolysis during mechanical thrombectomy for refractory thrombus are sparse. The aim of this study was to evaluate the efficacy and safety ...of local intra-arterial urokinase as an adjunct to mechanical thrombectomy for refractory large-vessel occlusion. MATERIALS AND METHODSWe retrospectively evaluated patients with acute ischemic stroke who underwent mechanical thrombectomy for anterior circulation large-vessel occlusion between January 2016 and December 2019. Patients were divided into 2 groups based on the use of intra-arterial urokinase as an adjunctive therapy during mechanical thrombectomy for refractory thrombus: the urokinase and nonurokinase groups. Herein, refractory thrombus was defined as the target occlusion with minimal reperfusion (TICI 0 or 1) despite >3 attempts with conventional mechanical thrombectomy. The baseline characteristics, procedural outcomes, and clinical outcome were compared between the 2 groups. RESULTSOne hundred fourteen cases of refractory thrombus were identified. A total of 45 and 69 patients were in the urokinase and the nonurokinase groups, respectively. The urokinase group compared with the nonurokinase group showed a higher rate of successful reperfusion (82.2% versus 63.8%, P = .034), with lower procedural times (54 versus 69 minutes, P = .137). The rates of good clinical outcome, distal embolism, and symptomatic intracranial hemorrhage were similar between the 2 groups. The use of intra-arterial urokinase (OR = 3.682; 95% CI, 1.156-11.730; P = .027) was an independent predictor of successful reperfusion. CONCLUSIONSThe use of local intra-arterial urokinase as an adjunct to mechanical thrombectomy may be an effective and safe method that provides better recanalization than the conventional mechanical thrombectomy for refractory thrombus in patients with embolic large-vessel occlusion.
To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to ...rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury.
Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer.
At the highest dose level, 6.6% of patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm(3) (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010).
Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.
Torsional Carbon Nanotube Artificial Muscles Foroughi, Javad; Spinks, Geoffrey M.; Wallace, Gordon G. ...
Science (American Association for the Advancement of Science),
10/2011, Letnik:
334, Številka:
6055
Journal Article
Recenzirano
Rotary motors of conventional design can be rather complex and are therefore difficult to miniaturize; previous carbon nanotube artificial muscles provide contraction and bending, but not rotation. ...We show that an electrolyte-filled twist-spun carbon nanotube yarn, much thinner than a human hair, functions as a torsional artificial muscle in a simple three-electrode electrochemical system, providing a reversible 15,000° rotation and 590 revolutions per minute. A hydrostatic actuation mechanism, as seen in muscular hydrostats in nature, explains the simultaneous occurrence of lengthwise contraction and torsional rotation during the yarn volume increase caused by electrochemical double-layer charge injection. The use of a torsional yarn muscle as a mixer for a fluidic chip is demonstrated.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is a type II transmembrane cytokine molecule. Soluble TRAIL has been shown to induce apoptosis in a ...wide variety of cancer cells in vitro and to suppress tumor growth specifically without damaging normal cells and tissues in vivo. In our previous report, we have demonstrated that an artificial gene encoding the polypeptide composed of the three functional elements (a secretion signal, a trimerization domain and an apoptosis-inducing moiety of TRAIL gene sequence) expresses and secretes highly apoptotic trimeric TRAIL into the culture supernatant. Here, as an approach to TRAIL-based cancer gene therapy, we developed an adenoviral vector delivering the gene that encodes our secretable trimeric TRAIL (stTRAIL). This adenovirus (Ad-stTRAIL) potently induced apoptosis in vitro in cancer cell lines such as HeLa, MDA-MB-231, A549, HCT116 and U-87MG. In an animal xenograft tumor model bearing a human glioma cell line U-87MG, intratumoral delivery of Ad-stTRAIL dramatically suppressed tumor growth without showing detectable adverse side effects. Histological analysis revealed that Ad-stTRAIL suppresses tumor growth by inducing apoptotic cell death. Contrary to the known rapid clearance of systemically delivered TRAIL protein from the blood circulation, stTRAIL expressed by Ad-stTRAIL in tumor tissues persisted for more than 4 days. In a comparison of tumor suppressor activity between Ad-stTRAIL and Ad-flTRAIL (delivering the full-length TRAIL gene) after mixing infected cells with uninfected cells and implanting these mixed cells in nude mice, Ad-stTRAIL showed higher tumor suppressor activity than that of Ad-flTRAIL. Our data reveal that a gene therapy using Ad-stTRAIL has a promising potential to treat human cancers including gliomas.
DNA strand displacement is a key reaction in DNA homologous recombination and DNA mismatch repair and is also heavily utilized in DNA-based computation and locomotion. Despite its ubiquity in science ...and engineering, sequence-dependent effects of displacement kinetics have not been extensively characterized. Here, we measured toehold-mediated strand displacement kinetics using single-molecule fluorescence in the presence of a single basepair mismatch. The apparent displacement rate varied significantly when the mismatch was introduced in the invading DNA strand. The rate generally decreased as the mismatch in the invader was encountered earlier in displacement. Our data indicate that a single base pair mismatch in the invader stalls branch migration and displacement occurs via direct dissociation of the destabilized incumbent strand from the substrate strand. We combined both branch migration and direct dissociation into a model, which we term the concurrent displacement model, and used the first passage time approach to quantitatively explain the salient features of the observed relationship. We also introduce the concept of splitting probabilities to justify that the concurrent model can be simplified into a three-step sequential model in the presence of an invader mismatch. We expect our model to become a powerful tool to design DNA-based reaction schemes with broad functionality.
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