Objectives
Adenoid cystic carcinoma (ACC) is one of the most common salivary gland cancers. The prognosis of adenoid cystic carcinoma is poor for its high frequency of distant metastases and ...insensitivity to chemotherapy or molecular therapies. This study investigated the effect of Obatoclax on adenoid cystic carcinoma cells and its cytotoxic mechanism.
Methods
Western blot, transmission electron microscopy, and pEGFP‐LC3 plasmids transfection were carried out to detect autophagy in ACC cells treated with Obatoclax. 3‐MA and RNA interference against Beclin 1 and ATG5 were used to inhibit autophagy. Then we used Western blot and Hochest 33342 staining for apoptosis assessment. Finally, cell viability was assessed by MTT assay.
Results
We found that Obatoclax induced cytoprotective autophagy which depended on ATG5 and partly on Beclin 1 in adenoid cystic carcinoma cells. Furthermore, pharmacologically inhibiting Obatoclax‐induced autophagy promoted apoptosis. Downregulation of Beclin 1 or ATG5 attenuated the cytotoxicity of Obatoclax by suppressing both autophagy and apoptosis. Finally, when apoptosis was pharmacologically inhibited, autophagic cell death was initiated in adenoid cystic carcinoma cells treated with Obatoclax.
Conclusion
In summary, Beclin 1 and ATG5 play important roles in regulating both Obatoclax‐induced autophagy and apoptosis in adenoid cystic carcinoma.
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CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
This study compares efficacy of ALN/D5600 versus that of calcitriol in osteoporotic Chinese postmenopausal women. ALN/D5600 produced greater bone mineral density (BMD) increases, greater bone ...turnover marker decreases, and less vitamin D insufficiency. This study provided detailed clinical information regarding ALN/D5600 treatment versus calcitriol 0.25 μg/day. The study did not evaluate fracture risk.
Introduction
The aim of this study is to investigate efficacy of alendronate 70 mg/vitamin D
3
5600 IU combination tablets (ALN/D5600) versus calcitriol in osteoporotic Chinese postmenopausal women.
Methods
This study is a 6-month, randomized, open-label, active-comparator study with 6-month extension (clinicaltrials.gov number NCT01350934) in postmenopausal women aged >55 years with osteoporosis (low bone mineral density (BMD) with/without prior fragility fracture). Patients were randomized to ALN/D5600 once weekly or calcitriol 0.25 μg daily. The primary efficacy end point of the base study was percent change from baseline in lumbar spine BMD (month 6). Hypercalcemia and hypercalciuria were safety events of special interest.
Results
A total of 219 patients (ALN/D5600
n
= 111, calcitriol
n
= 108) were randomized. Baseline characteristics were similar, 30.3 % baseline 25-hydroxyvitamin D (25(OH)D) ≤15 ng/mL. At months 6 and 12, changes in lumbar spine BMD from baseline were 3.5 versus 1.6 % and 5.2 versus 2.3 % for ALN/D5600 versus calcitriol (between-group differences
p
< 0.001), respectively. Between-group differences for ALN/D5600 versus calcitriol were significant (
p
< 0.001) at months 6 and 12 for change from baseline in procollagen type 1 N-terminal propeptide (−59.1 versus −16.8 %, −68.1 versus −17.0 %) and serum C-telopeptides (−79.2 versus −27.2 %, −76.2 versus −24.2 %). Drug-related adverse events (AEs) and discontinuations due to drug-related AEs occurred in 15 (14.0 %) versus 8 (7.4 %) patients and 3 (2.8 %) versus 0 patients in the ALN/D5600 and calcitriol group, respectively. Hypercalciuria 12-month incidence (24-h urine Ca >300 mg) was 8.4 (ALN/D5600) versus 13.9 % (calcitriol) (
p
> 0.05). One patient (calcitriol) had hypercalcemia.
Conclusions
ALN/D5600 produced greater increases in lumbar spine BMD and greater decreases in bone turnover markers versus calcitriol in osteoporotic Chinese women. It is not known whether the greater increase in BMD results in fewer fractures. ALN/D5600 was generally well tolerated in Chinese patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Converging lines of evidence implicate the beta‐amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting ...γ‐secretase, the activity responsible for the carboxy‐terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N‐N‐(3,5‐difluorophenacetyl)‐l‐alanyl‐S‐phenylglycine t‐butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose‐dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ‐secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To investigate the expression and diagnostic values of CD200 and insulinoma associated protein 1 (INSM1) in gastrointestinal and pancreatic neuroendocrine neoplasm (GIP-NEN).
The expression of CD200, ...INSM1, Syn and CgA was detected in 69 cases of GIP-NEN, 66 cases of gastrointestinal and pancreatic non-neuroendocrine neoplasm (GIP-nonNEN) and 16 cases of metastatic neuroendocrine neoplasm by immunohistochemistry, to compare the values of CD200, INSM1, Syn, CgA and their combinations in diagnosing GIP-NEN. Receiver operating characteristics (ROC) curve was used.
The immunoreactivity of CD200 was present in the cytoplasma and/or membrane of the neoplasms cells, the positive expression rates in GIP-NEN and GIP-nonNEN were significantly different (
<0.01). The sensitivity and specificity of CD200 for diagnosing GIP-NEN were 95.7% and 78.8%, respectively. There was significant difference of the positive rates of CD200 between neuroendocrine tumor and neuroendocrine carcinoma (
=0.05). The immunoreactivity of INSM1
The dynamic response and failure characteristics of reinforced concrete beams under explosion loads are affected by various factors. To study the effect of reinforcement strength on the deformation ...properties of RC beams and to analyze the deformation differences of high-strength RC beams under different explosion loads, comparative explosion tests on two kinds of simply supported RC beams with longitudinal reinforcement yield strength of 400 MPa and 700 MPa were carried out respectively in this paper. The test results show that the deformation of the mid-span section concrete of the high-strength RC beam is basically the same as that of the ordinary RC beam when the peak overpressure value is small, and the strength advantage of the high-strength reinforcement has not been fully exerted. With the increase of explosion load, the maximum tensile strain and compressive strain of concrete at the mid-span section of high-strength RC beams are 46.6% and 43.5% of ordinary RC beams respectively. Under the action of high overpressure explosion load, the deformation of RC beams can be significantly reduced by high-strength reinforcement, which limits the development of cracks.
In this paper, the creep behavior of a Fe-based bulk metallic glass (BMG) was studied by using the nanoindentation testing. According to the microstructural evolution in BMGs, the generalized Kelvin ...model was employed to describe the creep behavior of this BMG, and a method of separating the viscoelastic and viscoplastic deformation from the indentation creep was proposed. The creep behaviors at various loading rates were systematically analyzed. The obtained results indicated that the viscoelastic or viscoplastic characteristics of Fe-based BMG exhibited a strong dependency on the loading rate. Moreover, the volume of shear transformation zone (STZ) during the creep of Fe-based BMG has also been calculated to further explore its creep mechanism.
Nanotechnology, as a new enabling technology, has the potential to revolutionize food systems. However, much attention has been focused on nanoparticle foods due to their potential physiological ...properties. This study was aimed to evaluate the mutagenic safety and fatty liver improvement of black soybean in senescence-accelerated mice (SAMP8). The mutagenic activity of black soybeans was investigated using the Ames test (Salmonella Typhimurium TA98, 100, 102, and 1535). Furthermore, senescence-accelerated prone-8 mice (SAMP8) have been reported to display spontaneous fatty liver. Male SAMP8 mice were divided into control and supplemented with 10% micronized or nanonized black soybeans diet and fed for 12 wk. The results revealed that the Ames test of micronized and nanonized black soybeans exhibited no mutagenicity. Administration of black soybeans to mice showed no effects on food intake and body and organ weights. The nanonized black soybean group had a lower degree of spontaneous fatty liver, alanine aminotransferase, and thiobarbituric acid-reactive substance concentrations, and had enhanced superoxide dismutase, catalase, and glutathione peroxidase activities of livers when compared with the SAMP8 control and micronized black soybean groups. The mice fed with black soybeans had significantly lower triglyceride concentrations than the SAMP8 control group. The results of this study suggest that nanonized black soybeans have no side effects and, moreover, may minimize liver lesions in SAMP8 mice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
BackgroundDurable efficacy of immune checkpoint blockade (ICB) occurred in a small number of patients with metastatic gastric cancer (mGC) and the determinant biomarker of response to ICB remains ...unclear.MethodsWe developed an open-source TMEscore R package, to quantify the tumor microenvironment (TME) to aid in addressing this dilemma. Two advanced gastric cancer cohorts (RNAseq, N=45 and NanoString, N=48) and other advanced cancer (N=534) treated with ICB were leveraged to investigate the predictive value of TMEscore. Simultaneously, multi-omics data from The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) and Asian Cancer Research Group (ACRG) were interrogated for underlying mechanisms.ResultsThe predictive capacity of TMEscore was corroborated in patient with mGC cohorts treated with pembrolizumab in a prospective phase 2 clinical trial (NCT02589496, N=45, area under the curve (AUC)=0.891). Notably, TMEscore, which has a larger AUC than programmed death-ligand 1 combined positive score, tumor mutation burden, microsatellite instability, and Epstein-Barr virus, was also validated in the multicenter advanced gastric cancer cohort using NanoString technology (N=48, AUC=0.877). Exploration of the intrinsic mechanisms of TMEscore with TCGA and ACRG multi-omics data identified TME pertinent mechanisms including mutations, metabolism pathways, and epigenetic features.ConclusionsCurrent study highlighted the promising predictive value of TMEscore for patients with mGC. Exploration of TME in multi-omics gastric cancer data may provide the impetus for precision immunotherapy.
Aims
The characteristics and response to ablation therapy of focal atrial tachycardia (AT) originating from the distal portion of left atrial appendage (LAAd) are still not quite clear up to now. The ...goal of this study is to characterize electrocardiographic and electrophysiological features and radiofrequency ablation (RFA) outcomes in patients with focal AT originating from the LAAd.
Methods and results
Fourteen patients (2.1%) (mean age, 25 ± 10 years; nine women; mean symptom duration, 5 ± 5 years) undergoing RFA of focal AT originating from the LAAd were included out of 668 RFA patients. Activation mapping was performed. P waves were classified as negative, positive, isoelectric, or biphasic. Tachycardia that was incessant in all, demonstrated a characteristic P-wave morphology and endocardial activation pattern: P wave was negative in leads I and aVL, highly positive in the inferior leads, and broad and positive in lead V1. Radiofrequency ablation was acutely successful in 13 of 14 patients. The endocardial activation time of the successful RFA sites was 47.1 ± 4.3 ms before the onset of P wave. There were no complications in any of the 14 patients and long-term success was achieved in 13 of 13 successful RFA patients during follow-up (5 ± 2 years).
Conclusion
The LAAd is an uncommon site of origin for focal AT (2.1% incidence). In this case series, focal ATs originating from the LAAd had typical electrophysiological and electrocardiographic characteristics. Focal ablation yielded high acute success rate with low rate of recurrence during follow-up.
Rosenbrock methods are popular for solving a stiff initial-value problem of ordinary differential equations. One advantage is that there is no need to solve a nonlinear equation at every iteration, ...as compared with other implicit methods such as backward difference formulas or implicit Runge–Kutta methods. In this article, we introduce a trust-region technique to select the time steps of a second-order Rosenbrock method for a special initial-value problem, namely, a gradient system obtained from an unconstrained optimization problem. The technique is different from the local error approach. Both local and global convergence properties of the new method for solving an equilibrium point of the gradient system are addressed. Finally, some promising numerical results are also presented.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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