Genexol-PM is a novel Cremophor EL (CrEL)-free polymeric micelle formulation of paclitaxel (Taxol). This multicenter phase II study was designed to evaluate the efficacy and safety of the combination ...of Genexol-PM and cisplatin for the treatment of advanced non-small-cell lung cancer (NSCLC).
Patients with advanced NSCLC received Genexol-PM 230 mg/m2 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle as first-line therapy. Intrapatient dose escalation of Genexol-PM to 300 mg/m2 was carried out from the second cycle if the prespecified toxic effects were not observed after the first cycle.
Sixty-nine patients were enrolled in this study. Overall response rate was 37.7%. The median time to progression was 5.8 months and the median survival period was 21.7 months. The major non-hematologic toxic effects included grade 3 peripheral sensory neuropathy (13.0%) and grade 3/4 arthralgia (7.3%). Four patients (5.8%) experienced grade 3/4 hypersensitivity reactions. The major hematological toxic effects were grade 3/4 neutropenia (29.0% and 17.4%, respectively).
Genexol-PM plus cisplatin combination chemotherapy showed significant antitumor activity. The use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel compared with the CrEL-based formulation without significant increased toxicity.
Objective:MicroRNAs (miRNAs) have been shown to offer great potential in the diagnosis of cancer. We investigated whether plasma miRNAs could discriminate between patients with and without colorectal ...cancer (CRC).Methods:This study was divided into three phases: (1) marker discovery using real-time PCR-based miRNA profiling on plasma, corresponding cancerous and adjacent non-cancerous colonic tissues of five patients with CRC, along with plasma from five healthy individuals as controls; (2) marker selection and validation by real-time quantitative RT-PCR on a small set of plasma; and (3) independent validation on a large set of plasma from 90 patients with CRC, 20 patients with gastric cancer, 20 patients with inflammatory bowel disease (IBD) and 50 healthy controls.Results:Of the panel of 95 miRNAs analysed, five were upregulated both in plasma and tissue samples. All the five miRNAs were validated on the plasma of 25 patients with CRC and 20 healthy controls. Both miR-17-3p and miR-92 were significantly elevated in the patients with CRC (p<0.0005). The plasma levels of these markers were significantly reduced after surgery in 10 patients with CRC (p<0.05). Further validation with an independent set of plasma samples (n = 180) indicated that miR-92 differentiates CRC from gastric cancer, IBD and normal subjects. This marker yielded a receiver operating characteristic curve area of 88.5%. At a cut-off of 240 (relative expression in comparison to RNU6B snRNA), the sensitivity was 89% and the specificity was 70% in discriminating CRC from control subjects.Conclusion:MiR-92 is significantly elevated in plasma of patients with CRC and can be a potential non-invasive molecular marker for CRC screening.
Background
Since the recent establishment of a murine model of eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), both the development of new drugs for treatment or prevention of ...eosinophilic CRSwNP and elucidation of their pathogenesis have been feasible. We investigated the therapeutic effects of resveratrol on CRSwNP and its mechanism of action using a murine model.
Methods
After induction of eosinophilic CRSwNP, the therapeutic effects of resveratrol were tested and compared with those of triamcinolone acetonide. Histopathologic changes were evaluated using hematoxylin and eosin for overall inflammation, Sirius red for eosinophils, and Masson's trichrome stain for collagen. The expression levels of the interleukin (IL)‐4, IL‐5, prostaglandin D synthase, and leukotriene C4 synthase genes were assessed by quantitative real‐time PCR. Cyclooxygense‐2 and 5‐lipoxygense levels were evaluated by immunohistochemical staining and Western blot analysis.
Results
The degree of eosinophilic infiltration and subepithelial fibrosis was significantly decreased by administration of high‐dose resveratrol, the potency of which was similar to that of triamcinolone acetonide. The expression levels of the IL‐4, IL‐5, prostaglandin D synthase, and leukotriene C4 synthase genes were significantly decreased by administration of low‐ or high‐dose resveratrol. The production of 5‐lipoxygenase was strongly inhibited by high‐dose resveratrol.
Conclusions
Resveratrol may be useful for the prevention of eosinophilic CRSwNP. A key mechanism of its action is believed to be its anti‐inflammatory effect, particularly on eosinophils, by inhibiting the lipoxygenase pathway.
We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with ...Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.
Gene fusion is involved in the development of various types of malignancies. Recent advances in sequencing technology have facilitated identification of gene fusions and have stimulated the research ...of this field in cancer. In the present study, we performed next-generation transcriptome sequencing in order to discover novel gene fusions in gastric cancer. A total of 282 fusion transcript candidates were detected from 12 gastric cancer cell lines by bioinformatic filtering. Among the candidates, we have validated 19 fusion transcripts, which are 7 inter-chromosomal and 12 intra-chromosomal fusions. A novel DUS4L-BCAP29 fusion transcript was found in 2 out of 12 cell lines and 10 out of 13 gastric cancer tissues. Knockdown of DUS4L-BCAP29 transcript using siRNA inhibited cell proliferation. Soft agar assay further confirmed that this novel fusion transcript has tumorigenic potential. We also identified that microRNA-coding gene PVT1, which is amplified in double minute chromosomes in SNU-16 cells, is recurrently involved in gene fusion. PVT1 produced six different fusion transcripts involving four different genes as fusion partners. Our findings provide better insight into transcriptional and genetic alterations of gastric cancer: namely, the tumorigenic effects of transcriptional read-through and a candidate region for genetic instability.
The motion of atoms in a solid always responds to cooling or heating in a way that is consistent with the symmetry of the given space group of the solid to which they belong. When the atoms move, the ...electronic structure of the solid changes, leading to different physical properties. Therefore, the determination of where atoms are and what atoms do is a cornerstone of modern solid-state physics. However, experimental observations of atomic displacements measured as a function of temperature are very rare, because those displacements are, in almost all cases, exceedingly small. Here we show, using a combination of diffraction techniques, that the hexagonal manganites RMnO3 (where R is a rare-earth element) undergo an isostructural transition with exceptionally large atomic displacements: two orders of magnitude larger than those seen in any other magnetic material, resulting in an unusually strong magneto-elastic coupling. We follow the exact atomic displacements of all the atoms in the unit cell as a function of temperature and find consistency with theoretical predictions based on group theories. We argue that this gigantic magneto-elastic coupling in RMnO3 holds the key to the recently observed magneto-electric phenomenon in this intriguing class of materials.
To investigate the risk factors for acute GVHD (aGVHD), based on NIH consensus criteria (NCC), we evaluated 775 patients who underwent allogeneic transplantation. Of them, 346 patients developed ...aGVHD by NCC, in whom we also analyzed factors affecting aGVHD-specific survival. The cumulative incidence of aGVHD was 44.7%, consisting of classic aGVHD (n=320) and late-onset (n=26). Multivariate analyses revealed that younger age (P=0.015), unrelated donors (P=0.004) and acute leukemia compared with other hematologic malignancies (P=0.005) were significant risk factors for aGVHD, whereas PBSCs showed no association (P=0.720). Multivariate analyses, with only aGVHD patients, revealed that late-onset aGVHD had superior aGVHD-specific survival to classic aGVHD (P=0.044), and identified the association of visceral organ involvement (P=0.002), severity of aGVHD at onset (P=0.035) and advanced disease status (P<0.001) with inferior aGVHD-specific survival. In conclusion, this study demonstrates the risk and prognostic factors for aGVHD by NCC with some differences with the previous reports that were based on old criteria. The difference in the risk factors according to different criteria will give insights about the pathophysiology of GVHD. The better prognosis of late-onset aGVHD than of classic aGVHD raises the necessity for prospective trials with a large cohort focusing on the onset time.
Background Although remifentanil provides profound analgesia during operation, postoperative occurrence of hyperalgesia and tolerance after remifentanil administration could be a challenge to the ...postoperative pain control. In this investigation, we sought to determine the effect of maintenance with propofol or sevoflurane on postoperative analgesia after remifentanil-based anaesthesia. Methods Two hundred and fourteen women undergoing breast cancer surgery under remifentanil-based general anaesthesia were randomly included in this prospective and double-blind trial. The patients were anaesthetized with sevoflurane (S) or propofol (P) under high (H) or low (L) effect-site concentration (Ce) of remifentanil-based anaesthesia using a target-controlled infusion system; the patients were allocated into the SH, SL, PH, and PL groups. Pain intensity (visual analogue score, VAS) and cumulative morphine requirements were recorded 30 min, 1, 6, 12, and 24 h after operation. Results The patient characteristics were similar. Cumulative morphine consumption at 24 h after surgery was higher in the SH group 38.6 (sd 14.9) compared with the SL 31.5 (3.7), PH 31.7 (8.3), and PL groups 30.1 (6.1) (P<0.001). The VAS scores during 24 h after surgery were also higher in the SH group than the SL, PH, and PL groups (P<0.001). Conclusions Remifentanil hyperalgesia was induced by high dose of remifentanil-based anaesthesia during sevoflurane anaesthesia, whereas that was not apparent during propofol anaesthesia. Also, remifentanil hyperalgesia did not occur during low dose of remifentanil-based anaesthesia. Maintenance of propofol during high-dose remifentanil-based anaesthesia provided better postoperative analgesia.
Cu2ZnSnS4; commonly abbreviated as CZTS is a promising material for low cost thin film solar cells, because of its suitable band gap energy of around 1.5eV and large absorption coefficient of over ...104cm−1. All the constituents of this material are abundant in the earth’s crust, and they are not toxic making it a smarter choice. Since 1996, after the initial success of the CZTS based solar cell (with its light to electrical conversion efficiency of 0.6%), significant progress in this research area has been achieved, especially in the last five years. Now-a-days, the conversion efficiency of the CZTS thin film solar cell has improved to 12%. Over 600 papers on CZTS have been published since 2001, and the majority of these discuss the preparation of CZTS thin films by different methods. So far, many physical and chemical techniques have been employed for preparing CZTS thin films. Among them, the pulsed laser deposition (PLD) is a versatile deposition method. PLD is a simple, but multipurpose, experimental method that finds use as a means of modeling a very diverse range of materials, and in extensive areas of thin film deposition and multi-layer research. This technique is suitable for depositing high quality films with complex compositions because of its influencing properties such as harmonious transfer of species from the target to substrate, enrichment in crystallinity, clean deposition, and simplicity and flexibility in the engineering design. On the occasion of the 25th anniversary of PLD, this manuscript, reviews the synthesis of CZTS semiconductor thin films fabricated by PLD. This review begins with a description of the PLD system, and then introduces the CZTS and preparation of the CZTS target for PLD deposition. A survey of pulsed laser deposited CZTS thin films and their solar cell performance is discussed in detail. Finally, we present perspectives for further developments of PLD for a CZTS based solar cell absorber layer.
Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered ...proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Here, we use CasDrop, a novel CRISPR-Cas9-based optogenetic technology, to show that various IDPs phase separate into liquid condensates that mechanically exclude chromatin as they grow and preferentially form in low-density, largely euchromatic regions. A minimal physical model explains how this stiffness sensitivity arises from lower mechanical energy associated with deforming softer genomic regions. Targeted genomic loci can nonetheless be mechanically pulled together through surface tension-driven coalescence. Nuclear condensates may thus function as mechano-active chromatin filters, physically pulling in targeted genomic loci while pushing out non-targeted regions of the neighboring genome.
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•The CasDrop system enables controlled liquid condensation at specific genomic loci•The IDR-driven condensates grow preferentially in regions of low chromatin density•Condensate formation leads to mechanical exclusion of non-targeted chromatin•Condensates pull in targeted genomic loci, serving as mechanical chromatin filters
Nuclear condensates physically pull in targeted genomic loci while excluding non-targeted regions of the neighboring genome.
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