We aimed to reveal the prevalence and pattern of human papillomavirus (HPV) infection and p53 mutations among Japanese head and neck squamous cell carcinoma (HNSCC) patients in relation to ...clinicopathological parameters. Human papillomavirus DNA and p53 mutations were examined in 493 HNSCCs and its subset of 283 HNSCCs. Oropharyngeal carcinoma was more frequently HPV‐positive than non‐oropharyngeal carcinoma (34.4% vs 3.6%, P < 0.001), and HPV16 accounted for 91.1% of HPV‐positive tumors. In oropharyngeal carcinoma, which showed an increasing trend of HPV prevalence over time (P < 0.001), HPV infection was inversely correlated with tobacco smoking, alcohol drinking, p53 mutations, and a disruptive mutation (P = 0.003, <0.001, <0.001, and <0.001, respectively). The prevalence of p53 mutations differed significantly between virus‐unrelated HNSCC and virus‐related HNSCC consisting of nasopharyngeal and HPV‐positive oropharyngeal carcinomas (48.3% vs 7.1%, P < 0.001). Although p53 mutations were associated with tobacco smoking and alcohol drinking, this association disappeared in virus‐unrelated HNSCC. A disruptive mutation was never found in virus‐related HNSCC, whereas it was independently associated with primary site, such as the oropharynx and hypopharynx (P = 0.01 and 0.03, respectively), in virus‐unrelated HNSCC. Moreover, in virus‐unrelated HNSCC, G:C to T:A transversions were more frequent in ever‐smokers than in never‐smokers (P = 0.04), whereas G:C to A:T transitions at CpG sites were less frequent in ever‐smokers than in never‐smokers (P = 0.04). In conclusion, HNSCC is etiologically classified into virus‐related and virus‐unrelated subgroups. In virus‐related HNSCC, p53 mutations are uncommon with the absence of a disruptive mutation, whereas in virus‐unrelated HNSCC, p53 mutations are common, and disruptive mutagenesis of p53 is related with oropharyngeal and hypopharyngeal carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is etiologically classified into virus‐related and virus‐unrelated subgroups. In virus‐related HNSCC p53 mutations are uncommon with the absence of a disruptive mutation, whereas in virus‐unrelated HNSCC p53 mutations are common, and disruptive mutagenesis of p53 is closely related with oropharyngeal and hypopharyngeal carcinoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
While electrospun chitosan membranes modified to retain nanofibrous morphology have shown promise for use in guided bone regeneration applications in in vitro and in vivo studies, their mechanical ...tear strengths are lower than commercial collagen membranes. Elastin, a natural component of the extracellular matrix, is a protein with extensive elastic property. This work examined the incorporation of elastin into electrospun chitosan membranes to improve their mechanical tear strengths and to further mimic the native extracellular composition for guided bone regeneration (GBR) applications. In this work, hydrolyzed elastin (ES12, Elastin Products Company, USA) was added to a chitosan spinning solution from 0 to 4 wt% of chitosan. The chitosan-elastin (CE) membranes were examined for fiber morphology using SEM, hydrophobicity using water contact angle measurements, the mechanical tear strength under simulated surgical tacking, and compositions using Fourier-transform infrared spectroscopy (FTIR) and post-spinning protein extraction. In vitro experiments were conducted to evaluate the degradation in a lysozyme solution based on the mass loss and growth of fibroblastic cells. Chitosan membranes with elastin showed significantly thicker fiber diameters, lower water contact angles, up to 33% faster degradation rates, and up to seven times higher mechanical strengths than the chitosan membrane. The FTIR spectra showed stronger amide peaks at 1535 cm
and 1655 cm
in membranes with higher concentrated elastin, indicating the incorporation of elastin into electrospun fibers. The bicinchoninic acid (BCA) assay demonstrated an increase in protein concentration in proportion to the amount of elastin added to the CE membranes. In addition, all the CE membranes showed in vitro biocompatibility with the fibroblasts.
A new class of polylactide (PLA)-based block copolymers with thermoresponsive poly(vinyl ether) poly(VE) were precisely synthesized via successive living cationic polymerization of VE and ...ring-opening polymerization of lactide (LA). The synthetic route starts with precise end-functionalization of poly(VE) by living cationic polymerization to produce a macroinitiator having a hydroxy group at the α- and/or ω-end for ring-opening polymerization of LA. End-functionalized polymers of 2-methoxyethyl VE (MOVE) with highly controlled structures were obtained by either an initiation or a termination method under optimized conditions. Subsequent ring-opening polymerization of LA from the hydroxy group of the macroinitiator yielded block copolymers with well-defined structures. The obtained block copolymers were demonstrated to exhibit a thermoresponsive solubility transition in water; this transition was induced by the thermosensitivity of the poly(MOVE) segments. The transition between micelle-like aggregates and phase separation was reversible with a shorter PLA chain, whereas irreversible precipitation was observed with a longer PLA segment. The permanent precipitation upon heating is most likely attributable to crystalline formation of the longer PLA segments. The solution and bulk properties of the block copolymers with enantiomeric PLA were also governed by stereocomplex formation between poly(l-lactide) (PLLA) and poly(d-lactide) (PDLA) segments.
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IJS, KILJ, NUK, PNG, UL, UM
Jet set: Layer‐by‐layer alternate stepwise deposition of poly(L‐lactide) (PLLA) and poly(D‐lactide) (PDLA) is used to fabricate a polylactide (PLA) stereocomplex on a substrate (see picture). ...Multiple inkjet passes improve the crystal structure of the PLA composite without intermediate rinsing steps.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the ...core clock gene period (
) and cryptochrome (
) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (
) and brain and muscle Arnt-like protein-1 (
). By binding to E-box sequences in the promoters of
and
genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock's circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where ...adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal-embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph-ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Bicalutamide is the most widely used non-steroidal antiandrogen for treating early stage prostate cancer, but suffers variable oral absorption due to its limited aqueous solubility. Thus, ...our objective was to synthesize novel biodegradable copolymers for the systemic micellar delivery of bicalutamide. Flory–Huggins interaction parameter ( χFH ) was used to assess compatibility between bicalutamide and poly( l -lactide) or poly(carbonate-co-lactide) polymer pairs. Polyethylene glycol-b-poly(carbonate-co-lactide) PEG-b-P(CB-co-LA) copolymers were synthesized and characterized by NMR and gel permeation chromatography. These micelles had average diameter of 100 nm and had a smooth surface and distinct spherical shape. Drug loading studies revealed that adding the carbonate monomer could increase bicalutamide loading. Among the series, drug loading of micelles formulated with PEG-b-P(CB-co-LA) copolymer containing 20 mol% carbonate was about four-fold higher than PEG-b-PLLA and aqueous solubility of bicalutamide increased from 5 to 4000 μg/mL. CMC values for PEG-b-P(CB-co-LA) copolymers was up to 10-fold lower than those of PEG-b-PLLA. In vitro release experiments showed PEG-b-P(CB-co-LA) copolymers to be more efficient in sustaining the release of bicalutamide compared to PEG-b-PLLA. Bicalutamide-loaded PEG-b-P(CB-co-LA) micelles showed significant inhibition of LNCaP cell growth in a dose-dependent manner which was similar to the methanol solution of free drug.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Desirable characteristics of electrospun chitosan membranes (ESCM) for guided bone regeneration are their nanofiber structure that mimics the extracellular fiber matrix and porosity for the exchange ...of signals between bone and soft tissue compartments. However, ESCM are susceptible to swelling and loss of nanofiber and porous structure in physiological environments. A novel post-electrospinning method using di-tert-butyl dicarbonate (tBOC) prevents swelling and loss of nanofibrous structure better than sodium carbonate treatments. This study aimed to evaluate the hypothesis that retention of nanofiber morphology and high porosity of tBOC-modified ESCM (tBOC-ESCM) would support more bone mineralization in osteoblast-fibroblast co-cultures compared to Na
CO
treated membranes (Na
CO
-ESCM) and solution-cast chitosan solid films (CM-film). The results showed that only the tBOC-ESCM retained the nanofibrous structure and had approximately 14 times more pore volume than Na
CO
-ESCM and thousands of times more pore volume than CM-films, respectively. In co-cultures, the tBOC-ESCM resulted in a significantly greater calcium-phosphate deposition by osteoblasts than either the Na
CO
-ESCM or CM-film (
< 0.05). This work supports the study hypothesis that tBOC-ESCM with nanofiber structure and high porosity promotes the exchange of signals between osteoblasts and fibroblasts, leading to improved mineralization in vitro and thus potentially improved bone healing and regeneration in guided bone regeneration applications.
Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. ...However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1‐overexpressing (Rev1‐Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N‐methyl‐N‐nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU‐induced TL tumorigenesis in wild‐type (WT) and Rev1‐Tg mice using diverse approaches, including whole‐exome sequencing (WES). In Rev1‐Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1‐Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging‐related) and SBS11 (alkylation‐related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1‐Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1‐Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1‐Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU‐induced TL by shortening the latency period, which may be associated with more frequent DNA damage‐induced genetic instability.
Rev1 overexpression accelerates mutagenesis and increases the incidence of N‐methyl‐N‐nitrosourea (MNU)‐induced thymic lymphoma (TL) by shortening the latency period, which may be associated with more frequent DNA damage‐induced genetic instability.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective Although recent reports have highlighted the benefits of multidisciplinary team care (MTC) for chronic kidney disease (CKD) in slowing the progress of renal insufficiency, its long-term ...effects have not been evaluated for patients with diabetes mellitus (DM). We compared the renal survival rate between MTC and conservative care (CC). Methods In this five-year, single-center, prospective, observational study, we examined 24 patients (mean age 65.5±12.1 years old, men/women 18/6) with DM-induced CKD stage ≥3 in an MTC clinic. The control group included 24 random patients with DM (mean age 61.0±12.8 years old, men/women 22/2) who received CC. MTC was provided by a nephrologist and medical staff, and CC was provided by a nephrologist. Results In total, 10 MTC and 20 CC patients experienced renal events creatinine doubling, initiation of renal replacement therapy (RRT), or death due to end-stage CKD. During the five-year observation period, there were significantly fewer renal events in the MTC group than in the CC group according to the cumulative incidence method (p=0.006). Compared to CC, MTC significantly reduced the need for urgent initiation of hemodialysis (relative risk reduction 0.79, 95% confidence interval CI 0.107-0.964). On a multivariate analysis, MTC (hazard ratio HR, 0.434, 95% CI 0.200-0.939) and the slope of the estimated glomerular filtration rate during the first year (HR, 0.429 per 1 mL/min/m2/year, 95% CI 0.279-0.661) were negatively associated with renal events. Conclusion MTC for DM-induced CKD is an effective strategy for delaying RRT. Long-term MTC can demonstrate reno-protective effects.
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