It is of great valuable in drug delivery to fabricate multifunctional nanovehicle for cancer therapy. Herein, hollow-structured hCu2-xS@Au nanoshell/satellite composite with doxorubicin-carrying was ...designed and synthesized for intelligent and visible drug delivery and satisfactory photothermal therapy. By modification of disulfide linkage bridged Au nanoshell and multi-carboxylic graphene quantum dots (MC-GODs) on the surface of hCu2-xS@Au nanoparticles, both the high concentration of glutathione and low pH in cancer cell/tissue can induce responsive drug release. The satisfactory photothermal conversion efficiency (32%) of hCu2-xS@Au@MC-GODs under 808 nm near-infrared (NIR) laser irradiation ascribed to the reduced bandgap and more circuit paths for electron transitions for hCuS modified with Au nanoparticles depend on density functional theory, which antitumor therapy efficacy was greatly enhanced by combining chemo- and photothermal therapy. Moreover, the fluorescence of MC-GODs was quenched/“turn off” as linking to the surface of hCu2-xS@Au, and also restored/“turn on” as the MC-GODs detaching from the surface of hCu2-xS@Au. The fluorescent switch of MC-GODs can serve as both a controllable drug release “guard” and “eyes” for visualized monitoring. The multi-modality therapy with controllable drug delivery, visual monitoring and high photothermal conversion efficiency may be anticipated by this versatile strategy.
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•The novel nanovehicle possesses tumor microenvironment-responsive release and visible therapy.•The nanovehicle possesses high photothermal conversion efficiency.•Surpassingly achieved chemo- and photothermal synergistic therapy with high efficacy.
Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial ...dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Ι inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells.
Objective: Meta-analysis to evaluate complications in the use of autogenous bone and bone substitutes and to compare bone substitutes, specifically HA, polyetheretherketone (PEEK) and titanium ...materials.
Methods: Search of PubMed, Cochrane, Embase and Google scholar to identify all citations from 2010 to 2019 reporting complications regarding materials used in cranioplasty.
Results: 20 of 2266 articles met the inclusion criteria, including a total of 2913 patients. The odds of overall complication were significantly higher in the autogenous bone group (n = 214/644 procedures, 33.2%) than the bone substitute groups (n = 116/436 procedures, 26.7%, CI 1.29-2.35, p < 0.05). In bone substitutes groups, there was no significant difference in overall complication rate between HA and Ti (OR, 1.2; 95% CI, 0.47-3.14, p = 0.69). PEEK has lower overall complication rates (OR, 0.51; 95% CI, 0.30-0.87, p = 0.01) and lower implant exposure rates (OR, 0.17; 95% CI, 0.06-0.53, p = 0.002) than Ti, but there was no significant difference in infection rates and postoperative hematoma rates.
Conclusions: Cranioplasty is associated with high overall complication rates with the use of autologous bone grafts compared with bone substitutes. PEEK has a relatively low overall complication rates in substitutes groups, but still high infection rates and postoperative hematoma rates. Thus, autologous bone grafts should only be used selectively, and prospective long-term studies are needed to further refine a better material in cranioplasty.
Background
The purpose of this study was to verify 10‐year results of survival and late toxicities and assess the ultimate therapeutic ratio of intensity‐modulated radiotherapy (IMRT) versus ...two‐dimensional radiotherapy (2DRT) in patients with nasopharyngeal carcinoma (NPC).
Materials and Methods
We retrospectively reviewed the data from 1,276 patients with nonmetastatic NPC who received IMRT or 2DRT from January 2003 to December 2006.
Results
Of the 1,276 patients, 512 were treated with IMRT and 764 with 2DRT. Median follow‐up was 115 months. At 10 years, the IMRT group demonstrated significantly better results than the 2DRT group in local failure‐free survival (L‐FFS; 90% vs. 84%; hazard ratio HR, 0.57, 95% confidence interval CI, 0.40–0.81; p = .001), failure‐free survival (FFS; 69% vs. 58%; HR, 0.69, 95% CI, 0.57–0.83; p < .001), and overall survival (OS; 75% vs. 63%; HR, 0.62, 95% CI, 0.51–0.77; p < .001). Subgroup multivariate analyses showed that radiotherapeutic technique (IMRT vs. 2DRT) remained an independent prognostic factor for L‐FFS in the T1 subgroup (HR, 0.30; 95% CI, 0.11–0.80; p = .02); for FFS in the stage II subgroup (HR, 0.42; 95% CI, 0.24–0.73; p = .002); and for OS in the stage I (HR, 0.20; 95% CI, 0.04–0.96; p = .04), stage II (HR, 0.39; 95% CI, 0.21–0.75; p = .004), and stage IVA–B (HR, 0.74, 95% CI, 0.56–0.98; p = .04) subgroups. The incidence of grade 3–4 temporal lobe necrosis, cranial neuropathy, eye damage, ear damage, neck soft tissue damage, trismus, and dry mouth was significantly lower in the IMRT group than in the 2DRT group.
Conclusion
IMRT demonstrated an improved ultimate therapeutic ratio compared with 2DRT in patients with NPC after a 10‐year follow‐up, with significant improvement of L‐FFS, FFS, and OS and decrease in most late toxicities.
Implications for Practice
The ultimate therapeutic ratio of intensity‐modulated radiotherapy versus two‐dimensional radiotherapy in patients with nasopharyngeal carcinoma is unclear. In this retrospective study of 1,276 patients with nonmetastatic nasopharyngeal carcinoma with a follow‐up of 115 months, intensity‐modulated radiotherapy demonstrated an improved ultimate therapeutic ratio compared with two‐dimensional radiotherapy, with significant improvement of local failure‐free survival, failure‐free survival, and overall survival and decrease in most late toxicities and noncancer deaths. However, distant control remains insufficient with this treatment modality.
摘要
背景。本研究旨在验证鼻咽癌 (NPC) 患者调强放疗 (IMRT) 对比二维放疗 (2DRT) 的生存率和晚期毒性的 10 年结果并评估最终治疗比。
材料和方法。我们对 1 276 名在 2003 年 1 月至 2006 年 12 月期间接受 IMRT 或 2DRT 的非转移性 NPC 患者的数据进行回顾性分析。
结果。在这 1 276 名患者中,512 名患者接受 IMRT 治疗,764 名患者接受 2DRT 治疗。中位随访时间为 115 个月。到第 10 年的时候,IMRT 组比 2DRT 组在局部无失败生存率L‐FFS;90% vs. 84%;风险比(HR),0.57,95% 置信区间(CI),0.40–0.81;p = 0.001、无失败生存率(FFS;69% vs. 58%;HR,0.69,95% CI,0.57–0.83;p < 0.001)以及总生存率(OS;75% vs. 63%;HR,0.62,95% CI,0.51–0.77;p <0.001)等方面显示出明显更好的结果。亚组多变量分析表明, 就 T1 亚组中的 L‐FFS(HR,0.30;95% CI,0.11–0.80;p = 0.02) ;II 期亚组中的 FFS(HR,0.42;95% CI,0.24–0.73;p = 0.002);以及 I 期亚组中的 OS(HR,0.20;95% CI,0.04–0.96;p = 0.04)、II 期亚组中的 OS(HR,0.39;95% CI,0.21–0.75;p = 0.004)与 IVA–B 期亚组中的 OS(HR,0.74;95% CI,0.56–0.98;p = 0.04)而言,放疗技术(IMRT 与 2DRT)仍然是独立的预后因素。与 2DRT 组相比,IMRT 组的 3–4 级颞叶坏死、颅神经病变、眼部损伤、耳部损伤、颈部软组织损伤、牙关紧闭以及口腔干燥的发病率明显更低。
结论。在 10 年随访之后,与 2DRT 相比,IMRT 在 NPC 患者中显示出更好的最终治疗比,在 L‐FFS、FFS 和 OS 方面均有显著改进,大多数晚期毒性有所减少。
对临床实践的提示
鼻咽癌患者调强放疗对比二维放疗的最终治疗比尚不明确。在本次针对 1 276 名随访期历时 115 个月的非转移性鼻咽癌患者的回顾性研究中,与二维放疗相比,调强放疗显示出更好的最终治疗比,在局部无失败生存率、无失败生存率和总生存率方面均有显著改进,大多数晚期毒性和非肿瘤死亡均有减少。但是,远程控制对于这种治疗方式而言仍然不足。
Radiotherapy is the primary treatment modality for nondisseminated nasopharyngeal carcinoma. Treatment with two‐dimensional radiotherapy transitioned to three‐dimensional conformal radiotherapy, and in particular to intensity‐modulated radiotherapy, is a step forward in the treatment of nasopharyngeal carcinoma. This article describes a long‐term follow‐up to verify ten‐year results of survival and late toxicities and to assess ultimate therapeutic ratio by intensity‐modulated radiotherapy versus two‐dimensional radiotherapy in patients with nasopharyngeal carcinoma.
Nanoparticle-induced autophagy is crucial for its metabolism, cytotoxicity and therapy potency, but little is known about how the host immune system would respond to it. In this study, we ...demonstrated that two clinically used superparamagnetic iron oxide nanoparticles (SPIONs) specifically induced macrophage autophagy through activation of TLR4, followed by phosphorylation of p38 and nucleus translocation of Nrf2, leading to upregulation of p62/SQSTM1 and macrophage scavenger receptor SR-AI mRNA expression. Overexpressed p62 conjugated with LC3 to form aggresome-like induced structures (ALIS) and then fused with SPIONs containing endosomes and lysosomes to form autolysosomes for degradation of endocytosed nanoparticles. More importantly, SPIONs also could promote macrophage autophagy in mouse liver which is their imaging target. We also discovered that SPIONs could stimulate the expression of inflammatory cytokines through activation of TLR4 signaling in macrophage. In general, our findings indicate that SPIONs would interact with TLR4 on the macrophage membrane and trigger its downstream signaling pathway, independent of the classic autophagic p62 reduction pathway. The observed autophagy and induced inflammatory responses in macrophages provide unique and novel perspectives in optimizing imaging/therapy nanoparticle performance in addition to analysis by traditional biochemical evaluation methods. It also enriches our understanding of NP/macrophage interaction mechanisms in reticular endothelial system (RES) organs.
A palladium-catalyzed carbonylative Sonogashira/annulation reaction for the synthesis of indolo1,2-bisoquinolines has been developed. Tetracyclic 6/5/6/6 indoline skeletons were synthesized in ...moderate to good yields from easily available 2-bromo-N-(2-iodophenyl)benzamides and terminal alkynes. Notably, this efficient methodology established three C–C bonds and a C–N bond through a one-step transformation and provided a new method for the synthesis of indolo1,2-bisoquinoline derivatives.
Problem
This study aimed to identify subsets of regulatory T cells (Tregs) associated with ovarian aging and determine whether they can be used as markers of reproductive aging.
Method
This ...prospective cohort study was conducted among women of reproductive age. Basic physiological characteristics, reproductive hormones, Treg cell subsets, and correlations between these parameters were assessed. The POSEIDON criteria was used to identify women with low reproductive potential.
Results
The percentages of HLA‐DR+ CD45RAˉ Tregs and CD28ˉ Treg‐like cells significantly increased with age. Women between 40 and 49 years had significantly higher percentages of HLA‐DR+ CD45RAˉ Tregs and CD28ˉ Treg‐like cells than those at 20–29, 30–34, and 35–39 years old. Age positively correlated with FSH levels and the percentages of HLA‐DR+ CD45RAˉ Tregs and CD28ˉ Treg‐like cells, but inversely correlated with antral follicle count (AFC) and AMH levels. Interestingly, a positive correlation was found between the percentages of HLA‐DR+ CD45RAˉ Tregs and FSH levels, whereas an inverse correlation was found between those of HLA‐DR+ CD45RAˉ Tregs and AFC or AMH levels. Furthermore, a significant positive correlation was observed between the percentages of CD28ˉ Treg‐like cells and AFC. Based on POSEIDON criteria, women with the percentages of HLA‐DR+ CD45RAˉ Tregs and CD28ˉ Treg‐like cells above reference value ranges were assigned to the low prognosis groups.
Conclusion
These findings suggest that HLA‐DR+ CD45RAˉ Tregs and CD28ˉ Treg‐like cells can be used as immunologic markers of reproductive aging, which helps clinicians identify women with low reproductive potential and establish individualized therapeutic strategies.
Disease impacts important metabolic pathways and the alteration of metabolites may serve as a potential biomarker for early-stage diagnosis. High-resolution mass spectrometry-based metabolomics have ...been used to discover new biomarker metabolites. Rheumatoid arthritis (RA) seriously affects the quality of life in patients, but its pathophysiology remains unclear. This study aimed to develop a high-throughput approach by screening potential biomarkers to facilitate the diagnosis using metabolomics. The alteration of the metabolic profile of RA was investigated in human urine samples based on high-resolution UPLC-QTOF/MS and multivariate statistical analysis. Furthermore, ingenuity pathway analysis (IPA) was performed for the bioinformatics analysis of the data. Variable importance for projection values was determined, and the t -test was conducted for selecting a biomarker panel for RA. Receiver operating characteristic analysis was used to evaluate diagnostic accuracy of metabolites. We found that the score plot of orthogonal partial least squares discriminant analysis showed significant discrimination between RA and healthy groups. Five metabolites were identified as potential biomarkers for RA. The values of AUC, ranging from 0.819 to 0.993, indicated the potential capacity of these metabolites to distinguish RA patients and demonstrated that the differentially expressed metabolites might be a useful tool for the effective diagnosis of RA. The most significantly altered networks included FXR/RXR activation and bile acid biosynthesis. This study demonstrates that a high-resolution mass spectrometry-based metabolomics approach could provide crucial insight into the pathogenesis mechanism of RA.
To better understand the relationship between dietary factors and thyroid cancer risk, we summarized the published evidence on relationship between dietary factors and thyroid cancer incidence. ...Searching several databases for relevant studies published by March 2014 included a total of 19 studies. We calculated summary odds ratios (ORs) for each risk factor. Based on the highest level of total consumption vs. the lowest level, the summary OR 95% (confidence interval) CI of thyroid cancer was 0.79 (0.66, 0.94) for fish; 0.95 (0.74, 1.23) for salt water fish; 0.86 (0.63, 1.16) for fresh water fish; 0.76 (0.58, 1.00) for vegetables; 0.88 (0.72, 1.08) for shellfish; 0.93 (0.66, 1.29) for cruciferous vegetables; 0.97 (0.78, 1.21) for fruits; 0.96 (0.70, 1.34) for meat; and 1.11 (0.86, 1.42) for grains. Subgroup analysis showed that fish (OR 0.74, 95%CI: 0.59, 0.92) and shellfish (OR 0.46, 95%CI: 0.27, 0.75) consumption have a protective effect in iodine deficiency areas, whereas the ORs were not statistically significant in iodine-rich areas. Our findings indicated that fish and shellfish consumption may decrease the risk of thyroid cancer in iodine deficiency areas, although no such effect was observed in iodine-rich areas.
The use of the frozen elephant trunk technique for type A aortic dissection in Marfan syndrome is limited by the lack of imaging evidence for long-term aortic remodeling. We seek to evaluate the ...changes of the distal aorta and late outcomes after frozen elephant trunk and total arch replacement for type A aortic dissection in patients with Marfan syndrome.
Between 2003 and 2015, we performed frozen elephant trunk + total arch replacement for 172 patients with Marfan syndrome suffering from type A aortic dissection (94 acute; 78 chronic). Mean age was 34.6 ± 9.3 years, and 121 were male (70.3%). Early mortality was 8.1% (14/172), and follow-up was complete in 98.7% (156/158) at a mean of 6.2 ± 3.3 years. Aortic dilatation was defined as a maximal diameter of greater than 50 mm or an average growth rate of greater than 5 mm/year at any segment detected by computed tomographic angiography. Temporal changes in the false and true lumens and maximal aortic size were analyzed with linear mixed modeling.
After surgery, false lumen obliteration occurred in 86%, 39%, 26%, and 21% at the frozen elephant trunk, unstented descending aorta, diaphragm, and renal artery, respectively. The true lumen expanded significantly over time at all segments (P < .001), whereas the false lumen shrank at the frozen elephant trunk (P < .001) and was stable at distal levels (P > .05). Maximal aortic size was stable at the frozen elephant trunk and renal artery (P > .05), but grew at the descending aorta (P = .001) and diaphragm (P < .001). Respective maximal aortic sizes before discharge were 40.2 mm, 32.1 mm, 31.6 mm, and 26.9 mm, and growth rate was 0.4 mm/year, 2.8 mm/year, 3.6 mm/year, and 2.6 mm/year. By the latest follow-up, distal maximal aortic size was stable in 63.5% (99/156), and complete remodeling down to the mid-descending aorta occurred in 28.8% (45/156). There were 22 late deaths and 23 distal reoperations. Eight-year incidence of death was 15%, reoperation rate was 20%, and event-free survival was 65%. Preoperative distal maximal aortic size (mm) predicted dilatation (hazard ratio, 1.11; P < .001) and reoperation (hazard ratio, 1.07; P < .001). A patent false lumen in the descending aorta predicted dilatation (hazard ratio, 3.88; P < .001), reoperation (hazard ratio, 3.36; P = .014), and late death (hazard ratio, 3.31; P = .045).
The frozen elephant trunk technique can expand the true lumen across the aorta, decrease or stabilize the false lumen, and stabilize the distal aorta in patients with Marfan syndrome with type A aortic dissection, thereby inducing favorable remodeling in the distal aorta. This study adds long-term clinical and radiologic evidence supporting the use of the frozen elephant trunk technique for type A dissection in Marfan syndrome.
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