Solid tumors characteristically display higher levels of lactate production due to anaerobic metabolism of glucose. Meanwhile, the U.S. Food and Drug Administration (FDA) has approved virotherapy for ...use in cancer treatment; however systemic administration remains as a particular challenge. Here we report exploitation of tumor lactate production in designing a hypoxia-responsive carrier, self-assembled from hyaluronic acid (HA) conjugated with 6-(2-nitroimidazole)hexylamine, for localized release of recombinant adeno-associated virus serotype 2 (AAV2). The carrier is loaded with lactate oxidase (LOX) and is permeable to small molecules such as the lactate that accumulates in the tumor. Subsequently, LOX oxidizes the lactate to pyruvate inside the carrier, accompanied by internal lowering of oxygen partial pressure. Bioreduction of the 2-nitroimidazole of the HA conjugated with 6-(2-nitroimidazole)hexylamine converts it into a hydrophilic moiety and electrostatically dissociates the carrier and virus. Efficacious and specific delivery was proven by transduction of a photosensitive protein (KillerRed), enabling significant limitation in tumor growth in vivo with photodynamic therapy. An approximate 2.44-fold reduction in tumor weight was achieved after a 2-week course, compared with control groups. Furthermore, conjugation of the AAV2 with iron oxide nanoparticles (“magnetized” AAV2) facilitated magnetic resonance imaging tracking of the virus in vivo. Taken together, the solid tumor microenvironment promotes bioreduction of the lactate-responsive carrier, providing rapid and specific delivery of AAV2 for light-triggered virotherapy via systemic administration.
Numerous studies have shown that long noncoding RNAs (lncRNAs) are involved in cancer progression and chemotherapy resistance. Nuclear enriched abundant transcript 1 (NEAT1) is an lncRNA. It affects ...tumor cell progression and drug resistance in various tumors. However, the relation of NEAT1 and survival rate in oral squamous cell carcinoma (OSCC) requires further study.
One normal gingival epithelium cell line, SG, three oral cancer cell lines (HSC3, OEC-M1, and SAS), 34 paired non-cancerous matched tissues (NCMT), and OSCC tissues were used in this study. Tri-reagent was used for total RNA extraction. NEAT1 expression was assessed by reverse transcription-quantitative PCR (RT-qPCR).
NEAT1 expression in oral cancer cell lines was lower than that in normal cells and was significantly downregulated in OSCC. NEAT1 upregulation reduced the survival rate of patients with OSCC. NEAT1 upregulation also reduced the survival rate of OSCC patients treated with chemotherapy and radiotherapy.
These results indicate that NEAT1 expression is a valuable biomarker for the prediction and prognosis of oral cancer.
Quercetin is a bioflavonoid that exhibits several biological functions in vitro and in vivo. Quercetin 3-O-methyl ether (Q3) is a natural product reported to have pharmaceutical activities, including ...antioxidative and anticancer activities. However, little is known about the mechanism by which it protects cells from oxidative stress. This study was designed to investigate the mechanisms by which Q3 protects against Cu2+-induced cytotoxicity. Exposure to Cu2+ resulted in the death of mouse liver FL83B cells, characterized by apparent apoptotic features, including DNA fragmentation and increased nuclear condensation. Q3 markedly suppressed Cu2+-induced apoptosis and mitochondrial dysfunction, characterized by reduced mitochondrial membrane potential, caspase-3 activation, and PARP cleavage, in Cu2+-exposed cells. The involvement of PI3K, Akt, Erk, FOXO3A, and Mn-superoxide dismutase (MnSOD) was shown to be critical to the survival of Q3-treated FL83B cells. The liver of both larval and adult zebrafish showed severe damage after exposure to Cu2+ at a concentration of 5μM. Hepatic damage induced by Cu2+ was reduced by cotreatment with Q3. Survival of Cu2+-exposed larval zebrafish was significantly increased by cotreatment with 15μM Q3. Our results indicated that Cu2+-induced apoptosis in FL83B cells occurred via the generation of ROS, upregulation and phosphorylation of Erk, overexpression of 14-3-3, inactivation of Akt, and the downregulation of FOXO3A and MnSOD. Hence, these results also demonstrated that Q3 plays a protective role against oxidative damage in zebrafish liver and remarked the potential of Q3 to be used as an antioxidant for hepatocytes.
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► Protective effects of Q3 on Cu2+-induced oxidative stress in vitro and in vivo. ► Cu2+ induced apoptosis in FL83B cells via ROS and the activation of Erk. ► Q3 abolishes Cu2+-induced apoptosis through the PI3K/Akt and MAPK/Erk pathway.
Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer's disease (AD). However, the relationships among AD, hypertension, and ...oxidative stress remain to be elucidated. Here, we aimed to determine whether reactive oxygen species (ROS) reduction by resveratrol in the brain leads to cognitive impairment reduction in rats with angiotensin II (Ang-II)-induced early AD. Male Wistar Kyoto (WKY) rats with Ang-II-induced AD were treated with losartan or resveratrol for two weeks. Our results show decreased blood pressure, increased hippocampal brain-derived neurotrophic factor (BDNF) level, and decreased nucleus tractus solitarius (NTS) ROS production in the Ang-II groups with losartan (10 mg/kg), or resveratrol (10 mg/kg/day) treatment. Furthermore, losartan inhibition of hippocampal Tau
phosphorylation activated Akt
phosphorylation, and significantly abolished Ang-II-induced Aβ precursors, active caspase 3, and glycogen synthase kinase 3β (GSK-3β)
expressions. Consistently, resveratrol showed similar effects compared to losartan. Both losartan and resveratrol restored hippocampal-dependent contextual memory by NADPH oxidase 2 (NOX2) deletion and superoxide dismutase 2 (SOD2) elevation. Our results suggest that both losartan and resveratrol exert neuroprotective effects against memory impairment and hippocampal damage by oxidative stress reduction in early stage AD rat model. These novel findings indicate that resveratrol may represent a pharmacological option similar to losartan for patients with hypertension at risk of AD during old age.
Acute kidney injury (AKI) is detrimental after cardiac surgery. In this multicenter study, the novel biomarker hemojuvelin (HJV) was evaluated for AKI prediction following cardiac surgery. Urinary ...HJV, neutrophil gelatinase-associated lipocalin (NGAL), and urinary creatinine were measured in 151 patients after surgery. The outcomes of advanced AKI (KDIGO stages 2 and 3) and all causes of in-hospital mortality as the composite outcome were recorded. Areas under the receiver operator characteristic curves (AUC) and a multivariate generalized additive model (GAM) were applied to predict these outcomes of interest. Urinary HJV differentiated patients with/without AKI, advanced AKI or composite outcome after surgery (p < 0.001, by a generalized estimating equation) in this study. At three hours post-surgery, urinary HJV predicted advanced AKI (p < 0.001) and composite outcome (p < 0.001) with corresponding AUC values of 0.768 and 0.828, respectively. The performance of creatinine-adjusted HJV was also superior to NGAL in predicting advanced AKI (AUC = 0.784 and 0.694; p = 0.037) and composite outcome (AUC = 0.842 and 0.676; p = 0.002). The integration of HJV into the Cleveland Clinic score for advanced AKI led to a significant increase in risk stratification (net reclassification improvement NRI = 0.598; p < 0.001).
This report describes a post hoc analysis of data from a randomized, double-blinded, placebo-controlled, flexible-dose, sildenafil trial in men with erectile dysfunction.
To simplify interpretation ...of erectile function (EF) domain scores of the International Index of Erectile Function (IIEF).
Men at least 18 years old with erectile dysfunction were randomized to receive sildenafil or placebo for 12 weeks. Men taking nitrates or nitric oxide donors were excluded. Responses for each IIEF EF domain question (questions 1-5 and 15) were combined into two broad categories ("success" for responses of the two most favorable categories of a question and "no success" for other responses). Each question was expressed in a logistic regression model (sildenafil and placebo groups combined) as a function of overall EF domain score.
IIEF EF domain score and items.
A four-point increase in the IIEF EF domain score was associated with an odds ratio of success of 6.1 for getting an erection, 29.2 for having a firm erection, 10.0 for able to penetrate,12.8 for maintaining erection, 4.0 for maintaining erection to completion, and 3.7 for erection confidence. An EF domain score of 22 was associated with a probability of success of 81% for getting an erection, 86% for having a firm erection, 89% for able to penetrate, 67% for maintaining an erection, 70% for maintaining an erection to completion, and 32% for erection confidence. For an EF domain score of 16, the corresponding probabilities of success were 22%, 4%, 20%, 4%, 22%, and 6%, respectively.
These results provide stakeholders with a simplified and meaningful interpretation of IIEF EF domain scores based on six key aspects of EF.
To focus on the potential beneficial effects of the pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP4is) on attenuating progression of diabetic kidney disease in reducing the long-term ...effect of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition.
Data from the National Health Insurance Research Database from January 1, 1999, to July 31, 2011, were analyzed, and patients with diabetes weaning from dialysis-requiring AKI were identified. Cox proportional hazards models and inverse-weighted estimates of the probability of treatment were used to adjust for treatment selection bias. The outcomes were incident end-stage renal disease (ESRD) and mortality, major adverse cardiovascular events, and hospitalized heart failure.
Of a total of 6165 patients with diabetes weaning from dialysis-requiring AKI identified, 5635 (91.4%) patients were DPP4i nonusers and 530 (8.6%) patients were DPP4i users. Compared with DPP4i nonusers, DPP4i users had a lower risk of ESRD (hazard ratio, 0.81; 95% CI, 0.70-0.94; P=.04) and all-cause mortality (hazard ratio, 0.28; 95% CI, 0.23-0.34; P<.001) after adjustments for CKD, advanced CKD, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. In contrast, the risk of major adverse cardiovascular events and hospitalized heart failure did not differ significantly between groups.
Dipeptidyl peptidase-4 inhibitor users had a lower risk of ESRD and mortality than did nonusers among patients with diabetes after weaning from dialysis-requiring AKI. Therefore, a prospective study of AKI to CKD transitions after episodes of AKI is needed to optimally target DPP4i interventions.
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments' inherent physicochemical and biological characteristics. Often, therapeutic effect can be ...increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours' acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.
This paper presents an integrated servo-feed-drive model including the cutting force and structural effect to predict tracking errors in an end-milling process. Most conventional approaches consider ...the cutting force to be an equivalent torque to servo feed drive. However, in addition to acting as the equivalent torque to the servo feed drive, cutting forces also cause the machine table to vibrate. This paper considers the aforementioned cutting-force effects to predict tracking errors and then verifies the tracking errors using experimental results. Experiments are conducted on a 3-axis computer numerical control (CNC) machining center to validate the tracking errors predicted by the proposed servo-feed-drive model. For one case study, the peak-to-peak tracking errors from the experimental, proposed, and traditional models are 3 μm, 2.8 μm, and 0.5 μm, respectively, for the
x
-axis, and 2.1 μm, 1.7 μm, and 0.4 μm, respectively, for the
y
-axis. The experimental results illustrate that the tracking errors predicted using the proposed model are more accurate than those predicted using the traditional model without consideration of the transmission path. Therefore, it can be concluded that the proposed integrated model provides much accurate tracking-error prediction, and thus, the ball-screw and machine-table flexibilities should be considered.
Lung cancer is the primary cause of cancer-related death worldwide. 85%–90% of cases are non-small cell lung cancer (NSCLC) which characteristically exhibits altered epidermal growth factor receptor ...(EGFR) signaling is a major driver pathway. Unfortunately, therapeutic outcomes in treating NSCLC are compromised by the emergence of drug resistance in response to EGFR-tyrosine kinase inhibitor (TKI) targeted therapy due to the acquired resistance mutation EGFR T790M or activation of alternative pathways. There is current need for a new generation of TKIs to be developed to treat EGFR-TKI-resistant NSCLC. To overcome the above problems and improve clinical efficacy, nanotechnology with targeting abilities and sustained release has been proposed for EGFR-TKI-resistant NSCLC treatment and has already achieved success in in vitro or in vivo models. In this review, we summarize and illustrate representative nano-formulations targeting EGFR-TKI-resistant NSCLC. The described advances may pave the way to better understanding and design of nanocarriers and multifunctional nanosystems for efficient treatment for drug resistant NSCLC.
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•NSCLC patients with EGFR mutation inevitably develop acquired TKIs resistance within one year of treatment.•Advances in nano science have led to development of targeting delivery systems in tumor microenvironment.•These nano-modified therapies show improved in vivo penetration and retention of therapeutic drugs.•A decrease in the side-effect and off targeting through systemic circulation has confirmed.•These nano-modified therapies can provide synergistic anticancer effects and overcome drug resistance in NSCLC.
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