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Studies have shown that disulfiram (DSF) can combine with Cu

One major challenge of photothermal therapy (PTT) is achieving thermal ablation of the tumor without damaging the normal cells and tissues. Here, we designed a self-regulating photothermal conversion system for selective thermotherapy based on self-assembling gold nanoparticles (S-AuNPs) and investigated the selectivity effect using a novel home-made in vitro selective photothermal transformation model and an in vivo skin damaging assessment model. In the in vitro selective photothermal transformation model, laser irradiation selectively increased the temperature of the internal microenvironment (pH 5.5) and resulted in an obvious temperature difference (ΔT ≥ 5 °C) with that of the external environment (pH 7.4). More importantly, in the in vivo skin damaging assessment model, S-AuNPs achieved good tumor inhibition without damaging the normal skin tissue compared with the conventional photothermal material. This work provides not only a novel validation protocol for tumor thermotherapy to achieve the biosafety of specifically killing tumor cells and normal tissue but also an evaluation methodology for other precise therapy for cancers.

Graphical abstract, Highlights • Facile antigen/adjuvant co-loaded nanovaccine made by convenient green preparation. • The immunological activity of the antigen and adjuvant was maximally preserved. • The minimalist nanovaccine had excellent stability and antitumor immune activation. • Nanovaccine combined with PD-1 antibody synergistically enhanced therapy outcome. • Good practicability for expanding clinical translation and personalized therapy., Introduction Tumor vaccine has been a research boom for cancer immunotherapy, while its therapeutic outcome is severely depressed by the vulnerable in vivo delivery efficiency. Moreover, tumor immune escape is also another intractable issue, which has badly whittled down the therapeutic efficiency. Objectives Our study aims to solve the above dilemmas by cooperating minimalist nanovaccine with PD-1 blockade for effective and feasible cancer immunotherapy. Methods The minimalist antigen and adjuvant co-delivery nanovaccine was developed by employing natural polycationic protamine (PRT) to carry the electronegative ovalbumin (OVA) antigen and unmethylated Cytosine-phosphorothioate-Guanine (CpG) adjuvant via convenient chemical bench-free “green” preparation without chemical-synthesis and no organic solvent was required, which could preserve the immunological activities of the antigens and adjuvants. On that basis, PD-1 antibody (aPD-1) was utilized to block the tumor immune escape and cooperate with the nanovaccine by maintaining the tumoricidal-activity of the vaccine-induced T cells. Results Benefited from the polycationic PRT, the facile PRT/CpG/OVA nanovaccine displayed satisfactory delivery performance, involving enhanced cellular uptake in dendritic cells (DCs), realizable endosomal escape and promoted stimulation for DCs’ maturation. These features would be helpful for the antitumor immunotherapeutic efficiency of the nanovaccine. Furthermore, the cooperation of the nanovaccine with aPD-1 synergistically improved the immunotherapy outcome, profiting by the cooperation of the “T cell induction” competency of the nanovaccine and the “T cell maintenance” function of the aPD-1. Conclusion This study will provide new concepts for the design and construction of facile nanovaccines, and contribute valuable scientific basis for cancer immunotherapy.

Developing chemotherapy drugs with high efficacy and few side effects has been a bottleneck problem that requires an efficient solution. The active cancer treatment ingredient disulfiram (DSF), inspired by the copper(II) diethyldithiocarbamate complex (CuET), can be used in a one-pot synthesis method to construct a CuET delivery nanosystem (CuET-ZIFCu@HA). Due to the high biocompatibility, targeting of CD44 overexpressed cancer cells, and acid response of zeolitic imidazolate framework (ZIF) materials of hyaluronic acid (HA), we realized that CuET-ZIFCu@HA could become an effective and highly selective cancer treatment. Both in vivo and in vitro experiments have demonstrated that CuET-ZIFCu@HA has robust anti-tumor properties without evident side effects. This research provided a promising strategy for DSF nanosystems that involves simple preparation and high efficacy, both of which are key to reusing DSF in cancer treatment.

MHealth service is widely accepted as a good path towards healthcare promotion. However, patients’ low-level usage restricted its effectiveness. This work draws upon the elaboration likelihood model and mindfulness theory to investigate the mindfulness mechanism in mHealth service usage, which highlights: First, both perceived information quality and mindfulness positively affect mHealth service usage. Also, perceived information quality is observed to affect the establishment of mindfulness positively. These findings stress that both perceived information quality and mindfulness are essential for mHealth service usage. Second, peer patient influence and physicians’ recommendations positively affect the establishment of mindfulness. These findings stress that human factors are essential for consumers’ establishment of mindfulness. Third, mindfulness mediates the relationship between human factors and mHealth service usage. This phenomenon indicates that when consumers adopt a mHealth service, both peer patient influence and physicians’ recommendations have a positive impact on mHealth service usage indirectly. Fourth, the effects of both peer patient influence and physicians’ recommendations on mindfulness depend on patients’ perceived eHealth literacy levels. This finding illustrates that while peer patient influence is especially crucial for improving mindfulness in a cohort with a high-level perceived eHealth literacy, physicians’ recommendations are especially crucial for improving mindfulness in a cohort with low-level perceived eHealth literacy.

Dong Zhang,1– 3,* Weifen Zhang,1,2,* Xinghan Wu,1 Qian Li,1,2 Zhiyi Mu,1,2 Fengshuo Sun,1,2 Mogen Zhang,1 Guoyan Liu,3 Linlin Hu1,2 1Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang, 261053, People’s Republic of China; 2College of Pharmacy, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoyan Liu; Linlin Hu Tel/Fax +86 15715369896Email wfliuguoyan@126.com; hull@wfmc.edu.cnPurpose: Malignant melanoma is one of the most devastating types of cancer with rapid relapse and low survival rate. Novel strategies for melanoma treatment are currently needed to enhance therapeutic efficiency for this disease. In this study, we fabricated a multifunctional drug delivery system that incorporates dacarbazine (DTIC) and indocyanine green (ICG) into manganese-doped mesoporous silica nanoparticles (MSN(Mn)) coupled with magnetic resonance imaging (MRI) and photothermal imaging (PI), for achieving the superior antitumor effect of combined chemo-photothermal therapy.Materials and Methods: MSN(Mn) were characterized in terms of size and structural properties, and drug loading and release efficiency MSN(Mn)-ICG/DTIC were analyzed by UV spectra. Photothermal imaging effect and MR imaging effect of MSN(Mn)-ICG/DTIC were detected by thermal imaging system and 3.0 T MRI scanner, respectively. Then, the combined chemo-phototherapy was verified in vitro and in vivo by morphological evaluation, ultrasonic and pathological evaluation.Results: The as-synthesized MSN(Mn) were characterized as mesoporous spherical nanoparticles with 125.57± 5.96 nm. MSN(Mn)-ICG/DTIC have the function of drug loading-release which loading ratio of ICG and DTIC could reach to 34.25± 2.20% and 50.00± 3.24%, and 32.68± 2.10% of DTIC was released, respectively. Manganese doping content could reach up to 65.09± 2.55 wt%, providing excellent imaging capability in vivo which the corresponding relaxation efficiency was 14.33 mM− 1s− 1. And outstanding photothermal heating ability and stability highlighted the potential biomedical applicability of MSN(Mn)-ICG/DTIC to kill cancer cells. Experiments by A375 melanoma cells and tumor-bearing mice demonstrated that the compound MSN(Mn)-ICG/DTIC have excellent biocompatibility and our combined therapy platform delivered a superior antitumor effect compared to standalone treatment in vivo and in vitro.Conclusion: Our findings demonstrate that composite MSN(Mn)-ICG/DTIC could serve as a multifunctional platform to achieve a highly effective chemo-photothermal combined therapy for melanoma treatment.Keywords: Mn-doped mesoporous silica, drug delivery, magnetic resonance imaging, combination therapy

Suppression of tumor development by inducing ferroptosis may provide a potential remedy for triple-negative breast cancer, which is sensitive to intracellular oxidative imbalance. Recently, artemisinin (ART) and its derivatives have been investigated as potential anticancer agents for the treatment of highly aggressive cancers via the induction of ferroptosis by iron-mediated cleavage of the endoperoxide bridge. Owing to its poor water solubility and limited intracellular iron content, it is challenging for further application in antitumor therapy. Herein, we developed ferrous-supply nano-carrier for ART based on tannic acid (TA) and ferrous ion (Fe(II)) coated on the zeolitic imidazolate framework-8 (ZIF) with ART encapsulated (TA-Fe/ART@ZIF) via coordination-driven self-assembly. Drug release experiments showed that ART was not nearly released in pH 7.4, while 59% ART was released in pH 5.0 after 10 h, demonstrating the excellent pH-triggered release. Meanwhile, a high level of intracellular ROS and MDA, accompanied with decreasing GSH and GPX4, displayed a newly developed nano-drug system displayed markedly enhanced ferroptosis. Compared with monotherapy, in vitro and vivo tumor inhibition experiments demonstrated higher efficiency of tumor suppression of TA-Fe/ART@ZIF. This work provides a novel approach to enhance the potency of ferroptotic nano-medicine and new directions for TBNC therapy.

Ferroptosis is a newly discovered form of regulated cell death and characterized by an iron-dependent accumulation of lethal lipid reactive oxygen species (ROS), ferroptosis may exhibit a novel spectrum of clinical activity for cancer therapy. However, the significance of ferroptosis in the context of carcinoma biology is still emerging. Glycogen synthase kinase-3β (GSK-3β) has been found to be a fundamental element in weaking antioxidant cell defense by adjusting the nuclear factor erythroid 2-related factor 2 (Nrf2). In our study, decreased expression of GSK-3β was observed in the cancer tissues of breast cancer patients, results of immunohistochemistry indicated that Nrf2 was highly expressed in low-GSK-3β-expressed breast cancer tissues. The contributions of aberrant expression of GSK-3β and Nrf2 to the erastin-induced ferroptosis in breast cancer were further assessed, silence of GSK-3β blocked erastin-induced ferroptosis with less production of ROS and malondialdehyde (MDA) via upregulation of GPX4 and downregulation of arachidonate 15-lipoxygenase (Alox15), overexpression of GSK-3β enhanced erastin-triggered ferroptosis with elevated ROS and MDA. Enhanced erastin-induced ferroptosis by overexpression of GSK-3β was blocked by activating Nrf2. We further confirmed that overexpression of GSK-3β strengthened erastin-induced tumor growth inhibition in breast cancer xenograft models in vivo. In summary, our findings conclude that modulation the balance between GSK-3β/Nrf2 is a promising therapeutic approach and probably will be important targets to enhance the effect of erastin-induced ferroptosis in breast cancer.

BACKGROUND Quality control system is one of the hospital information systems. The adoption of quality control system increases the work efficiency; however, to some extent, it also increases the workload for physicians. OBJECTIVE The purpose of this study is to investigate the impacts of the quality control system on quality of care (e.g., process and outcome performance). METHODS Our study collected physicians' behavior information from a large urban hospital in China. We constructed the fixed-effect model to examine the relationship between the quality control system adoption and quality of care. RESULTS Using the quality control system has a significant (p< 0.001) and negative effect on patients' stay length in the hospital (process performance). Furthermore, using the quality control system has a significant (p< 0.001) and positive effect on the trends of cure rate in the hospital (outcome performance). The coefficient of the dependent variable from the patients' stay length (process performance) is lower than the trends of cure rate (outcome performance). CONCLUSIONS The controlling system can improve medical quality even though it limits physician behavior to some extent. The controlling system improves both the process performance and outcome performance, and it brings more benefits to outcome performance rather than process performance which means the reflection of the new technology may have more evident on outcome variables.

Maternal obesity is associated with multiple adverse reproductive outcomes, whereas the underlying molecular mechanisms are still not fully understood. Here, we found the reduced nicotinamide phosphoribosyl transferase (NAMPT) expression and lowered nicotinamide adenine dinucleotide (NAD+ ) content in oocytes from obese mice. Next, by performing morpholino knockdown assay and pharmacological inhibition, we revealed that NAMPT deficiency not only severely disrupts maturational progression and meiotic apparatus, but also induces the metabolic dysfunction in oocytes. Furthermore, overexpression analysis demonstrated that NAMPT insufficiency induced NAD+ loss contributes to the compromised developmental potential of oocytes and early embryos from obese mice. Importantly, in vitro supplement and in vivo administration of nicotinic acid (NA) was able to ameliorate the obesity-associated meiotic defects and oxidative stress in oocytes. Our results indicate a role of NAMPT in modulating oocyte meiosis and metabolism, and uncover the beneficial effects of NA treatment on oocyte quality from obese mice.

It has been widely reported that advanced maternal age impairs oocyte quality. To date, various molecules have been discovered to be involved in this process. However, prevention of fertility issues associated with maternal age is still a challenge. In the present study, we find that both in vitro supplement and in vivo administration of melatonin are capable of alleviating the meiotic phenotypes of aged oocytes, specifically the spindle/chromosome disorganization and aneuploidy generation. Furthermore, we identify SIRT2 as a critical effector mediating the effects of melatonin on meiotic structure in old oocytes. Candidate screening shows that SIRT2-controlled deacetylation of histone H4K16 is essential for maintaining the meiotic apparatus in oocytes. Importantly, non-acetylatable-mimetic mutant H4K16R partially rescues the meiotic deficits in oocytes from reproductive aged mice. In contrast, overexpression of acetylation-mimetic mutant H4K16Q abolishes the beneficial effects of melatonin on the meiotic phenotypes in aged oocytes. To sum up, our data uncover that melatonin alleviates advanced maternal aged-associated meiotic defects in oocytes through the SIRT2-depenendet H4K16 deacetylation pathway.

Maternal obesity is associated with multiple adverse reproductive outcomes, whereas the underlying molecular mechanisms are still not fully understood. Here, we found the reduced nicotinamide phosphoribosyl transferase (NAMPT) expression and lowered nicotinamide adenine dinucleotide (NAD+) content in oocytes from obese mice. Next, by performing morpholino knockdown assay and pharmacological inhibition, we revealed that NAMPT deficiency not only severely disrupts maturational progression and meiotic apparatus, but also induces the metabolic dysfunction in oocytes. Furthermore, overexpression analysis demonstrated that NAMPT insufficiency induced NAD+ loss contributes to the compromised developmental potential of oocytes and early embryos from obese mice. Importantly, in vitro supplement and in vivo administration of nicotinic acid (NA) was able to ameliorate the obesity‐associated meiotic defects and oxidative stress in oocytes. Our results indicate a role of NAMPT in modulating oocyte meiosis and metabolism, and uncover the beneficial effects of NA treatment on oocyte quality from obese mice., This study reports that the potential pathway mediating the effects of NAD+ generation on the quality of HFD oocytes. Loss of NAD+ content and NAMPT protein results in the meiotic defects and oxidative stress in oocytes from obese mice. Nicotinic acid (NA) supplement could partly rescue the defective phenotype of these oocytes.

Additional file 1: Fig. 1s. X-ray photoelectron spectroscopic of TA-Fe/ART@ZIF. Fig. 2s. EDS spectrum of TA-Fe/ART@ZIF. Fig. 3s. Hydrodynamic size of ZIF-8, ZIF-ART and TA-Fe/ART@ZIF in different raw material proportions. Fig. 4s. Zeta potential of ZIF-8, ZIF-ART and TA-Fe/ART@ZIF in different raw material proportions. Fig. 5s. Time course of size distribution of TA-Fe/ART@ZIF nanoparticles. Fig. 6s. ART, TA-Fe/ZIF and TA-Fe/ART@ZIF nanoparticles induced apoptosis in MDA-MB-231 cells detected by flow cytometry.

Suppression of tumor development by inducing ferroptosis may provide a potential remedy for triple-negative breast cancer (TNBC), which is sensitive to intracellular oxidative imbalance. Recently, artemisinin (ART) and its derivatives have been investigated as potential anticancer agents for the treatment of highly aggressive cancers via the induction of ferroptosis by iron-mediated cleavage of the endoperoxide bridge. Poor water solubility and insufficient availability of intracellular ferrous ions, limit the further application of ART in antitumor therapy. In this study, ferrous-supply nanocarrier was constructed based on tannic acid (TA) and ferrous ion (Fe2+)-coated on the zeolitic imidazolate framework-8(ZIF) with ART encapsulated (TA-Fe/ART@ZIF). via supramolecular coordination. Following the internalization of the as-prepared nano-system in cells, acidic degradation of the vehicles would facilitate the release of ART and accumulation of Fe2+. The results revealed that the newly developed nano-drug system displayed a high level of intracellular ROS generation, and markedly enhanced ferroptosis. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine and new directions for TBNC therapy.

Although ferroptosis has been recognized as a novel antitumoral treatment, high expression of nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to be an antioxidant transcript factor that protects malignant cells from ferroptosis. Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. Here we aimed at assessing whether MT1DP could regulate erastin-induced ferroptosis on non-small cell lung cancer (NSCLC) and elucidating the mechanism. We found that ectopic expression of MT1DP sensitized A549 and H1299 cells to erastin-induced ferroptosis through downregulation of NRF2; in addition, ectopic MT1DP upregulated malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increased intracellular ferrous iron concentration, and reduced glutathione (GSH) levels in cancer cells exposed to erastin, whereas downregulation of MT1DP showed the opposite effect. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. As low solubility of erastin limits its efficient application, we further prepared folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination. Erastin/MT1DP@FA-LPs (E/M@FA-LPs) sensitized erastin-induced ferroptosis with decreased cellular GSH levels and elevated lipid ROS. In vivo analysis showed that E/M@FA-LPs had a favorable therapeutic effect on lung cancer xenografts. In short, our findings identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.

Monitoring the concentration of ascorbic acid (AA) in biological samples is essential to food quality and healthcare. Various fluorescence methods widely reported for the detection of AA are usually based on “turn-on” or “turn-off” principle. However, few ratiometric fluorescent sensors were reported for AA determination. Additionally, the application of ratiometric fluorescence probe is usually limited by the narrow range of color changes and insensitivity color change of the AA concentration. Herein, a novel ratiometric fluorescent test paper to achieve the continuous color changes from red to blue was developed for the fluorometric qualitative and quantitative determination of AA. The nanoprobe consists of blue-emitting carbon dots (C-dots) and red-emitting silica coated quantum dots (QDs@SiO2) with certain ratiometric fluorescence intensity of blue to red. The fluorescence of blue-emitting CDs (peaking at 450 nm) is quenched by Fe3+, then the blue fluorescence is restored consecutively with the gradual increasing of AA concentration due to the reduction from Fe3+ to Fe2+ by using AA. While the fluorescence of red-emitting QD@SiO2 (peaking at 630 nm) works as a stable internal standard. Therefore, a distinguish color transition from red to blue can be observed by naked eyes intuitively with the increasing of AA concentration. By calculating the ratiometric fluorescent intensity at 450 nm and 630 nm or observing the color of the mixture solution by naked eyes, the concentration of AA can be detected easily and accurately. Under optimized conditions, the fluorescent intensity ratio (I450/I630) shows linear relationship with the concentration of AA from 0 to 70 μM with the detection limit as low as 3.17 μM. Finally, a ratiometric fluorescent sensor paper was further developed for AA detection with satisfactory results in fruit juice. The method proposed here gives the wide applications of fluorescent test paper in food and biological assays.

BACKGROUND Diabetes and related complications are estimated to cost US $727 billion worldwide annually. Type 1 diabetes, type 2 diabetes, and gestational diabetes are three subtypes of diabetes that share the same behavioral risk factors. Efforts in lifestyle modification, such as daily physical activity and healthy diets, can reduce the risk of prediabetes, improve the health levels of people with diabetes, and prevent complications. Lifestyle modification is commonly performed in a face-to-face interaction, which can prove costly. Mobile phone apps provide a more accessible platform for lifestyle modification in diabetes. OBJECTIVE This review aimed to summarize and synthesize the clinical evidence of the efficacy of mobile phone apps for lifestyle modification in different subtypes of diabetes. METHODS In June 2018, we conducted a literature search in 5 databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and PsycINFO). We evaluated the studies that passed screening using The Cochrane Collaboration’s risk of bias tool. We conducted a meta-analysis for each subtype on the mean difference (between intervention and control groups) at the posttreatment glycated hemoglobin (HbA1c) level. Where possible, we analyzed subgroups for short-term (3-6 months) and long-term (9-12 months) studies. Heterogeneity was assessed using the I2 statistic. RESULTS We identified total of 2669 articles through database searching. After the screening, we included 26 articles (23 studies) in the systematic review, of which 18 studies (5 type 1 diabetes, 11 type 2 diabetes, and 2 prediabetes studies) were eligible for meta-analysis. For type 1 diabetes, the overall effect on HbA1c was statistically insignificant (P=.46) with acceptable heterogeneity (I2=39%) in the short-term subgroup (4 studies) and significant heterogeneity between the short-term and long-term subgroups (I2=64%). Regarding type 2 diabetes, the overall effect on HbA1c was statistically significant (P CONCLUSIONS There is strong evidence for the efficacy of mobile phone apps for lifestyle modification in type 2 diabetes. The evidence is inconclusive for the other diabetes subtypes.

Advanced maternal age has been reported to impair oocyte quality; however, the underlying mechanisms remain to be explored. In the present study, we identified the lowered NAD+ content and decreased expression of NMNAT2 protein in oocytes from old mice. Specific depletion of NMNAT2 in mouse oocytes disturbs the meiotic apparatus assembly and metabolic activity. Of note, nicotinic acid supplementation during in vitro culture or forced expression of NMNAT2 in aged oocytes was capable of reducing the reactive oxygen species (ROS) production and incidence of spindle/chromosome defects. Moreover, we revealed that activation or overexpression of SIRT1 not only partly prevents the deficient phenotypes of aged oocytes but also ameliorates the meiotic anomalies and oxidative stress in NMNAT2‐depleted oocytes. To sum up, our data indicate a role for NMNAT2 in controlling redox homeostasis during oocyte maturation and uncover that NMNAT2‐ NAD+‐SIRT1 is an important pathway mediating the effects of maternal age on oocyte developmental competence.

SIRT4 modulates energy homeostasis in multiple cell types and tissues. However, its role in meiotic oocytes remains unknown. Here, we report that mouse oocytes overexpressing SIRT4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization. Moreover, we find that phosphorylation of Ser293‐PDHE1α mediates the effects of SIRT4 overexpression on metabolic activity and meiotic events in oocytes by performing functional rescue experiments. By chance, we discover the SIRT4 upregulation in oocytes from aged mice; and importantly, the maternal age‐associated deficient phenotypes in oocytes can be partly rescued through the knockdown of SIRT4. These findings reveal the critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and indicate that SIRT4 is an essential factor determining oocyte quality.