Search

This study aimed to explore the role of CD4+ T cells in the mechanisms of COVID-19 related diarrhea.We analyzed lymphocyte subsets in patients with COVID-19 and the expression of angiotensin-converting enzyme 2 (ACE2), the transmembrane protease serine 2, and CD4+ T cell-related indicators in the colon were compared between patients with and without diarrhea. Correlation analyses were performed for ACE2 and other indicators to identify the relationship between SARS-CoV-2 infection and CD4+ mediated inflammation. The expression and distribution of CD4+ T cell-associated chemokines and their receptors were detected to determine the possibility of migration of CD4+ T cells to inflammation sites.The CD4+ T cell counts and percentages and CD4/CD8 ratio showed the most significant differences between the 2 groups. The diarrhea group expressed higher levels of ACE2, T-box expressed in T cells (Tbet), and tumor necrosis factor-alpha (TNFα) at both the mRNA and protein levels, with no difference from the nondiarrhea group for the percentage of ACE2+TNFα+ cells, indicating an indirect association between ACE2 and TNFα. The mRNA expression of CXCL10, CXCL11, and CXCR3 and the number of CD4+CXCR3+T cells were increased in the diarrhea group.CD4+ T cell-mediated inflammation may contribute to COVID-19 related diarrhea. CXCR3+ mediated migration of CD4+ T cells into the gut may perpetuate inflammation.

Previous prediction studies for 30 day readmission in patients with heart failure were built mainly based on electronic medical records and rarely involved patient-reported outcomes. This study aims to develop and validate a nomogram including patient-reported outcomes to predict the possibility of 30 day all-cause readmission in older patients with heart failure and to explore the value of patient-reported outcomes in prediction model.This was a prospective cohort study. The nomogram was developed and internally validated by Logistic regression analysis based on 381 patients in training group from March to December 2019. The nomogram was externally validated based on 170 patients from July to October 2020. Receiver operating characteristic curves, calibration plots and decision-curve analysis were used to evaluate the performance of the nomogram. A total of 381 patients' complete data were analysed in the training group and 170 patients were enrolled in the external validation group. In the training group, 14.4% (n = 55) patients were readmitted to hospitals within 30 days of discharge and 15.9% (n = 27) patients were readmitted in the external validation group. The nomogram included six factors: history of surgery, changing the type of medicine by oneself, information acquisition ability, subjective support, depression level, quality of life, all of which were significantly associated with 30 day readmission in older patients with heart failure. The areas under the receiver operating characteristic curves of nomogram were 0.949 (95% CI: 0.925, 0.973, sensitivity: 0.873, specificity: 0.883) and 0.804 (95% CI: 0.691, 0.917, sensitivity: 0.778, specificity: 0.832) respectively in the training and external validation groups, which indicated that the nomogram had better discrimination ability. The calibration plots demonstrated favourable coordination between predictive probability of 30 day readmission and observed probability. Decision-curve analysis showed that the net benefit of the nomogram was better between threshold probabilities of 0-85%.A novel and easy-to-use nomogram is constructed and demonstrated which emphasizes the important role of patient-reported outcomes in predicting studies. The performance of the nomogram drops in the external validation cohort and the nomogram must be validated in a wide prospective cohort of HF patients before its clinical relevance can be demonstrated. All these findings in this study can assist professionals in identifying the needs of HF patients so as to reduce 30 day readmission.

Recently, mesenchymal stem cell (MSC) therapy has been suggested as an effective alternative approach for the treatment of hepatic diseases. MSCs have potential therapeutic value, because they have high self-renewal ability, are capable of multipotent differentiation, and have low immunogenicity. Furthermore, MSCs have the potential to differentiate into hepatocytes, and the therapeutic value exists in their immune-modulatory properties and secretion of trophic factors, such as growth factors and cytokines. Moreover, MSCs can suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, regress liver fibrosis, and enhance liver functionality.

Gastric cancer (GC) mortality continues to fall in industrialized countries, but still remains a public health concern in China, accounting for more than 370 000 deaths. We aimed to evaluate the survival of GC in China from 2000 to 2022 through a nationwide systematic review of hospital-based studies and to identify whether hospital-based studies show higher survival rates than population-based studies.We searched PubMed, Embase, Web of Science, and the Chinese databases of CNKI and Wanfang for hospital-based studies on GC survival published between January 1, 2000, and January 20, 2022. We calculated the nationwide GC survival rate (SR) and its 95% confidence interval (CI) and conducted subgroup analyses on histologic type, subsite, tumour node metastasis (TNM) stage, therapy type, study design, and participant region. The study protocol was registered in PROSPERO (CRD-42019121559).The initial literature search returned 36 613 publications, among which 664 studies (180 798 participants) matched the inclusion criteria and were included in the meta-analysis. The pooled one-, two-, three- and five-year SRs of GC were 75.4% (95% CI = 74.0%-76.8%), 54.3% (95% CI = 50.1%-58.6%), 53.4% (95% CI = 50.4%-56.4%), and 44.5% (95% CI = 41.5%-47.5%), respectively. Subgroup analyses revealed an increase in three- and five-year SRs from 2006 to 2022. The five-year SR was highest among patients without lymph node metastasis (pooled SR = 67.8%, 95% CI = 62.8%-72.7%) and lowest among those with distant metastasis (pooled SR = 8.4%, 95% CI = 5.1%-11.7%).Our findings illustrate that the long-term survival of GC has improved in China since 2000. Hospital-based studies have presented higher SRs than population-based surveillance.

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound

Convenient, ultrasensitive, and accurate detection of rare variants is essential for early cancer diagnosis and precision medicine, however, despite years of efforts, tools that have all these qualities remain elusive. Here, we developed a one-step CRISPR/Cas12a-based digital diagnostic platform for accurately quantifying mutant alleles, referred to as the CRISPR ASsoaciated Mutation Allele Rapid Test (CASMART). The platform accurately quantifies the variant allele frequency of EGFR L858R within 1 h at 42 °C and can detect mutant targets as low as 0.3 copies/μL (0.498 aM) in mock multiplex cfDNA samples. We further investigated the applicability of CASMART using human genomic samples with confirmed EGFR L858R mutations previously measured variant allele frequency by next-generation sequencing. Comparison across platforms revealed equivalent detection performance (Pearson's correlation coefficient, R

Many current chemodynamic therapy (CDT) strategies suffer from either low therapeutic efficiency or the deficiency of poor targeting. The low therapeutic efficiency is mainly ascribed to the intracellular antioxidant system and the inefficient Fenton reaction in the weakly acidic tumor microenvironment (TME). Herein, by exploitation of the diverse function and programmability of functional nucleic acid, aptamer-tethered nanotrains of DNA copper nanoclusters (aptNTDNA-CuNCs) were assembled to simultaneously achieve targeted recognition, loading, and delivery of CDT reagents into tumor cells without an external carrier. The intracellular hydrogen peroxide (H

The automatic generation algorithm of optical coherence tomography (OCT) images based on generative adversarial networks (GAN) can generate a large number of simulation images by a relatively small number of real images, which can effectively improve the classification performance.We proposed an automatic generation algorithm for retinal OCT images based on GAN to alleviate the problem of insufficient images with high quality in deep learning, and put the diagnosis algorithm toward clinical application.We designed a generation network based on GAN and trained the network with a data set constructed by 2014_BOE_Srinivasan and OCT2017 to acquire three models. Then, we generated a large number of images by the three models to augment age-related macular degeneration (AMD), diabetic macular edema (DME), and normal images. We evaluated the generated images by subjective visual observation, Fréchet inception distance (FID) scores, and a classification experiment.Visual observation shows that the generated images have clear and similar features compared with the real images. Also, the lesion regions containing similar features in the real image and the generated image are randomly distributed in the image field of view. When the FID scores of the three types of generated images are lowest, three local optimal models are obtained for AMD, DME, and normal images, indicating the generated images have high quality and diversity. Moreover, the classification experiment results show that the model performance trained with the mixed images is better than that of the model trained with real images, in which the accuracy, sensitivity, and specificity are improved by 5.56%, 8.89%, and 2.22%. In addition, compared with the generation method based on variational auto-encoder (VAE), the method improved the accuracy, sensitivity, and specificity by 1.97%, 2.97%, and 0.99%, for the same test set.The results show that our method can augment the three kinds of OCT images, not only effectively alleviating the problem of insufficient images with high quality but also improving the diagnosis performance.

Hypoxia, the most common feature in the tumor microenvironment, is closely related to tumor malignant progression and poor patient’s prognosis. Exosomes, initially recognized as cellular “garbage dumpsters”, are now known to be important mediums for mediating cellular communication in tumor microenvironment. However, the mechanisms of hypoxic tumor cell-derived exosomes facilitate colorectal cancer progression still need further exploration. In the present study, we found that exosomes from hypoxic colorectal cancer cells (H-Exos) promoted G1-S cycle transition and proliferation while preventing the apoptosis of colorectal cancer cells by transmitting miR-210-3p to normoxic tumor cells. Mechanistic investigation indicated that miR-210-3p from H-Exos elicited its protumoral effect via suppressing CELF2 expression. A preclinical study further confirmed that H-Exos could promote tumorigenesis in vivo. Clinically, the expression of miR-210-3p in circulating plasma exosomes was markedly upregulated in colorectal cancer patients, which were closely associated with multiple unfavorable clinicopathological features. Taken together, these results suggest that hypoxia may stimulate colorectal cancer cells to secrete miR-210-3p-enriched exosomes in tumor microenvironment, which elicit protumoral effects by inhibiting CELF2 expression. These findings provide new insights on the mechanism of colorectal cancer progression and potential therapeutic targets for colorectal cancer.

Aims/Introduction This study aimed to evaluate the association between time in range (TIR) obtained from continuous glucose monitoring and the prevalence and degree of painful diabetic neuropathy. Materials and Methods A total of 364 individuals with diabetic peripheral neuropathy were enrolled in this study. Sensor‐based flash glucose monitoring systems were used to monitor the participants’ glucose levels, and the glycemic variability metrics were calculated, including the TIR, glucose coefficient of variation, standard deviation and the mean amplitude of glycemic excursions. The participants were asked to record any form of pain during the 2 weeks of monitoring, and score the pain every day on a numerical rating scale. Based on the numerical rating scale, the patients were divided into the pain‐free group, mild pain group and moderate/severe pain group. Results Overall, 51.92% (189/364) of the participants were diagnosed with painful diabetic neuropathy. Compared with the pain‐free group, the level of TIR decreased significantly in the mild pain and moderate/severe pain groups (P, Time in range is correlated with the degree of painful diabetic neuropathy independently of the glycated hemoglobin level, other glycemic variability metrics and risk factors among diabetes patients. Furthermore, time in range was a valuable clinical evaluation indicator for patients with diabetes.

Increase in infections with Gram-negative Pseudomonas aeruginosa (P. aeruginosa) is a serious global challenge in healthcare. Sinoporphyrin sodium (DVDMS) combined with photodynamic antimicrobial chemotherapy (PACT) can effectively eradicate Gram-positive organisms. However, the poor penetration of DVDMS into the Gram-negative bacterial cell membrane and bacterial biofilm greatly limits the photo-inspired antimicrobial activity. This study optimized the cationic lipid-mediated nano-DVDMS delivery to improve the cellular uptake, and evaluated the antimicrobial efficacy of cationic DVDMS-liposome (CDL)-provoked PACT in both P. aeruginosa and its multidrug resistant strain. The results showed that the positively charged liposome modification promoted the enrichment of DVDMS in Gram-negative bacteria. CDL-PACT-produced ROS and caused bacterial death, accompanied by the decreased expression levels of virulence factor-related genes. The P. aeruginosa-infected burn model indicated satisfactory bacterial eradication and accelerated wound healing after CDL-PACT, in addition to gradually increasing bFGF, VEGF, TGF-β1 and Hyp levels and reducing TNF-α and IL-6, with no detectable side-effects. Overall, these findings provide fundamental knowledge that enables the design of feasible and efficient PACT treatments, including biophysical membrane permeabilization and photodynamic eradication, which are promising to overcome the infection and resistance of highly opportunistic Gram-negative bacteria.

Cancer phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) has recently attracted much attention owing to its high efficacy and good safety compared with that in the first near-infrared window (NIR-I, 650-950 nm). However, the lack of theranostic nanoagents with active-targeting features limits its further application in cancer precision therapies. Herein, we constructed platelet-camouflaged nanoprobes with active-targeting characteristics for NIR-II cancer phototheranostics. The as-prepared biomimetic nanoprobes can not only escape phagocytosis by macrophages but also specifically bind to CD44 on the surface of most cancer cells. We evaluated the active-targeting performance of biomimetic nanoprobes in pancreatic cancer, breast cancer, and glioma mouse models and achieved NIR-II photoacoustic imaging with a high signal-to-background ratio and photothermal treatment with excellent tumor growth inhibition. Our results show the great potential of platelet-camouflaged nanoprobes with NIR-II active-targeting features for cancer precision diagnosis and efficient therapies.

To determine the impact of symptom clusters on clinical outcomes among heart failure patients.Systematic review and meta-analysis.Peer-reviewed articles were searched from 12 English and Chinese language databases from inception to August 2021.Narrative syntheses were first conducted to integrate symptom clusters reported in the identified studies. This was followed by meta-analysis to synthesize the evidence on the association or predictive effects of symptom clusters on clinical outcomes.Twelve studies were identified. Among studies which identified highly correlated symptoms as in a cluster, meta-analysis indicated that severe congestive (r = .45, 95% CI = 0.38-0.52), weary (r = .41, 95% CI = 0.33-0.50), ischaemic (r = .29, 95% CI = 0.04-0.51) and stress-related (r = .62, 95% CI = 0.31-0.81) symptom clusters were correlated with a poorer health-related quality of life. As for studies used latent class to identified patient cohorts of similar symptom pattern, high symptom cohorts (hazard ratio = 1.86, 95% CI = 1.39-2.48) and incongruent physical and psycho-cognitive symptom cohorts was associated with a significantly higher risk (hazard ratio = 2.10, 95% CI = 1.44-3.07) of combined event rate relative to low symptom presentation.This review has identified the impact of symptom clusters on clinical outcomes in heart failure patients. In addition to the classical physical symptoms highlighted in the clinical management guidelines, our findings suggested the important predictive role of psycho-cognitive and weary symptoms in determining the clinical outcomes of HF patients.This review concluded the promising prospect of symptom clusters in shaping clinical outcomes of heart failure. The findings highlighted the importance of integrating care to minimize the disease impact on psycho-cognitive function and weary symptoms among this clinical cohort. The review also inform the direction on how to advance the knowledge on symptom clusters among this clinical cohort.

Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent. However, the lack of a clear understanding of the indications of metformin limits its efficacy. Here, we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment (T18) compared to those of the untreated cells at day 0 (T0) yielded candidate genes. Knockdown of a group of cyclin-dependent kinases (CDKs), including CDK1, CDK4, and CDK6, confirmed the results of the screen. Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo. Although cell cycle parameters were not further altered under the combination treatment, investigation of the metabolome revealed significant changes in cell metabolism, especially with regard to fatty acid oxidation, the tricarboxylic acid cycle and aspartate metabolism. Such changes appeared to be mediated through inhibition of the mTOR pathway. Collectively, our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.

Objectives This study aims to characterize the expression profiles of circRNAs in primary Sjogren’s Syndrome (pSS) and examine the potential of noninvasive circular RNAs (circRNAs) as biomarkers of pSS. Methods We performed RNA sequencing of minor salivary gland (MSG) biopsies from four pSS and four non-pSS individuals (subjects undergoing MSG biopsies but not meeting 2012 or 2016 ACR classification criteria for SS). Differentially expressed circRNAs were identified by DESeq2, and confirmed by quantitative real-time PCR in the MSGs as well as in plasma exosomes in 37 pSS and 14 non-pSS subjects. Discriminatory capacity testing using receiver operating characteristic analysis was used to evaluate the performance of circRNAs as diagnostic biomarkers for pSS. Results Circ-IQGAP2 and circ-ZC3H6 had significantly upregulated expression in the MSGs of pSS patients, and this elevated expression was confirmed by quantitative real-time PCR of plasma exosome RNA. The expression of these circRNAs also showed significant correlation with both clinical features, serum IgG level and MSG focus scores. Receiver operating characteristic analysis showed that the indices comprised of both the two circRNAs and clinical features were better able to distinguish pSS from non-pSS subjects with high mean areas under the curve of 0.93 in the MSGs and 0.92 in the plasma exosomes. Conclusion This study indicated the potential roles of circ-IQGAP2 and circ-ZC3H6 as noninvasive biomarkers for the diagnosis of pSS.

Major salivary gland ultrasonography (SGUS) is increasingly being recognized as having critical roles in differentiating primary Sjögren’s syndrome (pSS) from other connective tissue disorders. Contrast-enhanced ultrasonography (CEUS) has been reported to evaluate microvascularity of lesions in different tissues with objective angiographic index, eliminating the observer-dependent defect of ultrasonography. However, there are few relevant studies concentrating on the application of CEUS in the diagnosis and assessment for pSS, and their clinical utility prospect remains uncertain. In this study, a total of 227 eligible patients were enrolled, including 161 pSS and 66 non-pSS patients with comprehensive ultrasonographic evaluation of the parotid and submandibular glands, including grayscale ultrasonography, color Doppler sonography (CDS), and CEUS. Compared with non-pSS, pSS patients had significantly higher grayscale ultrasound (US) scores and CDS blood grades in the parotid gland and significantly higher grayscale US and CEUS scores in the submandibular glands. Diagnostic model combining ultrasonographic signatures, anti-SSA/Ro60, and keratoconjunctivitis sicca (KCS) tests showed a remarkable discrimination [mean area under the curve (AUC)0.963 in submandibular glands and 0.934 in parotid glands] for pSS, and the nomogram provided excellent prediction accuracy and good calibration in individualized prediction of pSS. A combination of multiple ultrasonographical examinations of the major salivary glands (SGs) is a promising technique that may be used as a practical alternative to minor SG biopsy in the detection of pSS.

Simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) can reduce the risks of drug leakage, body burden, and preparation complexity in traditional combination PDT/PTT. Here, a versatile nanoporphyrin (Pp18-lipos) self-assembled from lipid-purpurin 18 conjugates (Pp18-lipids) and pure lipids is presented. The as-prepared Pp18-lipos with 2 mol% Pp18-lipids can perform effective PDT and fluorescence imaging. The Pp18-lipos with 65 mol% Pp18 can perform potent PTT and photoacoustic imaging. The chelation of Mn2+ endows the Pp18-lipids-Mn2+ a high T1 -weighted magnetic resonance imaging contrast. Notably, pretreatment of low-dose PDT facilitates the endocytosis and tumor accumulation of Pp18-lipos, thus achieving synergistic PDT/PTT. Upon exposure to a single 705 nm-laser, the combination of PDT/PTT achieves a significantly higher tumor growth inhibition rate than PDT or PTT alone. In addition, it is found that the synergistic PDT/PTT triggers more potent anti-tumor immune response including tumor infiltration of immune cells and release of related cytokines.

The human microbiome plays an important role in autoimmune diseases. However, there is limited knowledge regarding the microbiota in individuals with primary Sjögren's syndrome (pSS). Here, we perform 16S ribosomal RNA gene sequencing of fecal, oral, and vaginal samples from a cohort of 133 individuals with pSS, 56 with non-pSS, and 40 healthy control (HC) individuals. Dysbiosis in the gut, oral, and vaginal microbiome is evident in patients with pSS, and oral samples demonstrate the greatest extent of microbial variation. Multiple key indicator bacteria and clinical characteristics are identified across different body sites, implying that microbial dysbiosis has important roles in the pathogenesis of pSS. Furthermore, we observe pSS-like dysbiosis in individuals with pre-clinical pSS or non-pSS-related disease, revealing that microbial shifts could appear prior to pSS. After hydroxychloroquine (HCQ) treatment, microbial dysbiosis in individuals with pSS is partially resolved, although the microbiota composition remain disordered. These results contribute to the overall understanding of the relationship between the microbiome and pSS.

Sonodynamic therapy (SDT), wherein focused ultrasound is used to guide the site-specific delivery of nano-sonosensitizers and trigger profound sono-damage, has great potential in cancer theranostics. The development of nanosensitizers with high sono-activatable efficiency and good biosafety is however challenging. Methods: In this study, we designed a functionalized smart nanosonosensitizer (EXO-DVDMS) by loading sinoporphyrin sodium (DVDMS), an excellent porphyrin sensitizer with both potential therapeutic and imaging applications, onto homotypic tumor cell-derived exosomes. Because of the high binding-affinity between DVDMS and proteins, coincubation of DVDMS and exosome would result in DVDMS attached on the surface or loaded in the core of exosomes. The prepared EXO-DVDMS was applied for ultrasound-responsive controlled release and enhanced SDT. Results: Tumor cell-derived exosomes exhibited high stability and specificity towards the homotypic tumors, along with highly controlled ultrasound-responsive drug release, and boosted reactive oxygen species (ROS) generation to augment SDT. Intriguingly, EXO-DVDMS was endocytosed by lysosomes, and the low pH in the latter triggered DVDMS relocation synergistically with the ultrasound, thereby initiating multiple cell death-signaling pathways. Furthermore, the exosomal formulation served as a functionalized nanostructure, and facilitated simultaneous imaging and tumor metastasis inhibition, that were respectively 3-folds and 10-folds higher than that of free form. Conclusions: Taken together, our findings suggest that an extracorporeal ultrasound device can non-invasively enhance homogenous tumor targeting and SDT toxicity of EXO-DVDMS, and the developed endogenous nano-sonosensitizer is a promising nanoplatform for activated cancer theranostics.

Human embryonic stem cells (hESCs) have the potential to differentiate along the retinal lineage. We have efficiently differentiated human pluripotent stem cells into optic cup-like structures by using a novel retinal differentiation medium (RDM). The purpose of this study was to determine whether the retinal progenitor cells (RPCs) derived from hESCs can integrate into the host retina and differentiate into retinal ganglion cells (RGCs) in vivo. In this study, hESCs (H9-GFP) were induced to differentiate into optic cup-like structures by using our novel differentiation system. The RPCs extracted from the optic cup-like structures were transplanted into the vitreous cavity of N-methyl-d-aspartic acid-treated mice. Sham-treated eyes received the same amount of RDM. The host retinas were analyzed by triple immunofluorescence on the fourth and fifth weeks after transplantation. The optic cup-like structures were efficiently differentiated from hESCs by using our novel differentiation system in vitro for 6-8 weeks. The RPCs extracted from the optic cup-like structures migrated and integrated into the ganglion cell layer (GCL) of the host retina. Furthermore, the remaining transplanted cells were spread over the GCL and had a complementary distribution with host residual RGCs in the GCL of the mouse retina. Surprisingly, some of the transplanted cells expressed the RGC-specific marker Brn3a. These findings demonstrated that the RPCs derived from hESCs could integrate into the host GCL and differentiate into retinal ganglion-like cells in vivo, suggesting that RPCs can be used as an ideal source in supplying countless RGC and embryonic stem cell-based replacement therapies may be a promising treatment to restore vision in patients with degenerative retinal diseases.

A hybrid nanocomposite containing a moisture-resistant surface based on MOF-199 and carbon nanotubes (CNTs) was synthesized. Characterization was undertaken using powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). The adsorption behavior of the MOF-199/CNTs composite to ibuprofen was then investigated at room temperature. Experimentation revealed that the hybrid absorbent had excellent adsorption capacity for the nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, with maximum adsorption up to 40.8 mg/g. The adsorbent was able to be recycled several times without deactivation. Finally, the MOF-199/CNTs composite was used as the extraction sorbents for selective extraction of ibuprofen, ketoprofen and naproxen in human urine. The results showed successful application of the nanocomposite to NSAID analysis in spiked human urine samples. Recoveries at three concentrations were 89.7-96.8%, 79.3-85.5% and 95.6-97.5% for ibuprofen, ketoprofen and naproxen, respectively. The relative standard deviations (RSDs) were within the range of 2.9-5.3%. The results demonstrated that the MOF-199/CNTs composite is an excellent adsorbent for determination of NSAIDs in spiked urine samples.

The therapeutic efficacy of anti-cancer nanomedicines is generally constrained due to limited accumulation in the solid tumors. In this study, we developed a biomimetic nano-carrier to enhance the chemo-therapeutic efficacy of doxorubicin and icotinib in a chemo-resistant non-small cell lung cancer (NSCLC) cell line harboring a mutation in the epidermal growth factor receptor (EGFR). The unique nanomedicine was prepared by coating with targeting cancer cell membrane proteins as highly specific ligands. The resulting biomimetic nanoparticles were highly stable and exhibited superior homologous targeting ability in vitro compared with control groups. In a mouse EGFR-mutated NSCLC xenograft model, intravenous injection of the biomimetic nanomedicine led to a high tumour inhibition rate (87.56%). Histopathological analysis demonstrated that the biomimetic nanomedicine had minimal side effects. Taken together, a cancer cell membrane-based biomimetic drug carrier can significantly enhance drug accumulation and improve therapeutic efficacy in cancers.

Sepsis is a major cause of patient mortality and morbidity from bacterial infections. Although neutrophils are known to be important in the development of sepsis, how distinctive neutrophil subtypes regulate inflammatory processes involved in septicemia remains unclear. Preconditioning protects organisms against subsequent higher-dose exposures to the same, or even different, stimuli. Several studies have reported various effects of preconditioning on immune cells. However, the detailed mechanisms underlying neutrophil-mediated protection through preconditioning in sepsis remain unknown. Methods: Flow cytometry was conducted to sort the mice peritoneal lavage cells and the blood samples from patients with sepsis. Western blotting and ELISA were carried out to elucidate the expression of TLR9 signal transduction pathway proteins. Histological analysis was used to assess the effect of InP on intestine and liver structure in tlr9-/- and cav-1-/- mice. Fluorescence microscopy, Co-IP, and FRET were carried out to determine the association of TLR9 with Cav-1. Results: We show that membrane toll-like receptor-9 positive (mTLR9+) neutrophils exert a protective effect against fatal bacterial infections through the process of inflammatory preconditioning (InP). InP, which occurs in the setting of a low-dose bacterial challenge, active ingredient is Monophosphoryl lipid A (MPLA), triggers the membrane translocation of TLR9 from the neutrophil cytosol, where it binds to Cav-1. Our findings showed that InP enables TLR9 to facilitate MyD88-mediated TRAF3 and IRF3 signal transduction. Depletion of either TLR9 or Cav-1 largely eliminates the neutrophil-mediated InP effect in sepsis models in vitro and in vivo. Further, examination of clinical samples from patients with sepsis showed that clinical outcomes and likelihood of recovery are closely correlated with mTLR9 and Cav-1 expression in circulating neutrophils. Conclusion: These results demonstrate that the TLR9-Cav-1 axis is a critical signaling pathway involved in the regulation of neutrophil-dependent MPLA mediated InP, and the presence of mTLR9+ neutrophils could be an attractive indicator of clinical outcomes in bacterial sepsis that could be further explored as a potential therapeutic target.

EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (K

To translate the English version of general medication adherence scale (GMAS) into a Chinese version and test its reliability and validity in Chinese patients with chronic diseases.After translating the original English version into Chinese (GMAS-C) following the forward-backward translation and expert review procedure, we conducted a pilot study among 10 chronic disease patients. Each patient took about 10 min to complete the scale and was asked about the difficulty of understanding or filling the scale. Then a total of 312 patients aged 18 years or older with chronic illness were selected from the outpatient departments of two tertiary hospitals and a community center in Tianjin from April 2019 to May 2020 by convenience sampling. Cronbach's α coefficient, item-total correlation and test-retest reliability were used to evaluate the scale reliability; expert evaluation method was used to evaluate the content validity of the scale; and exploratory factor analysis, confirmatory factor analysis, and known group validity were used to evaluate the construct validity of the scale.As a result of the adaptation process, the GMAS-C's structure was determined. It included 3 dimensions and 11 items and was reliable and valid for Chinese patients with chronic diseases. Total Cronbach's α coefficient of the scale was 0.781 and test-retest reliability coefficient was 0.883 after two weeks. The item-level content validity indexes (CVIs) were ≥ 0.78 for all items. A Kaiser-Meyer-Olkin test and Bartlett' test of sphericity test indicated that the sample met the requirements of factor analysis. Exploratory factor analysis extracted three factors with eigenvalue1, and 60% of the total variance was explained by three-factor solution. Confirmatory factor analysis showed acceptable fit indices (The GMAS-C demonstrates satisfactory reliability and validity. This scale can be a clinically useful tool to identify the levels of medication adherence and possible barriers for adherence of the medication regime in patients with chronic diseases.

Highlights • COVID-19 keeps substantial nucleotide similarity and shares common receptor (ACE2) with SARS-Cov. • ACE2 was overexpressed in both SARS-Cov and SARS-Cov-2 infection and might regulate immunological pathways in COVID-19. • SARS-Cov-2 infection was accompanied by the activation and inhibition of immunological cells. • JAK-STAT signaling pathway participated in COVID-19 infection subsequent the overactivation of ACE2., COVID-19, a novel identified coronavirus disease due to Severe Acute Respiratory Syndrome coronaviruses 2 (SARS-Cov-2) infection, has posed a significant threat to public health worldwide. It has been reported COVID-19 keeps substantial nucleotide similarity and shares common receptor, Angiotensin-converting enzyme 2 (ACE2) with Severe Acute Respiratory Syndrome coronaviruses (SARS-Cov). Here, we investigated the gene expression of ACE2 and identified associated pathways of SARS-Cov as a useful reference for a deepening understanding of COVID-19. The results indicated the ACE2 was overexpressed in human airway epithelial cells (HAEs), especially at 72 h after SARS-Cov infection. We found ACE2 might regulate immune response through immunological activation-associated pathways in the process of in both SARS-Cov and SARS-Cov-2 infection, where the activation of B cells, macrophages, helper T cells 1 (Th1 cells) and the inhibition of Foxp3 + regulatory T (Treg) cells and CD8 + T cells were found to be prominent. Finally, significant correlation between ACE2 and JAK-STAT signaling pathway was identified which indicate that JAK-STAT signaling pathway might involve in the downstream action of the overactivation of ACE2. These findings are expected to gain a further insight into the action mechanism of COVID-19 infection and provide a promising target for designing effective therapeutic strategies.

The induction of inflammation and cytokine storm was proposed to play a critical role in COVID-19. This study is aimed at investigating the relationship between glucose metabolism and the inflammatory state of inpatients with COVID-19. 71 inpatients with COVID-19 were classified into nondiabetes mellitus (NDM) group, impaired fasting glucose (IFG) group, and diabetes mellitus (DM) group. The average hospitalization days were significantly shorter in DM patients when compared with patients in the IFG group and NDM group. CD4+ T cell percentage was higher while CD8+ T cells percentage was lower in the DM group than those in the NDM group. The serum levels of IL-6, IL-2, IL-10, and INF-γ in the DM group were upregulated when compared with those in the NDM group. The serum levels of TNF-α, IL-4, IL-2, IL-10, and INF-γ were significantly higher in the DM group than those in the IFG group. A significant difference was observed in CD4+ T cell, CD4+/CD8+ ratio percentage, IL-6, and IL-10 between the NDM group and DM group with adjusted BMI. In conclusion, COVID-19 patients with elevated glucose levels have promoted cytokine profiles and immune response.

Aims Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor‐related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. Materials and Methods We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non‐CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme‐linked immunosorbent assay, and the tertiles were calculated. Results Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P, We evaluated the association between CTRP9 levels and the prevalence and severity of cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus. We found that serum levels of CTRP9 were reduced significantly in CAN patients with type 2 diabetes mellitus. Further, we found that decreased serum CTRP9 levels significantly correlated with an increased prevalence ratio of CAN. Moreover, after adjusting for other risk factors, decreased serum CTRP9 levels were associated with an increased prevalence ratio of definite CAN.

The incidence of re-positive virus detection in patients who recovered from COVID-19 during quarantine was 6.2% in two designated locations, in Wuhan, indicating that suggestions for patients after discharge to be quarantined before leaving for home might be necessary. This experience might be referred to by other countries with epidemic outbreak.

In recent years, the number of acute pancreatitis cases caused by hypertriglyceridemia has increased gradually, which has caught the attention of the medical community. However, because the exact mechanism of hypertriglyceridemic acute pancreatitis (HTG-AP) is not clear, treatment and prevention in clinical practice face enormous challenges. Animal models are useful for elucidating the pathogenesis of diseases and developing and testing novel interventions. Therefore, animal experiments have become the key research means for us to understand and treat this disease. We searched almost all HTG-AP animal models by collecting many studies and finally collated common animals such as rats, mice and included some rare animals that are not commonly used, summarizing the methods to model spontaneous pancreatitis and induce pancreatitis. We sorted them on the basis of three aspects, including the selection of different animals, analyzed the characteristics of different animals, different approaches to establish hypertriglyceridemic pancreatitis and their relative advantages and disadvantages, and introduced the applications of these models in studies of pathogenesis and drug therapy. We hope this review can provide relevant comparisons and analyses for researchers who intend to carry out animal experiments and will help researchers to select and establish more suitable animal experimental models according to their own experimental design.

Objectives To describe the clinical characteristics of patients in a Fangcang Hospital. Methods Non-critically ill individuals with positive SARS-CoV-2 RT-PCR tests admitted between 7 February and 12 February 2020 to Dongxihu Fangcang Hospital, which was promptly constructed because of the rapid, exponential increase in COVID-19 patients in Wuhan, China, were included; clinical course through to 22 February was recorded. Results A total of 1012 non-critically ill individuals with positive SARS-CoV-2 RT-PCR tests were included in the study. Thirty (of 1012, 3.0%) individuals were asymptomatic on admission. During hospitalization, 16 of 30 (53.3%) asymptomatic individuals developed different symptoms. Fourteen of 1012 patients (1.4%) remained asymptomatic from exposure to the end of follow up, with a median duration of 24 days (interquartile range 22–27). Fever (761 of 1012, 75.2%) and cough (531 of 1012, 52.4%) were the most common symptoms. Small patchy opacities (355 of 917, 38.7%) and ground-glass opacities (508 of 917, 55.4%) were common imaging manifestations in chest CT scans. One hundred patients (9.9%) were transferred to designated hospitals due to aggravation of illness. Diarrhoea emerged in 152 of 1012 patients (15.0%). Male, older age, diabetes, cardiovascular diseases, chills, dyspnoea, So2 value of ≤93%, white blood cell counts of >10 × 109/L and large consolidated opacities on CT images were all risk factors for aggravation of illness. Conclusions Non-critically ill individuals had different clinical characteristics from critically ill individuals. Asymptomatic infections only accounted for a small proportion of COVID-19. Although with a low incidence, diarrhoea was observed in patients with COVID-19, indicating the possibility of faecal–oral transmission.

Background Pulmonary arterial hypertension (PAH) is a life-threatening condition. The aim of this study was to explore potential crucial genes and pathways associated with PAH based on integrative analyses of gene expression and to shed light on the identification of biomarker for PAH. Methods Gene expression profile of pulmonary tissues from 27 PAH patients and 22 normal controls were downloaded from public database (GSE53408 and GSE113439). After the identification of differentially expressed genes (DEGs), hub pathways and genes were identified based on the comprehensive evaluation of protein-protein interaction (PPI) network analysis, modular analysis and cytohubba’s analysis, and further validated in another PAH transcriptomic dataset (GSE33463). Potentially associated micro-RNAs (miRNAs) were also predicted. Results A total of 521 DEGs were found between PAH and normal controls, including 432 up-regulated DEGs and 89 down-regulated DEGs. Functional enrichment analysis showed that these DEGs were mainly enriched in mitotic cell cycle process, mitotic cell cycle and microtubule cytoskeleton organization. Moreover, five key genes (CDK1, SMC2, SMC4, KIF23, and CENPE) were identified and then further validated in another transcriptomic dataset associated with special phenotypes of PAH. Furthermore, these hub genes were mainly enriched in promoting mitotic cell cycle process, which may be closely associated with the pathogenesis of PAH. We also found that the predicted miRNAs targeting these hub genes were found to be enriched in TGF-β and Hippo signaling pathway. Conclusion These findings are expected to gain a further insight into the development of PAH and provide a promising index for the detection of PAH.

Periodontitis is an inflammatory disease which is characterized by progressive destruction of the periodontium and causes tooth loss in adults. Periodontitis is known to be associated with dysbiosis of the oral microflora, often linked to various diseases. However, the complexity of plaque microbial communities of periodontitis, and antibiotic resistance and enhanced virulence make this disease difficult to treat. Therefore, we used metagenomic shotgun sequencing in this study to investigate the etiology, antibiotic-resistant genes (ARGs) and virulence genes (VirGs) of periodontitis. We revealed a significant shift in the composition of oral microbiota as well as several functional pathways that were represented significantly more abundant in periodontitis patients than in controls. Additionally, we observed several positively selected ARGs and VirGs with the Ka/Ks ratio > 1 by analyzing our data and a previous periodontitis dataset, indicating that ARGs and VirGs in oral microbiota may suffer from positive selection. Moreover, 5 of 12 positively selected ARGs and VirGs in periodontitis patients were found in the genomes of respiratory tract pathogens. Of note, 91.8% of the background VirGs with at least one non-synonymous single-nucleotide polymorphism for natural selection were also from respiratory tract pathogens. These observations suggest a potential association between periodontitis and respiratory infection at the gene level. Our study enriches the knowledge of pathogens and functional pathways as well as the positive selection of antibiotic resistance and pathogen virulence in periodontitis patients, and provides evidence from the gene level for an association between periodontitis and respiratory infection.

Background The concept of perceived control reflects the belief that one has resources needed to cope with negative events and the ability to positively influence consequences of those negative events. In patients with heart failure, perceived control is associated with a variety of health outcomes. Perceived control is commonly measured using the Control Attitudes Scale-Revised (CASR). There is no Chinese version of the CAS-R (CCAS-R). Objective The purpose of this article was to perform linguistic validation and psychometric evaluation of the CCAS-R. Methods The CAS-R was translated into Chinese according to Brislin's model. Then, a multicenter observational study was performed. Floor and ceiling effects, internal consistency, structural validity, and hypothesis testing were all assessed for psychometric validation of the CCAS-R. Results A total of 227 patients with chronic heart failure were included. There were no ceiling or floor effects detected. Cronbach α was 0.94, indicating a high reliability. The results of the confirmatory factor analysis showed that the 1-factor structure as proposed by the original CAS-R fits the data well. The results of the principal component analysis suggested that the 1-factor structure was optimal as well, accounting for 71.6% of the total variance. The a priori hypothesis was supported by a statistically significant correlation between the CCAS-R and 3 theoretically related variables. Conclusion We developed a semantically equivalent version of the CAS-R in Chinese. The evaluation of the instruments' psychometric properties demonstrated that the CCAS-R has good reliability and validity for use in Chinese patients with chronic heart failure.

Burn infection is one of the commonest causes of death in severely burned patients. Developing multifunctional biological nanomaterials has a great significance for the comprehensive treatment of burn infection. In this paper, we developed a hydrogel-based nanodelivery system with antibacterial activity and skin regeneration function, which was used for photodynamic antimicrobial chemotherapy (PACT) in the treatment of burns. The treatment system is mainly composed of porphyrin photosensitizer sinoporphyrin sodium (DVDMS) and poly(lactic-co-glycolic acid) (PLGA)-encapsulated basic fibroblast growth factor (bFGF) nanospheres that are embedded in carboxymethyl chitosan (CMCS)–sodium alginate to form CSDP hybrid hydrogel. We systematically evaluated the inherent antibacterial performance, rheological properties, fluorescence imaging, and biocompatibility of the CSDP nanosystem. Under mild photoirradiation (30 J/cm2, 5 min), 10 μg/mL CSDP showed excellent antibacterial and anti-biofilm activities, which eradi...

Background Genome-wide chromosomal instability, instead of specific somatic mutations or copy-number alterations in selected genes, is a significant property of cancer and may suggest a new strategy for treatment. Here we utilized cell-free DNA (cfDNA) sequencing to display the whole picture of chromosomal instability in patients with metastatic breast cancer (MBC), and evaluate its predictive value for patient survival. Methods The clinical data of 65 patients who had frozen plasma and planned to change the therapeutic regimen were retrospectively enrolled. Low-coverage whole-genome sequencing of cfDNA was performed to generate the chromosomal instability represented by chromosomal instability (CIN) score. Results Tumors with diverse status of hormone receptor and HER2 represented diverse chromosomal instability across the whole genome. According to the receiver operating characteristic curve and the statistical distribution, CIN score exceed 3881 was defined as “High”. 32 (53.3%) patients with high CIN score had similar clinicopathologic characteristics compared with low CIN score patients. The median overall survival of patients with high CIN score was 21.2 months (95% CI 14.1–28.3), which was significantly inferior to those with low CIN score (not reached, P = 0.006). Regardless of various treatment regimens, the median progression free survival in patients with high CIN score was 7.3 months, which was significantly worse than those in the low CIN score population (11.0 months, P = 0.034). Multivariate analysis revealed that CIN score was an independent prognostic factor, with hazard ratio of 3.563 (P = 0.005). Conclusions To our knowledge, this is the first study illustrating the prognostic value of chromosomal instability derived from cfDNA in MBC., Highlights • Novel UCAD pipeline to profile genome-wide chromosomal instability in cfDNA. • Genome-wide chromosomal instability is a robust independent prognostic biomarker. • HER2 amplification was successfully identified from cfDNA in our cohort.

Objective To investigate distinct features of renal involvement in patients with primary Sjögren’s syndrome (pSS) and to identify potential factors associated with renal involvement. Methods Four hundred and thrity‐four pSS patients from the Rheumatology Department of the First Affiliated Hospital of Wenzhou Medical University from 2013 to 2017 were included in a cross‐sectional study. Patients with renal involvement were compared with their age‐ and gender‐matched controls (pSS without renal involvement). Demographic, clinical, histological, nephritic, immunological features of renal involvement in pSS were systematically analyzed. Possible factors related to renal involvement were identified using multivariate logistic regression analyses. Results One hundred and ninety‐two pSS patients (88.48%) with renal involvement were women with mean age of nearly 58 years and mean disease duration of above 4 years. Clinical manifestation, serologic and immunological features and renal biopsy class of the pSS patients with renal involvement were presented. By multivariate analyses, xerophthalmia, histological positivity for lower salivary gland biopsy (LSGB), anti‐SSA/Ro52‐positive, reduced complement 3 (C3) levels, hypoalbuminemia and anemia retained significant association with renal involvement in pSS (all P

The aim of this study was to compare the different responses to hypocrellin B (HB)-mediated sonodynamic treatment between human gastric adenocarcinoma cell line SGC7901 and SGC7901/ADR. Tumor cells in culture dishes (35-mm diameter) were exposed to planar ultrasound at an intensity of 0.5 W/cm2 for 60 s combined with/without 2.5 μM HB. Cell viability was determined by MTT and Guava ViaCount assay. Production of reactive oxygen species (ROS) and destabilization of the mitochondrial membrane potential were assessed by flow cytometry. Apoptosis was analyzed using annexin-PE/7-amino-actinomycin D staining. The cell membrane integrity was estimated by isothiocyanate–dextran (FD500) uptake assay. Ultrastructural alterations on the membrane surface were observed by scanning electron microscopy. The membrane fluidity was also compared between the two cell lines using spectrophotometry. Compared with SGC7901 cells, HB-mediated sonodynamic therapy (HB-SDT) showed higher cytotoxic in SGC7901/ADR cells at the same treatment doses. Abundant intracellular ROS, a decrease in the mitochondrial membrane potential, and an increased rate of apoptosis were detected in the SDT group of both cell lines, wherein SGC7901/ADR cells showed a much more higher rate. Cell membrane permeability was remarkably enhanced after HB-SDT application. In addition, relatively severe cell damage was observed under scanning electron microscopy after HB-SDT treatment in SGC7901/ADR cells compared with SGC7901 cells. These results suggest that HB-SDT could induce apoptosis in SGC7901 and SGC7901/ADR cells via production of ROS. SGC7901/ADR was found to be more sensitive to HB-SDT than SGC7901 cells under the same experimental condition. Meanwhile, a noteworthy difference in cell membrane injury between SGC7901 and SGC7901/ADR cells was detected. The decreased membrane fluidity in SGC7901/ADR cells may be one of the reasons for its increased membrane damage.

Objectives Compared to normal cells, malignant cells have a high degree of aerobic glycolysis, also known as the Warburg effect. Therefore, supplementing photodynamic therapy (PDT), an established cancer therapy, with metabolic inhibitors can augment the mitochondrial damage by depleting ATP. To assess the combined impact of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and PDT on apoptosis and autophagy in human breast cancer cells, and examine the molecular basis. Methods Calcium-AM/PI double staining was used to evaluate cell viability. Reactive oxygen species (ROS), mitochondria membrane potential (MMP), nuclear morphology, and autophagosomes were measured using specific fluorescent markers. In addition, translocation of the apoptosis inducing factor (AIF) from the mitochondria to nucleus was imaged by confocal laser scanning microscopy, and DNA fragmentation was measured using PI staining and comet assay. PGC-1α expression, oxidative phosphorylation, ATP levels, and autophagy related proteins were detected by qRT-PCR, seahorse bioscience XFP extracellular flux analyzer, and Western blotting, respectively. Results Compared to with either monotherapy, 2-DG+PDT resulted in significantly higher cytotoxicity in the three breast cancer cell lines (MDA-MB-231, MCF-7, and 4T1), which was consistent with tumor growth regression trends seen in the 4T1 xenograft model. A synergistic augmentation of mitochondrial dysfunction (in terms of ROS generation, MMP loss, and PGC-1α down-regulation) and ATP depletion was seen in cells receiving 2-DG and PDT. In addition, nuclear translocation of AIF and the subsequent DNA damage indicated that the cytotoxic effects were mediated by a caspase-independent mechanism, which was relieved by the ROS scavenger N-acetylcysteine. Autophagy via the AMP-activated protein kinase (AMPK) was also observed following 2-DG+PDT, and reversed upon pre-treatment with the autophagy inhibitor 3-methyladenine. Conclusions The anti-cancer effects of 2-DG+PDT are mediated by both mitochondria triggered apoptosis and AMPK-mediated autophagy. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.

Small molecules that interfere with nucleic acid are widely used in chemotherapy, however, improved delivery approaches are required to improve anti-tumor outcomes. Here, we present the development of an ultrasound-activatable porphyrin-phospholipid-liposome (pp-lipo) that responds to low intensity focused ultrasound (LIFU) for sonodynamic therapy (SDT). The pp-lipo is constructed by incorporating a small proportion of porphyrin (pyropheophorbide) conjugated lipid into a liposome formulation. This enables sonosensitization-induced lipid oxidation and efficient disruption of liposomes to release loaded doxorubicin (Dox). This results in increased Dox nuclear subcellular location and cytotoxicity in cancer cells in vitro upon pp-lipo exposure to LIFU. Following intravenous administration, LIFU enhanced deposition of Dox within tumor tissue, suppressed tumor growth, and also increased porphyrin near infrared tumor fluorescence. Thus, pp-lipo is a versatile carrier that can be extended to many ultrasound-controllable drug delivery applications.

Background Alzheimer's disease (AD) as the most common cause of dementia among older people has aroused the universal concern of the whole world. However, until now there is still none effective treatments. Consequently, the development of new drugs targeting this complicated brain disorder is urgent and needs more efforts. In this review, we detailed the current state of knowledge about new candidate drugs targeting the pathological proteins especially the drugs which are employed using the combined methods of in vitro and in silico. Methods We looked up and reviewed online papers related to the pathogenesis and new drugs development of AD. Then, articles up to the requirements were respectively analyzed and summaried to provide the latest knowledge about the pathogenic effect and the new candidate drugs targeting Aβ and Tau proteins. Results New candidate drugs targeting the Aβ include decreasing the production, promoting the clearence and preventing aggregation. However these drugs have mostly failed in Phase III clinical trial stage due to the unsuccessful of reversing cognition symptoms. As to tau protein, the prevention of tau aggregation and propagation is a promising strategy to synthesize/design mechanismbased drugs against tauopathies. Some candidate drugs are under research. Moreover, because of the complex pathogenesis of AD, multi-target drugs have also shed light on the treatment of AD. Conclusion Given to the consecutive failure of Aβ-directed drugs and the feasibilities of tautargeted therapy, more and more researchers suggested that the AD treatment should be moved from Aβ to tau or focused on considering the soluble form of Aβ and tau as a whole. Moreover, the novel in silico methods also have great potential in drug discovery, drug repositioning, virtual screening of chemical libraries. No matter how many difficulties and challenges in prevention and treatment of AD, we firmly believe that the effective and safe drugs will be found using the combined methods in the immediate future with the global effort.

Inhibition of the increased aerobic glycolysis in cancer cells is a promising methodology for various malignant tumor therapies but is limited by systemic toxicity, at least in part. Recent studies suggest that dual restriction of glycolysis and mitochondrial function may overcome this issue. Sonodynamic therapy (SDT), a prospective therapeutic modality for cancers, has been reported to induce mitochondria-dependent cell damage. Here, we investigated the combined effect of SDT and 2-deoxyglucose (2DG), an anti-glycolytic agent, on breast cancer both in vitro and in vivo. In vitro, we found that, compared with a single treatment, SDT + 2DG co-treatment significantly decreased cell viability and increased cell apoptosis. Moreover, the generation of reactive oxygen species was enhanced and mitochondrial membrane potential (MMP) was reduced after SDT + 2DG co-treatment. Furthermore, the oxidative phosphorylation was also restrained after SDT + 2DG co-treatment, further to cause the blockage of ATP provision. In vivo, SDT + 2DG markedly reduced tumor volume and weight, consistent with the in vitro findings. Furthermore, toxicology tests concurrently indicated that the dosages of sinoporphyrin sodium and 2DG were comparatively tolerable. Generally, these results indicated that SDT + 2DG combination therapy may be an available, promising therapy for highly metastatic breast cancer.

BACKGROUND: In women, adhering to an overall healthy lifestyle is associated with a dramatically reduced risk of cardio-metabolic disorders. Whether such a healthy lifestyle exerts an intergenerational effects on child health deserves examination. METHODS: We included 5,701 children (9-14 years old at baseline) of the Growing Up Today Study 2, and their mothers, who are participants in the Nurses’ Health Study II. Pre-pregnancy healthy lifestyle was defined as a normal body mass index, no-smoking, physical activity ≥150min/week, and diet in the top 40% of the Alternative Healthy Eating Index–2010. Obesity during childhood and adolescence was defined using the International Obesity Task Force age- and sex-specific cutoffs. Multivariable log-binominal regression models with generalized estimating equations were used to evaluate the association of pre-pregnancy healthy lifestyle and offspring obesity. RESULTS: We identified 520 (9.1%) offspring who became obese during follow-up. A healthy body weight of mothers and no smoking before pregnancy were significantly associated with a lower risk of obesity among offspring: the relative risks [RRs; 95% confidence intervals (CIs)] were 0.37 (0.31-0.43) and 0.64 (0.49-0.84), respectively. Eating a healthy diet and regular moderate-to-vigorous physical activities were inversely related to offspring obesity risk, but these relations were not statistically significant. Compared to children of mothers who did not meet any low-risk lifestyle factors, offspring of women who adhered to all four healthy lifestyle factors had 75% lower risk of obesity (RR 0.25, 95%CI 0.14-0.43). CONCLUSION: Adherence to an overall healthy lifestyle before pregnancy is strongly associated with a low risk of offspring obesity in childhood, adolescence, and early adulthood. These findings highlight the importance of an overall healthy lifestyle before pregnancy as a potential strategy to prevent obesity in future generations.

Background Bacterial infection is a common clinical problem. Community-associated Staphylococcus aureus (S. aureus) infections can cause extensive tissue damage and necrosis. Photodynamic antimicrobial chemotherapy (PACT) has recently attracted attention as a feasible bacterial therapy. Octa-cationic zinc phthalocyanines are newly identified photosensitizers derived from phthalocyanines bearing 1, 2-ethanediamine groups and quaternized derivatives with different numbers of positive charges (ZnPcn+, n = 4 or 8). Here we report the antimicrobial effects of ZnPcn+-mediated PACT on planktonic and biofilm cultures of S. aureus. Methods ZnPcn+ uptake was detected by photometry after alkaline lysis. Dark-toxicity and light-mediated antimicrobial effects of the drug was determined by the plate count method. The production of intracellular reactive oxygen species (ROS) was detected by flow cytometry. SYTO 9 and propidium iodide (PI) were used to detect the bacterial cell membrane permeability. DNA damage after ZnPcn+-PACT was analyzed by flow cytometry and PI staining. The destruction of biofilm was evaluated by scanning electron microscope (SEM). Results The study of uptake showed that the relative fluorescence intensity of ZnPcn+ in S. aureus peaked at 15 min. Generation of reactive oxygen species (ROS) by ZnPcn+ was enhanced in PACT treatment groups. SYTO 9 and PI staining indicated that cell membrane was damaged. Flow cytometry and PI staining revealed DNA damage. Biofilms were damaged in PACT treatment groups. Conclusions Our results suggest that light-activated ZnPcn+ can efficiently inhibit planktonic and biofilm cultures of S. aureus.

Liposome nanomedicine has been successfully applied for cancer chemotherapy in patients. However, in general, the therapeutic efficacy is confined by its limited accumulation and penetration in solid tumors. Here, we established a biomimetic strategy for the preparation of highly penetrative liposome nanomedicine for enhanced chemotherapeutic efficacy. By applying this unique type of nanomedicine, membrane proteins on the cancer cells are used as highly penetrative targeting ligands. Biomimetic liposomes are highly stable, exhibiting a superior in vitro homologous targeting ability, and a 2.25-fold deeper penetration in 3D tumor spheroids when compared to conventional liposome nanomedicine. The fluorescence/photoacoustic dual-modal imaging approach demonstrated enhanced tumor accumulation and improved tumor penetration of the biomimetic liposome in C6 glioma tumor-bearing nude mice. Following the intravenous administration of biomimetic liposome nanomedicine, the tumor inhibition rate reached up to 93.3%, which was significantly higher when compared to that of conventional liposome nanomedicine (69.3%). Moreover, histopathological analyses demonstrated that biomimetic liposome nanomedicine has limited side effects. Therefore, these results suggested that a cancer cell membrane-based biomimetic strategy may provide a breakthrough approach for enhancing drug penetration and improving treatment efficacy, holding a great promise for further clinical studies.

This work reports a multifunctional nanoplatform (GNRs@mSiO2-HA-RGD) by conjugating targeting ligand hyaluronic acid (HA) and RGD with mesoporous silica-coated gold nanorods (GNRs@mSiO2) for dual-targeted chemo-photothermal therapy. Doxorubicin hydrochloride (DOX) was used as the model drug to investigate the drug loading, in vitro drug release profiles and cell evaluation. The nanoplatform has demonstrated a good photothermal effect and excellent drug loading capacity of about 20.16%. It also had pH-enzyme sensitive and NIR-triggered drug release properties. Cellular uptake experiment results indicated that DOX-GNRs@mSiO2-HA-RGD can be dual-targeted to ovarian cancer cells via CD44 and integrin receptor mediated endocytosis pathway. Cytotoxicity experiments demonstrated that combined therapy exhibited a better therapy effect compared to that of single chemotherapy or photothermal therapy. Our study demonstrates that DOX-GNRs@mSiO2-HA-RGD may be a new promising dual-targeted delivery system for chemo-photothermal therapy.

Precise targeting and high therapeutic efficiency are the major requisites of personalized cancer treatment. However, some unique features of the tumor microenvironment (TME) such as hypoxia, low pH and elevated interstitial fluid pressure cause cancer cells resistant to most therapies. Bacteria are increasingly being considered for targeted tumor therapy owing to their intrinsic tumor tropism, high motility as well as the ability to rapidly colonize in the favorable TME. Compared to other nano-strategies using peptides, aptamers, and other biomolecules, tumor-targeting bacteria are largely unaffected by the tumor cells and microenvironment. On the contrary, the hypoxic TME is highly conducive to the growth of facultative anaerobes and obligate anaerobes. Live bacteria can be further integrated with anti-cancer drugs and nanomaterials to increase the latter's targeted delivery and accumulation in the tumors. Furthermore, anaerobic and facultatively anaerobic bacteria have also been combined with other anti-cancer therapies to enhance therapeutic effects. In this review, we have summarized the applications and advantages of using bacteria for targeted tumor therapy (Scheme 1) in order to aid in the design of novel intelligent drug delivery systems. The current challenges and future prospects of tumor-targeting bacterial nanocarriers have also been discussed.

Active-targeted cancer imaging and therapy of glioma has attracted much attention in theranostic nanomedicine. As a promising tumor-targeting ligand, holo-transferrin (holo-Tf) has been applied for enhancing delivery of nanotheranostics. However, holo-Tf-based nanoassemblies for active targeting mediated multimodal imaging and therapeutics have not been previously reported. Here, we develop a one-step method for the preparation of holo-Tf-indocyanine green (holo-Tf-ICG) nanoassemblies for fluorescence (FL) and photoacoustic (PA) dual-modal imaging and photothermal therapy (PTT) of glioma. The nanoassemblies are formed by hydrophobic interaction and hydrogen bonds between holo-Tf and ICG, which exhibit excellent active tumor-targeting and high biocompability. The brain tumor with highly expressed Tf receptor can be clearly observed with holo-Tf-ICG nanoassemblies base on FL and PA dual-modal imaging in subcutaneous and orthotopic glioma models. Under the near-infrared laser irradiation, the holo-Tf-ICG nanoassemblies accumulated in tumor regions can efficiently convert laser energy into hyperthermia for tumor ablation. The novel theranostic nanoplatform holds great promise for precision diagnosis and treatment of glioma.