Risk factor evaluation of cuff pressure of >30 cmH2O to stop air leakage during mechanical ventilation: A prospective observational study.

AIM: The commonly recommended endotracheal tube cuff pressure is 20-30 cmH2O. However, some patients require a cuff pressure of >30 cmH2O to prevent air leakage. The study aims to determine the risk factors that contribute to the endotracheal tube cuff pressure of >30 cmH2O to prevent air leakage. DESIGN: A multi-centre prospective observational study. METHODS: Eligible patients undergoing mechanical ventilation in the intensive care unit of three hospitals between March 2020 and July 2022 were included. The endotracheal tube cuff pressure to prevent air leakage was determined using the minimal occlusive volume technique. The patient demographics and clinical information were collected. RESULTS: A total of 284 patients were included. Among these patients, 55 (19.37%) patients required a cuff pressure of >30 cmH2O to prevent air leakage. The multivariate logistic regression results revealed that the surgical operation (odds ratio [OR]: 8.485, 95% confidence interval [CI]: 1.066-67.525, p = 0.043) was inversely associated with the endotracheal tube cuff pressure of >30 cmH2O, while the oral intubation route (OR: 0.127, 95% CI: 0.022-0.750, p = 0.023) and cuff inner diameter minus tracheal area (OR: 0.949, 95% CI: 0.933-0.966, p < 0.001) were negatively associated with the endotracheal tube cuff pressure of >30 cmH2O. Therefore, a significant number of patients require an endotracheal tube cuff pressure of ＞30 cmH2O to prevent air leakage. Several factors, including the surgical operation, intubation route, and difference between the cuff inner diameter and tracheal area at the T3 vertebra, should be considered when determining the appropriate cuff pressure during mechanical ventilation.

Analyzing the factors affecting virus invasion by quantitative single-particle analysis.

Viral diseases are among the main threats to public health. Understanding the factors affecting viral invasion is important for antiviral research. Until now, it was known that most viruses have very low plaque-forming unit (PFU)-to-particle ratios. However, further investigation is required to determine the underlying factors. Here, using quantitative single-particle analysis methods, the invasion of Semliki Forest virus (SFV), Japanese encephalitis virus (JEV), and influenza A virus (IAV) containing attachment to the cell surface, entry into the cell, transport towards the cell interior, and fusion with endosomes to release nucleocapsids were quantitatively analysed in parallel. It was found that for SFV with an PFU-to-particle ratio of approximately 1:2, an entry efficiency of approximately 31% limited infection. For JEV, whose PFU-to-particle ratio was approximately 1:310, an attachment efficiency of approximately 27% and an entry efficiency of 10% were the main factors limiting its infection. Meanwhile, for IAV with PFU-to-particle ratios of 1:8100, 5% attachment efficiency, 9% entry efficiency, and 53% fusion efficiency significantly limited its infection. These results suggest that viruses with different infectivities have different limited steps in the invasion process. Moreover, there are significant differences in attachment efficiencies among viruses, emphasizing the pivotal role of attachment in viral invasion. The influence of the virus purification method on virus invasion was also investigated. This study, for the first time, reports the efficiencies of different stages of virus invasion, leading to a better understanding of virus invasion and providing a protocol to quantitatively analyse the virus invasion efficiency.

Establishment of acquired tracheoesophageal fistula using a modified magnetic compression technique in rabbits and its postmodeling evaluation.

BACKGROUND: Previous studies have validated the efficacy of both magnetic compression and surgical techniques in creating rabbit tracheoesophageal fistula (TEF) models. Magnetic compression achieves a 100% success rate but requires more time, while surgery, though less frequently successful, offers rapid model establishment and technical maturity in larger animal models. AIM: To determine the optimal approach for rabbit disease modeling and refine the process. METHODS: TEF models were created in 12 rabbits using both the modified magnetic compression technique and surgery. Comparisons of the time to model establishment, success rate, food and water intake, weight changes, activity levels, bronchoscopy findings, white blood cell counts, and biopsies were performed. In response to the failures encountered during modified magnetic compression modeling, we increased the sample size to 15 rabbit models and assessed the repeatability and stability of the models, comparing them with the original magnetic compression technique. RESULTS: The modified magnetic compression technique achieved a 66.7% success rate, whereas the success rate of the surgery technique was 33.3%. Surviving surgical rabbits might not meet subsequent experimental requirements due to TEF-related inflammation. In the modified magnetic compression group, one rabbit died, possibly due to magnet corrosion, and another died from tracheal magnet obstruction. Similar events occurred during the second round of modified magnetic compression modeling, with one rabbit possibly succumbing to aggravated lung infection. The operation time of the first round of modified magnetic compression was 3.2 ± 0.6 min, which was significantly reduced to 2.1 ± 0.4 min in the second round, compared to both the first round and that of the original technique. CONCLUSION: The modified magnetic compression technique exhibits lower stress responses, a simple procedure, a high success rate, and lower modeling costs, making it a more appropriate choice for constructing TEF models in rabbits.

Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.

Gut microbiota plays a significant role in gout.

With the development of social economy, the incidence of gout is increasing, which is closely related to people's increasingly rich diet. Eating a diet high in purine, fat, sugar and low-fibre for a long time further aggravates gout by affecting uric acid metabolism. The renal metabolism mechanism of uric acid has been thoroughly studied. To find a new treatment method for gout, increasing studies have recently been conducted on the mechanism of intestinal excretion, metabolism and absorption of uric acid. The most important research is the relationship between intestinal microbiota and the risk of gout. Gut microbiota represent bacteria that reside in a host's gastrointestinal tract. The composition of the gut microbiota is associated with protection against pathogen colonization and disease occurrence. This review focuses on how gut microbiota affects gout through uric acid and discusses the types of bacteria that may be involved in the occurrence and progression of gout. We also describe potential therapy for gout by restoring gut microbiota homeostasis and reducing uric acid levels. We hold the perspective that changing intestinal microbiota may become a vital method for effectively preventing or treating gout.

Near-Infrared Light-Powered and DNA Nanocage-Confined Catalytic Hairpin Assembly Nanobiosensor with a Nucleic Acid Restriction Behavior and Reinforced Enzymatic Resistance for Robust Imaging Assay in Live Biosystems.

While DNA amplifier-built nanobiosensors featuring a DNA polymerase-free catalytic hairpin assembly (CHA) reaction have shown promise in fluorescence imaging assays within live biosystems, challenges persist due to unsatisfactory precision stemming from premature activation, insufficient sensitivity arising from low reaction kinetics, and poor biostability caused by endonuclease degradation. In this research, we aim to tackle these issues. One aspect involves inserting an analyte-binding unit with a photoinduced cleavage bond to enable a light-powered notion. By utilizing 808 nm near-infrared (NIR) light-excited upconversion luminescence as the ultraviolet source, we achieve entirely a controllable sensing event during the biodelivery phase. Another aspect refers to confining the CHA reaction within the finite space of a DNA self-assembled nanocage. Besides the accelerated kinetics (up to 10-fold enhancement) resulting from the nucleic acid restriction behavior, the DNA nanocage further provides a 3D rigid skeleton to reinforce enzymatic resistance. After selecting a short noncoding microRNA (miRNA-21) as the modeled low-abundance sensing analyte, we have verified that the innovative NIR light-powered and DNA nanocage-confined CHA nanobiosensor possesses remarkably high sensitivity and specificity. More importantly, our sensing system demonstrates a robust imaging capability for this cancer-related universal biomarker in live cells and tumor-bearing mouse bodies, showcasing its potential applications in disease analysis.

Perspective view of allogeneic IgG tumor immunotherapy.

Allogeneic tumors are eradicated by host immunity; however, it is unknown how it is initiated until the report in Nature by Yaron Carmi et al. in 2015. Currently, we know that allogeneic tumors are eradicated by allogeneic IgG via dendritic cells. AlloIgG combined with the dendritic cell stimuli tumor necrosis factor alpha and CD40L induced tumor eradication via the reported and our proposed potential signaling pathways. AlloIgG triggers systematic immune responses targeting multiple antigens, which is proposed to overcome current immunotherapy limitations. The promising perspectives of alloIgG immunotherapy would have advanced from mouse models to clinical trials; however, there are only 6 published articles thus far. Therefore, we hope this perspective view will provide an initiative to promote future discussion.

The impact of preoperative biliary drainage on postoperative healthcare-associated infections and clinical outcomes following pancreaticoduodenectomy: a ten-year retrospective analysis.

BACKGROUND: Pancreaticoduodenectomy (PD) is a complex procedure and easily accompanied by healthcare-associated infections (HAIs). This study aimed to assess the impact of PBD on postoperative infections and clinical outcomes in PD patients. METHODS: The retrospective cohort study were conducted in a tertiary hospital from January 2013 to December 2022. Clinical and epidemiological data were collected from HAIs surveillance system and analyzed. RESULTS: Among 2842 patients who underwent PD, 247 (8.7%) were diagnosed with HAIs, with surgical site infection being the most frequent type (n = 177, 71.7%). A total of 369 pathogenic strains were detected, with Klebsiella pneumoniae having the highest proportion, followed by Enterococcu and Escherichia coli. Although no significant association were observed generally between PBD and postoperative HAIs, subgroup analysis revealed that PBD was associated with postoperative HAIs in patients undergoing robotic PD (aRR = 2.174; 95% CI:1.011-4.674; P = 0.047). Prolonging the interval between PBD and PD could reduce postoperative HAIs in patients with cholangiocarcinoma (≥4 week: aRR = 0.292, 95% CI 0.100-0.853; P = 0.024) and robotic PD (≤2 week: aRR = 3.058, 95% CI 1.178-7.940; P = 0.022). PBD was also found to increase transfer of patients to ICU (aRR = 1.351; 95% CI 1.119-1.632; P = 0.002), extended length of stay (P < 0.001) and postoperative length of stay (P = 0.004). CONCLUSION: PBD does not exhibit a significant association with postoperative HAIs or other outcomes. However, the implementation of robotic PD, along with a suitable extension of the interval between PBD and PD, appear to confer advantages concerning patients' physiological recuperation. These observations suggest potential strategies that may contribute to enhanced patient outcomes.

The integrated bioinformatic analysis identifies immune microenvironment-related potential biomarkers for patients with gestational diabetes mellitus.

Background: Gestational diabetes mellitus (GDM), a transient disease, may lead to short- or long-term adverse influences on maternal and fetal health. Therefore, its potential functions, mechanisms and related molecular biomarkers must be comprehended for the control, diagnosis and treatment of GDM. Methods: The differentially expressed genes (DEGs) were identified using GSE49524 and GSE87295 associated with GDM from the Gene Expression Omnibus database, followed by function enrichment analysis, protein-protein interactions network construction, hub DEGs mining, diagnostic value evaluation and immune infiltration analysis. Finally, hub DEGs, the strongest related to immune infiltration, were screened as immune-related biomarkers. Results: A hundred and seven DEGs were identified between patients with GDM and healthy individuals. Six hub genes with high diagnostic values, including ALDH1A1, BMP4, EFNB2, MME, PLAUR and SLIT2, were identified. Among these, two immune-related genes (PLAUR and SLIT2) with the highest absolute correlation coefficient were considered immune-related biomarkers in GDM. Conclusion: Our study provides a comprehensive analysis of GDM, which would provide a foundation for the development of diagnosis and treatment of GDM.

Ovarian Microcystic Stromal Tumor with Significant Nestin Expression: A Unique Case.

Ovary microcystic stromal tumor (MCST) is an extremely rare subtype of sex cord-stromal neoplasm, and only 57 cases have been reported. We herein report a unique case of ovarian MCST with positive nestin expression in a 39-year-old Chinese woman. The tumor showed microcystic stromal histological structures and characteristically expressed the CD10, WT-1, and Ki67 proteins. A molecular analysis identified a point mutation (c.110C > T) in exon 3 of the CTNNB1 gene. To our knowledge, no report has described a case of ovarian MCST with positive staining for nestin protein. Our study provides new insights into the tumor biology of ovarian MCST.

Miao medicine Gu Yan Xiao tincture inhibits mTOR to stimulate chondrocyte autophagy in a rabbit model of osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: The Gu Yan Xiao tincture, a blend of traditional Chinese herbs, is traditionally used for osteoarthritis and related pain. This study investigated its mechanism of action in order to rationalize and validate its therapeutic use. AIM OF THE STUDY: This study analyzed, in a rabbit model of knee osteoarthritis, whether and how Gu Yan Xiao tincture exerts therapeutic benefits by modulating chondrocyte autophagy. MATERIALS AND METHODS: The active constituents within the GYX tincture were identified using liquid chromatography-mass spectrometry. The rabbit model was established by injecting animals with type II collagenase intra-articularly, and the effects of topically applied tincture were examined on osteoarthritis lesions of the knee using histopathology, micro-computed tomography and x-ray imaging. Effects of the tincture were also evaluated on levels of inflammatory cytokines, matrix metalloproteases, and autophagy in chondrocytes. As a positive control, animals were treated with sodium diclofenac. RESULTS: The tincture mitigated the reduction in joint space, hyperplasia of the synovium and matrix metalloproteases in serum that occurred after injection of type II collagenase in rabbits. These therapeutic effects were associated with inhibition of mTOR and activation of autophagy in articular chondrocytes. Inhibiting mTOR with rapamycin potentiated the therapeutic effects of the tincture, while inhibiting autophagy with 3-methyladenine antagonized them. CONCLUSIONS: Gu Yan Xiao tincture mitigates tissue injury in a rabbit model of osteoarthritis, at least in part by inhibiting mTOR and thereby promoting autophagy in chondrocytes. These results rationalize the use of the tincture not only against osteoarthritis but also potentially other diseases involving inhibition of autophagy in bones and joints.

Analysis of airway structural parameters in Han Chinese adults: a prospective cross-sectional study.

INTRODUCTION: Establishing reference ranges for central airway parameters and exploring their influencing factors in Han Chinese non-smoking adults. METHODS: This prospective cross-sectional study was conducted on Han Chinese non-smoking adults who underwent chest CT scans at the Tongzhou Campus of Dongzhimen Hospital Affiliated with the Beijing University of Chinese Medicine between September 2022 and November 2022. The SYNAPSE 3D image analysis software was utilized, enabling the extraction of critical parameters such as central airway length, airway wall thickness (AWT), airway lumen area (ALA), and subcarinal angle (SCA). Pearson's correlation coefficient analysis and multiple linear regression analysis methods were employed to evaluate the relationship between central airway parameters and age, sex, weight, and height. RESULTS: The study encompassed 888 Han Chinese non-smoking adults, comprising 456 females and 432 males. Significant sex differences were noted in central airway length, AWT, and ALA, with measurements in males exceeding those in females (p < 0.01) with no significant difference in SCA. Correlation analyses unveiled relationships between central airway parameters and age, sex, weight, and height. During multiple linear regression analyses, no conclusive evidence emerged to demonstrate the independent or combined explanatory or predictive capacity of the aforementioned variables for central airway length and SCA. Although sex has a significant impact on AWT and ALA, its capability in explanation or prediction remains limited. The conclusions drawn from the primary analysis receive reinforcement from the outcomes of sensitivity analyses. CONCLUSION: Establishing the distribution range of central airway parameters in non-smoking Han Chinese adults. It observed significant sex differences in these parameters, except for the SCA. However, the study found that the predictive or explanatory power of age, sex, weight, and height for central airway parameters was either limited or non-significant.

Nomogram to predict severe retinopathy of prematurity in Southeast China.

AIM: To define the predictive factors of severe retinopathy of prematurity (ROP) and develop a nomogram for predicting severe ROP in southeast China. METHODS: Totally 554 infants diagnosed with ROP hospitalized in the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University and hospitalized in Taizhou Women and Children's Hospital were included. Clinical data and 43 candidate predictive factors of ROP infants were collected retrospectively. Logistic regression model was used to identify predictive factors of severe ROP and to propose a nomogram for individual risk prediction, which was compared with WINROP model and Digirop-Birth model. RESULTS: Infants from the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (n=478) were randomly allocated into training (n=402) and internal validation group (n=76). Infants from Taizhou Women and Children's Hospital were set as external validation group (n=76). Severe ROP were found in 52 of 402 infants, 12 of 76 infants, and 7 of 76 infants in training group, internal validation group, and external validation group, respectively. Birth weight [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.996-0.999; P<0.001], multiple births (OR, 1.885; 95%CI, 1.013-3.506; P=0.045), and non-invasive ventilation (OR, 0.288; 95%CI, 0.146-0.570; P<0.001) were identified as predictive factors for the prediction of severe ROP, by univariate analysis and multivariate analysis. For predicting severe ROP based on the internal validation group, the areas under receiver operating characteristic curve (AUC) was 78.1 (95%CI, 64.2-92.0) for the nomogram, 32.9 (95%CI, 15.3-50.5) for WINROP model, 70.2 (95%CI, 55.8-84.6) for Digirop-Birth model. In external validation group, AUC of the nomogram was also higher than that of WINROP model and Digirop-Birth model (80.2 versus 51.1 and 63.4). The decision curve analysis of the nomogram demonstrated better clinical efficacy than that of WINROP model and Digirop-Birth model. The calibration curves demonstrated a good consistency between the actual severe ROP incidence and the predicted probability. CONCLUSION: Birth weight, multiple births, and non-invasive ventilation are independent predictors of severe ROP. The nomogram has a good ability to predict severe ROP and performed well on internal validation and external validation in southeast China.

Efficacy of transcranial direct current stimulation for treating anhedonia in patients with depression: A randomized, double-blind, sham-controlled clinical trial.

BACKGROUND: Anhedonia, the core symptom of major depressive disorder (MDD), is highly prevalent in patients with depression. Anhedonia is associated with low efficacy of drug treatment, high suicide rates, and poor social function. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technology that uses constant, low-intensity direct current to treat MDD by regulating cortical activity and neuronal excitability. However, little is known about the efficacy of tDCS for treating anhedonia in patients with depression, and even the existing results of clinical trials are conflicting. In addition, there is no consensus on what brain regions should be targeted by tDCS during the treatment of anhedonia in patients with depression. OBJECTIVE: This study aimed to evaluate the efficacy and safety of tDCS over the left dorsolateral prefrontal cortex (DLPFC) and right orbitofrontal cortex (OFC) in the improvement of anhedonia in patients with depression and finally identified suitable brain regions to be stimulated during treatment. METHODS: This randomized, double-blind, sham-controlled clinical trial recruited 70 patients with anhedonia and depressive episodes. Patients were randomly assigned to three groups according to the stimulation site: right orbitofrontal cortex (OFC), left dorsolateral prefrontal cortex (DLPFC), and sham stimulation. Each group received twelve 20-min interventions (ten as primary treatment and two for consolidation). The primary outcome was a decrease in Snaith-Hamilton Pleasure Scale (SHAPS) scores after primary treatment. Evaluations were performed at baseline, post-treatment, and 8-week follow-up. RESULTS: The depression mood of the three groups of patients at each time point was better than the baseline, but there was no significant difference in the efficacy between the groups (p>0.05). On the basis of the improvement of depression, this study found that tDCS of the DLPFC significantly improved anhedonia (p = 0.028) after primary treatment (2 weeks), and tDCS of the DLPFC and OFC significantly improved social functioning (p = 0.005) at 8-week follow-up. LIMITATIONS: The sample size of this study was small, with only about 23/24 patients in each group completing the intervention assessments; due to the impact of the COVID-19 epidemic, data analysis was limited by the lack of patients during the follow-up period. CONCLUSIONS: tDCS of the DLPFC significantly improves anhedonia in depressed patients and is thus a potential adjuvant therapy for anhedonia in these patients.

Adjunctive duration-doubled transcranial direct current stimulation for the treatment of depressive patients with suicidal ideation: study protocol for a double-blind, randomized, sham-controlled trial.

BACKGROUND: The problem of suicide has become increasingly common in individuals with major depressive disorder (MDD). Transcranial direct current stimulation (tDCS) is an effective treatment for MDD with 2 milliamperes (mA) for at least 30 min per day for 2 weeks. This study aims to investigate the efficacy of daily duration-doubled tDCS as an adjunctive intervention for rapidly reducing suicidal ideation and improving depression in MDD patients. METHODS: In this double-blind, randomized, sham-controlled study, 76 MDD patients with suicidal ideation are randomly assigned to either active (n=38) or sham (n=38) tDCS group. The anode and cathode are placed over the scalp areas corresponding to left and right dorsolateral prefrontal cortex (DLPFC), respectively, and each stimulation lasts for 60 min. The primary outcome is defined as change of Beck Scale for Suicide Ideation (BSI) after 5 and 10 sessions. The change of other clinical assessments, blood biomarkers related to suicidal ideation and depressive sumptoms are defined as secondary outcomes. Blood biomarkers related to suicidal ideation are collected at baseline and after 10 sessions. DISCUSSION: This study suggests the adjunctive duration-doubled tDCS might be a novel method to rapidly reduce suicidal ideation and improve depressive symptom. The variation of biomarkers could be potential predictive models of suicide risk. TRIAL REGISTRATION: The trial protocol is registered with ClinicalTrials.gov under protocol registration number NCT05555927. Registered on September 25, 2022.

The burden of depression, anxiety and schizophrenia among the older population in ageing and aged countries: an analysis of the Global Burden of Disease Study 2019.

Background: Depression, anxiety and schizophrenia among older persons have become global public health challenges. However, the burden of these disorders in ageing and aged countries has not been analysed. Aims: To investigate the burden of depression, anxiety and schizophrenia among older adults in ageing and aged countries. Methods: Using data from the Global Burden of Disease Study 2019, we calculated the estimated annual percentage change (EAPC) in the age-standardised incidence rates (ASIR) and age-standardised disability-adjusted life years (DALYs) rates (ASDR) for depression, anxiety and schizophrenia of older people in ageing countries (China, India, Indonesia) and aged countries (Japan, Italy, Portugal) between 1990 and 2019. Trends in incidence and DALYs were analysed by gender and age. Results: In 2019, the highest incidence of depression, anxiety and schizophrenia in the older population in aged countries was in Japan (927 271.3 (752 552.3-1 125 796.5), 51 498.2 (37 625.7-70 487.3) and 126.0 (61.0-223.2), respectively), while the highest incidence in ageing countries was in China (5 797 556.9 (4 599 403.4-7 133 006.5), 330 256.1 (246 448.9-445 987.4) and 1067.7 (556.2-1775.9), respectively). DALYs for these disorders were similar, with the highest in Japan and China. From 1990 to 2019, the ASIR for depressive disorders decreased in aged countries but increased in ageing countries; the ASIR for anxiety disorders and schizophrenia declined in both ageing and aged countries. The ASDR for depressive disorders was consistent with the ASIR but not for anxiety disorders and schizophrenia. The ASIR for depressive disorders was higher in older women, while the opposite was observed in anxiety disorders and schizophrenia. Notably, the conditions of burden of depressive disorders, anxiety disorders and schizophrenia in the 65-70-year-old age group were the most burdensome. Conclusions: The incidence and DALYs of these three mental disorders increased while exhibiting differences between ageing and aged countries. Raising awareness about formulating health policies for preventing and treating mental disorders in the older population is necessary to reduce the future burden posed by the ageing challenge.

Photoresponsive CHA-Integrated Self-Propelling 3D DNA Walking Amplifier within the Concentration Localization Effect of DNA Molecular Framework Enables Highly Efficient Fluorescence Bioimaging.

While three-dimensional (3D) DNA walking amplifiers hold considerable promise in the construction of advanced DNA-based fluorescent biosensors for bioimaging, they encounter certain difficulties such as inadequate sensitivity, premature activation, the need for exogenous propelling forces, and low reaction rates. In this contribution, a variety of profitable solutions have been explored. First, a catalytic hairpin assembly (CHA)-achieved nonenzymatic isothermal nucleic acid amplification is integrated to enhance sensitivity. Subsequently, one DNA component is simply functionalized with a photocleavage-bond to conduct a photoresponsive manner, whereby the target recognition occurs only when the biosensor is exposed to an external ultraviolet light source, overcoming premature activation during biodelivery. Furthermore, a special self-propelling walking mechanism is implemented by reducing biothiols to MnO2 nanosheets, thereby propelling forces that are self-supplied to a Mn2+-reliant DNAzyme. By carrying the biosensing system with a DNA molecular framework to induce a unique concentration localization effect, the nucleic acid contact reaction rate is notably elevated by 6 times. Following these, an ultrasensitive in vitro detection performance with a limit of detection down to 2.89 fM is verified for a cancer-correlated microRNA biomarker (miRNA-21). Of particular importance, our multiple concepts combined 3D DNA walking amplifier that enables highly efficient fluorescence bioimaging in live cells and even bodies, exhibiting a favorable application prospect in disease analysis.

Discovery of a highly potent and orally available importin-ß1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-ß1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-ß1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-ß1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-ß1.