Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy.

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.

Effect of IL-17 on pulmonary artery smooth muscle cells and connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVE: To explore the role of interleukin (IL)-17 in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and to investigate its possible mechanism on pulmonary artery smooth muscle cells (PASMCs). METHODS: Enzyme-linked immunosorbent assay (ELISA) were used to compare levels of serum IL-17 in patients with CTD-PAH and healthy controls (HCs). After treatment for 3 months, the serum IL-17 levels were tested in CTD-PAH. ELISA and immunohistochemistry were used to compare levels of serum IL-17 and numbers of pulmonary artery IL-17+ cells, respectively, in a rat model of monocrotaline-induced PAH and untreated rats. Proliferation, migration, and inflammatory factors expression of PASMCs were assessed after stimulation with different concentrations of IL-17 for various time periods. Proteins in the mitogen-activated protein kinase (MAPK) pathway were examined by western blot. RESULTS: Levels of IL-17 were upregulated in patients with CTD-PAH compared to HCs. After 3 months of treatment, serum IL-17 levels were downregulated with pulmonary artery pressure amelioration. Moreover, serum IL-17 levels and numbers of IL-17+ cells infiltrating lung arterioles were increased in PAH model rats. IL-17 could dose- and time-dependently promote proliferation and migration of PASMCs as well as time-dependently induce IL-6 and intercellular cell adhesion molecule-1 (ICAM-1) expression. The levels of MKK6 increased after IL-17 treatment. Inhibition of MAPK decreased proliferation of PASMCs. CONCLUSION: Levels of IL-17 may increase in CTD-PAH, and IL-17 promotes proliferation, migration, and secretion of IL-6 and ICAM in PASMCs, respectively, which likely involves the p-38 MAPK pathway.

Exosome-associated miRNA-99a-5p targeting BMPR2 promotes hepatocyte apoptosis during the process of hepatic fibrosis.

Liver fibrosis is a serious stage of chronic liver injury. Inhibition of hepatic stellate cells activation and hepatocytes apoptosis is important measures in the treatment of liver fibrosis. Studies have shown that exosomes are involved in regulating the information transmission between cells, but there are few studies on the interaction between exosomes from HSC and hepatocytes. This study screened miRNAs with significant differences related to liver fibrosis in the database. Then, we activated HSC applying transforming growth factor ß1 (TGF-ß1) and collected exosomes. The expression of miRNA in HSC-derived exosomes was verified by quantitative real-time PCR (qRT-PCR). The results of cell function test showed that HSC-derived exocrine miRNA-99a-5p could inhibit hepatocytes proliferation and promote hepatocytes apoptosis. Conversely, inhibition of miRNA-99a-5p can promote hepatocytes proliferation and inhibit apoptosis. Target gene prediction and luciferase assay show that miRNA can specifically bind to BMPR2 site sequence. In addition, we also detected the expression of BMPR2 and apoptosis-related protein by qRT-PCR and Western blot (WB). In conclusion, this study demonstrates that HSC-derived exocrine miRNA-99a-5p can promote hepatocytes apoptosis and participate in the process of liver fibrosis by targeting BMPR2. Our findings highlight the therapeutic potential of HSC-derived exocrine miRNA-99a-5p in hepatic fibrosis.

Study of an Ultrasensitive Label-Free Electrochemiluminescent Immunosensor Fabricated with a Composite Electrode for Detecting the Glutamate Decarboxylase Antibody.

Antibody testing for the glutamic acid decarboxylase 65 antibody (GADA) is widely used as a golden standard for autoimmune diabetes diagnosis, while current methods for antibody testing are not sensitive enough for clinical usage. Here, a label-free electrochemiluminescent (ECL) immunosensor for detecting GADA in autoimmune diabetes is fabricated and investigated. In the designed immunosensor, a composite film including the multiwalled carbon nanotubes (MWCNTs), zinc oxide (ZnO), and Au nanoparticles (AuNPs) was prepared through nanofabrication processes to improve the performance of sensor. The MWCNTs, which can provide a larger specific surface area, ZnO as a good photocatalytic material, and AuNPs that can enhance the ECL signal of luminol and immobilize the GAD65 antigen were applied to prefunctionalize indium tin oxide (ITO) glass based on a nanofabrication process. The GADA concentration was detected using the ECL immunosensor after incubating with GAD65 antigen-coated prefunctionalized ITO glass. After a direct immunoreaction, it is found that the degree of decreased ECL intensity has a good linear regression toward the logarithm of the GADA concentration in the range of 0.01 to 50 ng mL-1 with a detection limit down to 10 pg mL-1. Human serum samples positive or negative for GADA all nicely fell in the expected area. The fabricated immunosensor with excellent sensitivity, specificity, and stability has potential capability for clinical usage in GADA detection.

Parents' personality, parenting stress, and problem behaviors of children with special needs in China before and during the COVID-19 pandemic.

The positive predictive effect of children's problem behaviors on parenting stress has been verified to some extent, but research on parents of children with special needs remains insufficient. Moreover, the role of parental personality traits in the relationship between children's problem behaviors and parenting stress, and whether it differs from before the COVID-19 pandemic, remains unclear. Accordingly, in this study, online questionnaires were used to survey parents of children with autism and intellectual disabilities in China - 337 parents before and 604 during the COVID-19 pandemic - to explore the relationship between problem behaviors in the children and parenting stress as well as the moderating effect of parents' personality. The results showed that problem behaviors of children with autism and intellectual disabilities had a positive predictive effect on parenting stress. However, there was no significant difference in this effect before and during the pandemic. In addition, the relationship between children's problem behaviors and parenting stress was moderated by the Agreeableness and Neuroticism of the parents, but only during COVID-19 pandemic. The research results suggest that, during the pandemic when facing problem behaviors of children with autism or intellectual disabilities, positive personality characteristics such as Agreeableness have a protective effect on parenting stress. By contrast, negative personality characteristics such as Neuroticism are risk factors. The study results provide evidence from special groups regarding the role of parents' personalities in the parent - child interaction and the parenting stress models.

Nondestructive isolation of mesenchymal stem cells from bone marrow using DNA aptamers.

Mesenchymal stem cells (MSCs) mainly found in the bone marrow of adult mammals demonstrate unique capacities of differentiating into multiple cell lineages and undifferentiated MSCs are considered an ideal source of seed cells for cell therapy and tissue engineering. However, MSCs are heterogeneous and not abundant in bone marrow, and there are few specific markers for these cells currently. Therefore, new methods to isolate and characterize MSCs are urgently required. To address the problem, we successfully developed a high-specificity aptamer, called Apt-W2, to specifically recognize mouse bone marrow mesenchymal stem cells (mBMSCs). We synthesized Apt-W2 modified magnetic beads (Apt-W2-MBs) and used them as bait to fish out the MSCs from mouse bone marrow accurately by magnetic-activated cell sorting (MACS). Next, the sorted cells could break free from the Apt-W2-MBs by the competition of C-W2 (complementary strands of Apt-W2). As a result, the sorted cells were intact, and maintained the stem cell phenotype and good proliferative ability. Simultaneously, the sorted cells showed high pluripotency to differentiate into osteoblasts, chondrocytes, and adipocytes. More importantly, the Apt-W2-MB cocktail showed a fine capture performance for MSCs (∼88.33%). This new methodological approach can greatly facilitate MSC isolation efficiently and intactly, thereby enhancing the rate of in vitro differentiation of MSC-derived cells for the emerging field of tissue engineering and regenerative medicine. This new instrumental application of aptamers is an important innovation that achieved both high efficiency and nondestructive cell sorting, opening the door to novel cell sorting approaches.

Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial.

PURPOSE: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM. DESIGN: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial. PARTICIPANTS: Fifteen CHM patients (ages 20-57 years at dosing). METHODS: Patients received uniocular subfoveal injections of low-dose (up to 5 × 1010 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 1011 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing. MAIN OUTCOME MEASURES: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF). RESULTS: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships. CONCLUSIONS: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.

Serum neuron-specific enolase, magnetic resonance imaging, and electrophysiology for predicting neurodevelopmental outcomes of neonates with hypoxic-ischemic encephalopathy: a prospective study.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality and morbidity. Effective indicators for the early diagnosis of brain injury after HIE and prognosis are lacking. This study aimed to examine the predictive value of serum neuron-specific enolase (NSE), amplitude-integrated electroencephalography (aEEG), and magnetic resonance imaging (MRI), alone and in combination, for the neurological outcomes in neonates with HIE. METHODS: Newborns with HIE born and treated at the Third Affiliated Hospital of An-Hui Medical University were consecutively included in this prospective cohort study (June 2013 to December 2020). Encephalopathy was classified as mild, moderate or severe according to Samat and Sarnat. All patients were assessed serum 1-day NSE and 3-day NSE levels after birth. The children were classified by neurological examination and Bayley Scales of Infant Development II at 18 months of age. ROC analysis was used to evaluate the predictive accuracy of the neurodevelopment outcomes. RESULTS: A total of 50 HIE neonates were enrolled (normal group: 32 (64.0%), moderate delay: 5 (10.0%), severe delay: 30(26.0%)) according to Bayley II scores. Serum 3-day NSE levels increased with worsening neurodevelopment outcomes (normal: 20.52 ± 6.42 µg/L vs. moderate: 39.82 ± 5.92 µg/L vs. severe: 44.60 ± 9.01 µg/L, P < 0.001). The MRI findings at 4-7 days after birth were significantly different among the three groups (P < 0.001). Forty-two (84.0%) children had abnormal aEEG. The combination of the three abnormalities combined together had 100% sensitivity, 97.70% specificity, 98.25% PPV, and 99.98% NPV. CONCLUSIONS: MRI, aEEG, and 3-day NSE can predict the neurological prognosis of newborns with HIE without hypothermia treatment. Their combination can improve the predictive ability for long-term neurobehavioral prognosis.

Investigation of stretchable strain sensor based on CNT/AgNW applied in smart wearable devices.

Stretchable strain sensor, an important paradigm of wearable sensor which can be attached onto clothing or even human skin, is widely used in healthcare, human motion monitoring and human-machine interaction. Pattern-available and facile manufacturing process for strain sensor is pursued all the time. A carbon nanotube (CNT)/silver nanowire (AgNW)-based stretchable strain sensor fabricated by a facile process is reported here. The strain sensor exhibits a considerable Gauge factor of 6.7, long-term durability (>1000 stretching cycles), fast response and recovery (420 ms and 600 ms, respectively), hence the sensor can fulfill the measurement of finger movement. Accordingly, a smart glove comprising a sensor array and a flexible printed circuit board is assembled to detect the bending movement of five fingers simultaneously. Moreover, the glove is wireless and basically fully flexible, it can detect the finger bending of wearer and display the responses distinctly on an APP of a smart phone or a host computer. Our strain senor and smart glove will broaden the materials and applications of wearable sensors.

A Fully Flexible Intelligent Thermal Touch Panel Based on Intrinsically Plastic Ag2 S Semiconductor.

Wearable touch panels, a typical flexible electronic device, can recognize and feed back the information of finger touch and movement. Excellent wearable touch panels are required to accurately and quickly monitor the signals of finger movement as well as the capacity of bearing various types of deformation. High-performance thermistor materials are one of the key functional components, but to date, a long-standing bottleneck is that inorganic semiconductors are typically brittle while the electrical properties of organic semiconductors are quite low. Herein, a high-performance flexible temperature sensor is reported by using plastic Ag2 S with ultrahigh temperature coefficient of resistance of -4.7% K-1 and resolution of 0.05 K, and rapid response/recovery time of 0.11/0.11 s. Moreover, the temperature sensor shows excellent durability without performance damage or loss during force stimuli tests. In addition, a fully flexible intelligent touch panel composed of a 16 × 10 Ag2 S-film-based temperature sensor array, as well as a flexible printed circuit board and a deep-learning algorithm is designed for perceiving finger touch signals in real-time, and intelligent feedback of Chinese characters and letters on an app. These results strongly show that high-performance flexible inorganic semiconductors can be widely used in flexible electronics.

Associations between sarcoidosis, autoimmune diseases, and autoantibodies: a single-center retrospective study in China.

To describe the clinical manifestations, immunological features, and risk factors in patients with sarcoidosis complicated with autoimmune diseases (ADs) as well as determine the frequency of autoantibodies and possible correlation between autoantibodies and laboratory data. Patients with pathologically confirmed sarcoidosis at Beijing Chaoyang Hospital (China) between January 2017 and October 2020 were included. Age- and sex-matched patients who visited the rheumatology outpatient clinic without systemic or ADs were included as controls. Demographic, clinical, serological, and radiological data of sarcoidosis patients were recorded and analyzed. To exclude ADs, autoantibodies, such as antinuclear antibody, extractable nuclear antigen antibodies, and anti-cyclic citrullinated peptide antibody were assessed in controls. A total of 154 sarcoidosis patients (111 females; 72.1%) with a mean ± standard deviation age of 50.7 ± 10.3 years were included. Nineteen patients (12.3%) had ADs; Hashimoto's thyroiditis (n = 6) and Sjogren's syndrome (n = 4) were common. Age, globulin, immunoglobulin G, erythrocyte sedimentation rate (ESR), and C-reactive protein were significantly different between sarcoidosis patients with and without ADs. The ESR level might be a risk factor for sarcoidosis complicated with ADs (RR = 1.053; P = 0.018). Autoantibodies were detected in 29 patients (18.8%), and the frequency was significantly higher than that in controls (18.8% vs. 3%; P = 0.001). Sarcoidosis patients were more likely to have autoantibodies despite the absence of ADs (10.4% vs. 3%; P = 0.031). Age may be a risk factor for sarcoidosis patients presenting with autoantibodies (RR = 1.077; P = 0.042). An association was identified between ADs and sarcoidosis. The inflammatory indexes, such as ESR, IgG, and CRP, were significantly different between sarcoidosis patients with and without ADs. ESR might be a risk factor for the coexistence of ADs and sarcoidosis. Sarcoidosis patients were prone to being autoantibody-positive despite the absence of ADs, and age might be a risk factor for sarcoidosis presenting with autoantibodies.

A New Ferroptosis-Related lncRNA Signature Predicts the Prognosis of Bladder Cancer Patients.

Background: Ferroptosis is closely related to the occurrence and development of cancer. An increasing number of studies have induced ferroptosis as a treatment strategy for cancer. However, the predictive value of ferroptosis-related lncRNAs in bladder cancer (BC) still need to be further elucidated. The purpose of this study was to construct a predictive signature based on ferroptosis-related long noncoding RNAs (lncRNAs) to predict the prognosis of BC patients. Methods: We downloaded RNA-seq data and the corresponding clinical and prognostic data from The Cancer Genome Atlas (TCGA) database and performed univariate and multivariate Cox regression analyses to obtain ferroptosis-related lncRNAs to construct a predictive signature. The Kaplan-Meier method was used to analyze the overall survival (OS) rate of the high-risk and low-risk groups. Gene set enrichment analysis (GSEA) was performed to explore the functional differences between the high- and low-risk groups. Single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between the predictive signature and immune status. Finally, the correlation between the predictive signature and the treatment response of BC patients was analyzed. Results: We constructed a signature composed of nine ferroptosis-related lncRNAs (AL031775.1, AL162586.1, AC034236.2, LINC01004, OCIAD1-AS1, AL136084.3, AP003352.1, Z84484.1, AC022150.2). Compared with the low-risk group, the high-risk group had a worse prognosis. The ferroptosis-related lncRNA signature could independently predict the prognosis of patients with BC. Compared with clinicopathological variables, the ferroptosis-related lncRNA signature has a higher diagnostic efficiency, and the area under the receiver operating characteristic curve was 0.707. When patients were stratified according to different clinicopathological variables, the OS of patients in the high-risk group was shorter than that of those in the low-risk group. GSEA showed that tumor- and immune-related pathways were mainly enriched in the high-risk group. ssGSEA showed that the predictive signature was significantly related to the immune status of BC patients. High-risk patients were more sensitive to anti-PD-1/L1 immunotherapy and the conventional chemotherapy drugs sunitinib, paclitaxel, cisplatin, and docetaxel. Conclusion: The predictive signature can independently predict the prognosis of BC patients, provides a basis for the mechanism of ferroptosis-related lncRNAs in BC and provides clinical treatment guidance for patients with BC.

Endogenous miRNA-Activated DNA Nanomachine for Intracellular miRNA Imaging and Gene Silencing.

The development of multifunctional nanoplatforms that integrate both diagnostic and therapeutic functions has always been extremely desirable and challenging in the cancer combat. Here, we report an endogenous miRNA-activated DNA nanomachine (EMDN) in living cells for concurrent sensitive miRNA imaging and activatable gene silencing. EMDN is constructed by interval hybridization of two functional DNA monomers (R/HP and F) to a DNA nanowire generated by hybridization chain reaction. After the target cell-specific transportation of EMDN, intracellular let-7a miRNA initiates the DNA nanomachine by DNA strand displacement cascades, resulting in an amplified fluorescence resonance energy-transfer signal and the release of many free HP sequences. The restoration of HP hairpin structures further activates the split-DNAzyme to identify and cleave the EGR-1 mRNA to realize gene silencing therapy. The proposed EMDN shows efficient cell internalization, good biological stability, rapid reaction kinetics, and the ability to avoid false-positive signals, thus ensuring reliable miRNA imaging in living cells. Meanwhile, the controlled activation of the split-DNAzyme activity regulated by the intracellular specific miRNA may be promising in the precise treatment of cancer. Collectively, this strategy provides a valuable nanoplatform for early clinical diagnosis and activatable gene therapy of tumors.

Hollow MXene Sphere-Based Flexible E-Skin for Multiplex Tactile Detection.

Skin-like electronics that can provide comprehensively tactile sensing is required for applications such as soft robotics, health monitoring, medical treatment, and human-machine interfaces. In particular, the capacity to monitor the contact parameters such as the magnitude, direction, and contact location of external forces is crucial for skin-like tactile sensing devices. Herein, a flexible electronic skin which can measure and discriminate the contact parameters in real time is designed. It is fabricated by integrating the three-dimensional (3D) hollow MXene spheres/Ag NW hybrid nanocomposite-based embedded stretchable electrodes and T-ZnOw/PDMS film-based capacitive pressure sensors. To the best of our knowledge, it is the first stretchable electrode to utilize the 3D hollow MXene spheres with the essential characteristic, which can effectively avoid the drawbacks of stress concentration and shedding of the conductive layer. The strain-resistance module and the pressure-capacitance module show the excellent sensing performance in stability and response time, respectively. Moreover, a 6 × 6 sensor array is used as a demonstration to prove that it can realize the multiplex detection of random external force stimuli without mutual interference, illustrating its potential applications in biomimetic soft wearable devices, object recognition, and robotic manipulation.

Rac3 Expression and its Clinicopathological Significance in Patients With Bladder Cancer.

Background: Ras-related C3 botulinum toxin substrate 3 (Rac3) is overexpressed in malignancies and promotes tumor progression. However, the correlations between Rac3 expression and the clinicopathological characteristics and prognoses of patients with bladder cancer (BC) remain unclear. Methods: Data from The Cancer Genome Atlas (TCGA) were used to analyze Rac3 expression in BC and normal bladder tissues and validated using the Oncomine database, quantitative real-time PCR (qRT-PCR) and western blot. The Kaplan-Meier method was used to analyze the relationship between Rac3 expression and the prognosis of patients with BC. Cox univariate and multivariate analyses of BC patients overall survival (OS) were performed. Signaling pathways that potentially mediate Rac3 activity in BC were then analyzed by gene set enrichment analysis (GSEA). Results: The Rac3 expression in BC tissues was significantly higher than that in normal bladder tissues. Rac3 expression was significantly correlated with grade and stage. Overexpression of Rac3 was associated with a poor prognosis. GSEA showed that the cell cycle, DNA replication, p53 signaling pathway and mismatch repair were differentially enriched in the high Rac3 expression phenotype. The qRT-PCR and western blot results confirmed that the Rac3 expression in BC tissues was higher than that in normal bladder tissues. Conclusion: Rac3 is highly expressed in BC, which is related to the advanced clinicopathological variables and adverse prognosis of patients with BC. These results provide a new therapeutic target for BC.

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link.

Bladder cancer is a common malignant tumor of the urinary system. Despite recent advances in treatments such as local or systemic immunotherapy, chemotherapy, and radiotherapy, the high metastasis and recurrence rates, especially in muscle-invasive bladder cancer (MIBC), have led to the evaluation of more targeted and personalized approaches. A fundamental understanding of the tumorigenesis of bladder cancer along with the development of therapeutics to target processes and pathways implicated in bladder cancer has provided new avenues for the management of this disease. Accumulating evidence supports that the tumor microenvironment (TME) can be shaped by and reciprocally act on tumor cells, which reprograms and regulates tumor development, metastasis, and therapeutic responses. A hostile TME, caused by intrinsic tumor attributes (e.g., hypoxia, oxidative stress, and nutrient deprivation) or external stressors (e.g., chemotherapy and radiation), disrupts the normal synthesis and folding process of proteins in the endoplasmic reticulum (ER), culminating in a harmful situation called ER stress (ERS). ERS is a series of adaptive changes mediated by unfolded protein response (UPR), which is interwoven into a network that can ultimately mediate cell proliferation, apoptosis, and autophagy, thereby endowing tumor cells with more aggressive behaviors. Moreover, recent studies revealed that ERS could also impede the efficacy of anti-cancer treatment including immunotherapy by manipulating the TME. In this review, we discuss the relationship among bladder cancer, ERS, and TME; summarize the current research progress and challenges in overcoming therapeutic resistance; and explore the concept of targeting ERS to improve bladder cancer treatment outcomes.

Identification of a New DNA Aptamer by Tissue-SELEX for Cancer Recognition and Imaging.

Cancer has become one of the most common diseases with high mortality in humans. Early and accurate diagnosis of cancer is of great significance to enhance the survival rate of patients. Therefore, effective molecular ligands capable of selectively recognizing cancer are urgently needed. In this work, we identified a new DNA aptamer named SW1 by tissue-based systematic evolution of ligands by exponential enrichment (tissue-SELEX), in which cancerous liver tissue sections were used as the positive control and adjacent normal liver tissue sections were used as the negative control. Taking immobilized liver cancer SMMC-7721 cells as the research object, aptamer SW1 exhibited excellent affinity with a Kd value of 123.62 ± 17.53 nM, and its binding target was preliminarily determined as a non-nucleic acid substance in the nucleus. Moreover, tissue imaging results showed that SW1 explicitly recognized cancerous liver tissues with a high detection rate of 72.7% but displayed a low detection rate to adjacent normal tissues. In addition to liver cancer cells and tissues, aptamer SW1 has been demonstrated to recognize various other types of cancer cells and tissues. Furthermore, SW1-A, an optimized aptamer of SW1, maintained its excellent affinity toward liver cancer cells and tissues. Collectively, these results indicate that SW1 possesses great potential for use as an effective molecular probe for clinical diagnosis of cancer.

Evaluation of three microhaplotypes in individual identification and ancestry inference.

Microhaplotype as an emerging genetic marker has attracted more attention in forensic field. The purpose of this study was to evaluate the potential of microhaplotypes in individual identification and ancestry inference in Chinese Hainan Li and 26 1000 G populations. Three microhaplotypes were genotyped from 100 Li individuals using Agena MassARRAY. Moreover, 2504 individuals from 26 populations (1000 Genomes Project database) were enrolled. The genotypes frequencies of microhaplotypes in each population were calculated by the Plink software. We used Structure, Arlequin, and MEGA6 software to analyze the genetic structure, differentiation and genetic background difference, respectively. The forensic parameters of these microhaplotypes were calculated using Modified Powerstats software. The distribution of genotypes frequencies of three microhaplotypes elaborated the high diversities among the Li and 26 1000 G populations. Li population had a close genetic relationship with EAS populations using structure analysis. No differentiation was observed between Li and CHS population by Fst analysis. The NJ tree showed that the genetic background of Li and CHS is most similar. The average heterozygosity (HE), probability of match (PM), power of discrimination (PD), probability of exclusion (PE) and polymorphism information content (PIC) values for the three microhaplotypes in 27 populations were 0.535, 0.497, 0.465, 0.325, and 0.481, respectively. In conclusion, our results revealed three microhaplotypes as individual identification and ancestry inference genetic markers among Li population and 26 1000 G populations. Future studies are needed to confirm our results with larger samples and select much higher forensic efficacy microhaplotypes.

Spider Web-like Flexible Tactile Sensor for Pressure-Strain Simultaneous Detection.

Multiparameter integrated sensors are required for the next generation of flexible wearable electronics. However, mutual interference between detected signals is a technical bottleneck for a flexible tactile sensor to realize pressure-strain monitoring simultaneously and sensitively. Herein, a flexible dual-parameter pressure-strain sensor based on the three-dimensional (3D) tubular graphene sponge (TGS) and spider web-like stretchable electrodes is designed and fabricated. As the pressure-sensitive module, the unique 3D-TGS with an uninterrupted network of tubular graphene and high graphitic degree demonstrates great robust compressibility, supporting compression to ∼20% without shape collapse. The spider web-like stretchable electrodes as the strain-sensitive module are fabricated by a spray-embedded process based on the hierarchical multiscale hybrid nanocomposite of Ag nanowires (NWs) and carbon nanotubes (CNTs) with an optimal mass ratio. By comparing the output signals of spider web-like flexible electrodes, the magnitude and direction of the applied force can be effectively monitored simultaneously. Moreover, the potential applications of the flexible dual-parameter pressure-strain device in human-machine interaction are also explored, showing great promise in artificial intelligence and wearable systems.

A novel palmitic acid hydroxy stearic acid (5-PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m-TOR-ULK1 pathway and regulating autophagy.

AIMS: Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5-PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic-related neurodegeneration. The aim of the present study was to investigate whether 5-PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy. METHODS: 5-PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5-PAHSA for 24 h, while mice were administered with 5-PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors. RESULTS: Although there was no significant improvement in glucose metabolism in mice administered with 5-PAHSA, ox-LDL decreased significantly following the administration of 5-PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m-TOR and ULK-1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5-PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5-PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high-dose group of 5-PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5-PAHSA. CONCLUSION: We found that 5-PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5-PAHSA inhibits phosphorylation of the m-TOR-ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice.