Circ_0007534 promotes cholangiocarcinoma stemness and resistance to anoikis through DDX3X-mediated positive feedback regulation of parental gene DDX42.

Cholangiocarcinoma (CCA) is a malignancy with an extremely poor prognosis, and much remains unknown about its pathogenesis and treatment modalities. Circular RNA (circRNA) has been proven to play regulatory roles in various tumorigenesis, yet its potential function and mechanism in cholangiocarcinoma require further investigation. This study is the first to identify the aberrant expression and functional role of a novel circRNA, circ_0007534, derived from the DDX42 gene, in cholangiocarcinoma. Compared to the normal control group, the expression of circ_0007534 was significantly elevated in the tissues and cells with CCA and that high expression correlated with lymph node invasion and poor prognosis. Functional experiments indicated that downregulating circ_0007534 markedly inhibited the proliferation, migration, invasion, stemness, and anti-anoikis ability of CCA cells, as well as the tumor growth and liver and lung metastasis in nude mice. Mechanistic studies revealed that DDX42, as the parent gene of circ_0007534, can mutually regulate each other's expression. Predominantly located in the cytoplasm, circ_0007534 can form a complex with the RNA-binding protein DDX3X, which enhances the stability of DDX42 mRNA, thereby upregulating the expression of DDX42. This creates a positive feedback loop among the three, collectively promoting the progression of cholangiocarcinoma. In conclusion, this study sheds light on the pivotal role and molecular mechanism of circ_0007534 in the development of CCA, offering potential new targets for early diagnosis and treatment.

LOXL1-AS1 inhibits JAK2 ubiquitination and promotes cholangiocarcinoma progression through JAK2/STAT3 signaling.

This study thoroughly investigated the role of the long non-coding RNA LOXL1-AS1 in the pathogenesis of cholangiocarcinoma (CCA). Through bioinformatics analysis and tissue samples validation, the study found that LOXL1-AS1 was significantly elevated in CCA, with its high expression closely tied to clinical pathological features and prognosis. In vitro and in vivo experiments revealed that LOXL1-AS1 was crucial in regulating CCA cell apoptosis, proliferation, migration, and invasion. Further investigations using FISH, subcellular localization experiments, RNA pull down, and RIP uncovered that LOXL1-AS1 primarily resided in the cytoplasm and influenced CCA progression by modulating the JAK2/STAT3 signaling pathway. Notably, LOXL1-AS1 might regulate the activity of JAK2 through modulating its ubiquitination and degradation. YY1 had also been found to act as an upstream transcription factor of LOXL1-AS1 to impact CCA cell malignancy. These findings shed light on the pivotal role of LOXL1-AS1 in CCA and offered potential directions for novel therapeutic strategies, providing a fresh perspective on tumor pathogenesis.

Wearable electrochemical glucose sensor of high flexibility and sensitivity using novel mushroom-like gold nanowires decorated bendable stainless steel wire sieve.

Long-term high blood glucose levels brings extremely detrimental effect on diabetic patients, such as blindness, renal failure, and cardiovascular diseases. Therefore, there is an urgent need to develop highly flexible and sensitive sensors for precisely non-invasive and continuous monitoring glucose levels. Herein, we present a highly flexible and sensitive wearable sensor for non-enzymatic electrochemical glucose analysis with vertically aligned mushroom-like gold nanowires (v-AuNWs) chemically grown on stainless steel wire sieve (SSWS) as integrated electrode. Owing to the unique nanostructures and excellent catalysis of the v-AuNWs, the as-fabricated glucose sensors exhibit superior flexibility and excellent electro-catalytic capability. In detail, these sensors display rapid response towards glucose within 5 s, and the sensor constructed with v-AuNWs for growth time of 15 min shows the highest sensitivity of 180.1 µA mM-1 cm-2 within a wide linear range of 6.5 × 10-4 mM-12.0 mM and the lowest detection limit of 0.65 µM (S/N = 3). It is noteworthy that due to the good ductility of the v-AuNWs and their strong contact with the SSWS substrate, these glucose sensors exhibit no obvious response variation after repeated bending for 100 times at bending angle of 180°. Additionally, the glucose sensors display superior anti-interfering capability as well as desirable repeatability. More importantly, these glucose sensors can be attached on human skin to determine sweat glucose reliably and analyze glucose concentration in human serum in vitro.

Nanoassembly with self-regulated magnetic thermal therapy and controlled immuno-modulating agent release for improved immune response.

Cancer immunotherapy is an emerging cancer therapeutic method by activating the patient's immune system but suffers from low immunogenicity at tumor sites. Fever-like heat is known to modulate an immune-friendly tumor microenvironment. Here, temperature-responsive iron oxide nanoassemblies (IONAs) are developed by crosslinking iron oxide nanoparticles (IONPs) and loaded with JQ1 (JQ1/IONAs), an immuno-modulating agent known to down-regulate PD-L1. In the presence of an alternating magnetic field (AMF), the IONAs demonstrate a much more effective magnetic thermal effect than IONPs and are responsively disassembled to prevent overheating. Compared with IONPs + AMF (∼ 41 °C) and unresponsive nanoassemblies (uIONAs) + AMF (∼ 50 °C), the IONAs + AMF with a temperature heated around 45 °C show a much better immune response and anti-tumor effect. Further combining the mild thermal therapy with controlled release of JQ1, the JQ1/IONAs + AMF completely eradicate the primary tumors and trigger a strong immune effect to inhibit the distant tumor growth as well as prevent tumor recurrence and metastasis. Our JQ1/IONAs not only provide a magnetic thermal agent with effective heating and temperature self-regulation ability but also serve as a heat-triggered JQ1 carrier to spontaneously combine mild magnetic thermal therapy with immune checkpoint blockade therapy.

Hot-band absorption assisted single-photon frequency upconversion luminescent nanophotosensitizer for 808 nm light triggered photodynamic immunotherapy of cancer.

Frequency upconversion luminescence (FUCL) based on hot-band absorption has attracted considerable attention in bioimaging and phototherapy fields for deep-seated cancer treatment. Photoimmunotherapy, a promising therapeutic approach induced by photodynamic therapy (PDT), can selectively kill cancer cells, reverse the immunosuppressive system, boost host immune response, and elicit durable antitumor immunity. To date, few near-infrared organic photosensitizers for photodynamic immunotherapy have been reported based on hot-band absorption. Herein, we report an upconversion luminescent phthalocyanine photosensitizer PdPc(OBu)8 with anti-Stokes emission at 748 nm and highly efficient singlet oxygen generation with hot-band absorption at 808 nm. Taking advantage of nanoliposomes, FUCL phthalocyanine nano-photosensitizers (PdPc NPs) were obtained to reduce the aggregation-caused quenching and improve water solubility and biocompatibility. PdPc NPs could be effectively accumulated in tumor tissues through intravenous administration, causing FUCL-induced PDT under 808 nm irradiation. Considering its finite immune responses and tumor ablation after PDT, a combination of PdPc NP-based PDT with checkpoint inhibitors (anti-PD-L1) for near-infrared photoimmunotherapy has been used to potentiate the antitumor efficacy that could simultaneously ablate primary tumors and inhibit the progression of distant tumors. This study can promote the development of upconversion-based PDT combined with immunotherapy for tumor precision therapy.

Temporal trends and rural-urban disparities in cerebrovascular risk factors, in-hospital management and outcomes in ischaemic strokes in China from 2005 to 2015: a nationwide serial cross-sectional survey.

BACKGROUND: Stroke is the leading cause of mortality in China, with limited evidence of in-hospital burden obtained from nationwide surveys. We aimed to monitor and track the temporal trends and rural-urban disparities in cerebrovascular risk factors, management and outcomes from 2005 to 2015. METHODS: We used a two-stage random sampling survey to create a nationally representative sample of patients admitted for ischaemic stroke in 2005, 2010 and 2015. We sampled participating hospitals with an economic-geographical region-stratified random-sampling approach first and then obtained patients with a systematic sampling approach. We weighed our survey data to estimate the national-level results and assess changes from 2005 to 2015. RESULTS: We analysed 28 277 ischaemic stroke admissions from 189 participating hospitals. From 2005 to 2015, the estimated national hospital admission rate for ischaemic stroke per 100 000 people increased (from 75.9 to 402.7, Ptrend<0.001), and the prevalence of risk factors, including hypertension, diabetes, dyslipidaemia and current smoking, increased. The composite score of diagnostic tests for stroke aetiology assessment (from 0.22 to 0.36, Ptrend<0.001) and secondary prevention treatments (from 0.46 to 0.70, Ptrend<0.001) were improved. A temporal decrease was found in discharge against medical advice (DAMA) (from 15.2% (95% CI 13.7% to 16.7%) to 8.6% (8.1% to 9.0%); adjusted Ptrend=0.046), and decreases in in-hospital mortality (0.7% in 2015 vs 1.8% in 2005; adjusted OR (aOR) 0.52; 95% CI 0.32 to 0.85) and the composite outcome of in-hospital mortality or DAMA (8.4% in 2015 vs 13.9% in 2005; aOR 0.65; 95% CI 0.47 to 0.89) were observed. Disparities between rural and urban hospitals narrowed; however, disparities persisted in in-hospital management (brain MRI: rural-urban difference from -14.4% to -11.2%; cerebrovascular assessment: from -20.3% to -16.7%; clopidogrel: from -2.1% to -10.3%; anticoagulant for atrial fibrillation: from -10.9% to -8.2%) and in-hospital outcomes (DAMA: from 2.7% to 5.0%; composite outcome of in-hospital mortality or DAMA: from 2.4% to 4.6%). CONCLUSIONS: From 2005 to 2015, improvements in hospital admission and in-hospital management for ischaemic stroke in China were found. A temporal improvement in DAMA and improvements in in-hospital mortality and the composite outcome of in-hospital mortality or DAMA were observed. Disparities between rural and urban hospitals generally narrowed but persisted.

Relatlimab: a novel drug targeting immune checkpoint LAG-3 in melanoma therapy.

Relatlimab is a type of human immunoglobulin G4 monoclonal blocking antibody. It is the world's first Lymphocyte-Activation Gene-3 (LAG-3) inhibitor and the third immune checkpoint inhibitor with clinical application, following PD-1 and CTLA-4. Relatlimab can bind to the LAG-3 receptor which blocks the interaction between LAG-3 and its ligand to reduce LAG-3 pathway-mediated immunosuppression and promote T-cell proliferation, inducing tumor cell death. On 18 March 2022, the U.S. FDA approved the fixed-dose combination of relatlimab developed by Bristol Myers Squibb with nivolumab, under the brand name Opdualag for the treatment of unresectable or metastatic melanoma in adult and pediatric patients aged 12 and older. This study comprehensively describes the mechanism of action and clinical trials of relatlimab and a brief overview of immune checkpoint drugs currently used for the treatment of melanoma.

Polysaccharides from Lachnum sp. Inhibited colitis-associated colon tumorigenesis in mice by modulating fecal microbiota and metabolites.

It is still uncertain whether the consumption of Lachnum sp. polysaccharides (LEP) alleviates colorectal cancer (CRC) through the gut microbiota. In this study, our efforts are focused on the influence of LEP on CRC, intestinal barrier and inflammation, and fecal microbiota and the metabolites, in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. Results showed that LEP inhibited CRC mouse colon shortening and weight loss, decreased tumor incidence, restored intestinal barrier integrity, and reduced excessive inflammation. LEP consumption significantly altered microbiota overall structure and community, with reduced pernicious bacteria (such as Parabacteroides, Escherichia_Shigella, Desulfovibrio and Helicobacter), and increased beneficial bacterium (such as Alistipes, Alloprevotella and Ruminiclostridium). Fecal-metabolome profile indicated that a total of 43 metabolites were clearly changed, with 10 down-regulated and 33 up-regulated metabolites. In addition, short-chain fatty acids (SCFAs), including acetic acid, propionic acid and n-butyric acid, were significantly increased after LEP administration. Moreover, a strong correlation between the fluctuant gut microbiota and metabolites was found. These findings provided not only deeper insights into the responsibility of LEP for CRC alleviation, and but also the potential of LEP as a promising candidate for CRC prevention and treatment.

Stabilization of lead and cadmium in soil by sulfur-iron functionalized biochar: Performance, mechanisms and microbial community evolution.

Sulfur-iron functionalized biochar (BC-Fe-S) was designed by simultaneously supporting Fe2O3 nanoparticles and grafting sulfur-containing functional groups onto biochar to stabilize Pb and Cd in soil. The BC-Fe-S exhibited excellent stabilization performance for Pb and Cd with fast kinetic equilibrium within 5 days associating with pseudo-second-order model. The bioavailable-Pb and -Cd contents decreased by 59.22% and 70.28% with 3% BC-Fe-S treatment after 20 days of remediation. Speciation transformation analysis revealed that the increase of stabilization time and BC-Fe-S dosage with appropriate soil moisture and pH promoted toxicities decrease of Pb and Cd with transformation of labile fractions to more steady fractions. The labile fractions of Pb and Cd decreased by 12.22% and 16.21% with 3% BC-Fe-S treatment, and transformed to the residual speciation. Meanwhile, wetting-drying and freezing-thawing aging did not markedly alter the bioavailability of Pb and Cd, proving that the BC-Fe-S holds promise for stabilization of Pb and Cd in varying environmental conditions. 16S rRNA sequencing analysis demonstrated that the BC-Fe-S significantly improved diversity and composition of microbial community, especially increasing the relative abundance of heavy metal-resistant bacteria. Overall, these results suggested BC-Fe-S as a high-performance and environmental-friendly amendment with stability to remediate heavy metals polluted soil.

Methylglyoxal induces p53 activation and inhibits mTORC1 in human umbilical vein endothelial cells.

Methylglyoxal (MGO), a precursor of advanced glycation end products (AGEs), is regarded as a pivotal mediator of vascular damage in patients with diabetes. We have previously reported that MGO induces transcriptional changes compatible with p53 activation in cultured human endothelial cells. To further substantiate this finding and to explore the underlying mechanisms and possible consequences of p53 activation, we aimed (1) to provide direct evidence for p53 activation in MGO-treated human umbilical vein endothelial cells (HUVECs), (2) to assess putative mechanisms by which this occurs, (3) to analyze down-stream effects on mTOR and autophagy pathways, and (4) to assess the potential benefit of carnosine herein. Exposure of HUVECs to 800 µM of MGO for 5 h induced p53 phosphorylation. This was paralleled by an increase in TUNEL and γ-H2AX positive cells, indicative for DNA damage. Compatible with p53 activation, MGO treatment resulted in cell cycle arrest, inhibition of mTORC1 and induction of autophagy. Carnosine co-treatment did not counteract MGO-driven effects. In conclusion, our results demonstrate that MGO elicits DNA damage and p53 activation in HUVECs, resulting in modulation of downstream pathways, e.g. mTORC1.

Chaperone-mediated autophagy affects tumor cell proliferation and cisplatin resistance in esophageal squamous cell carcinoma.

BACKGROUND: Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosomal membrane associated protein 2a (LAMP2a) is the lysosomal membrane receptor of CMA and influences CMA activity. Although it has been suggested that higher expression of LAMP2a is associated with more advanced tumor node metastasis (TNM) stages and shorter survival time in patients with esophageal squamous cell carcinoma (ESCC), the underlying mechanism has not been known yet. METHODS: In this study, we modulated the activity of CMA through LAMP2a or small molecular compounds in human ESCC cells to investigate its role in ESCC. RESULTS: We found that down-regulating the activity of CMA could inhibit the proliferation and colony formation of ESCC cells as well as increase their sensitivity to cisplatin. CONCLUSIONS: Our results promote better understanding of how CMA affects human ESCC and provide a new therapeutic target against ESCC through down-regulating LAMP2a.

Lachnum polysaccharide suppresses S180 sarcoma by boosting anti-tumor immune responses and skewing tumor-associated macrophages toward M1 phenotype.

Therapeutic strategies that targeting tumor-associated macrophages (TAMs) reprogramming play a crucial role in ameliorating the immunosuppressive tumor microenvironment and boosting anti-tumor immune responses. In this study, we demonstrated that Lachnum polysaccharide (LEP) could work as an immunomodulator to reset TAMs from pro-tumor M2 to anti-tumor M1 phenotype. Mechanistically, LEP promoted Th1 polarization and the secretion of IFN-γ, which played a key role in M1 phenotype polarization. In parallel, LEP might directly activate M1 macrophages via TLR4 mediated NF-κB signaling pathway. Moreover, LEP also resulted in the accumulation of anti-tumor immune cells and decreased the infiltration of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and Treg cells, thereby potentiating anti-tumor immunity. In summary, these results revealed a novel mechanism of the anti-tumor effect of LEP and provided a potential new avenue targeting TAMs and cancer immunotherapy.

Tunable magnetic and half-metallic properties of the two-dimensional electron gas in LaAlO3/SrTiO3(111) heterostructures.

Half-metallic materials have gained a lot of attention because of their unique properties and applications in spintronic devices. Despite the fact that these materials have been studied by several research groups there are very limited studies on their heterostructure (HS) systems. In the current study we have investigated the electronic and magnetic properties of (LaAlO3)6.5/(SrTiO3)2.5(111) HS using density functional theory (DFT) calculations. We demonstrate that the system exhibits a 100% spin-polarized two-dimensional electron gas (2DEG) which is extremely confined to the Ti 3d orbitals of the SrTiO3 layers. In particular, this system can keep its half-metallic properties under different in-plane strains from -3 to 2%. This property proves that this material has relatively stable half-metallic properties. In addition, the conducting and magnetic ground states of the system can also be tailored by changing in-plane strain and interfacial cation intermixing of La and Sr (Sr ⇔ La intermixing). By increasing the in-plane lattice parameters, this system has the ability to evolve from a nonmagnetic to a ferromagnetic metal and then to a half-metal and by further increasing the in-plane lattice parameter it becomes a ferromagnetic insulator. Sr ⇔ La intermixing can destroy the original half-metallic properties and the system exhibits an AFM Mott-type insulator phase. Our results demonstrate that the system has high potential for application in the field of spintronics, and opens the prospect of using LaAlO3/SrTiO3(111) HSs to explore quantum phase transitions.

The diagnostic accuracy of a real-time optoelectronic device in cervical cancer screening: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: This study aimed to assess the diagnostic accuracy of a real-time optoelectronic device (TruScreen) for uterine cervical cancer screening. METHODS: On the basis of Preferred Reporting Items for Systematic Reviews and Meta-analyses (the PRISMA statement) we performed this systematic review and meta-analysis. We searched PubMed, EMBASE, the Cochrane Library, CNKI, CBM, and WanFang Data using medical subject headings (MeSH) and text words. Title/abstract screening, full text check, data extraction, and methodological quality assessment (with the QUADAS-2 tool) were performed by 2 reviewers independently. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), the summary receiver operator characteristic curve, and the area under the curve (AUC) were analyzed with Meta-DiSc software. Statistical heterogeneity was evaluated by Cochran's Q test and I, meta-regression was conducted based on patient type, and the possibility of publication bias was evaluated using Deeks funnel plot in Stata software. RESULTS: Of 293 publications, nine met our inclusion criteria. These studies included a total of 2730 patients and 567 cervical intraepithelial neoplasias. The pooled test characteristics for the TruScreen were as follows: sensitivity 76% (95% CI, 73-80%), specificity 69% (95% CI, 67%-71%), PLR 2.30 (95% CI, 1.59-3.33), and NLR 0.34 (95% CI, 0.23-0.51). The corresponding pooled DOR was 7.03 (95% CI, 3.40-14.55). The AUC was 0.7859 (Q = 0.7236). CONCLUSION: The diagnostic accuracy of the TruScreen device is moderately good. The study findings are based on Chinese studies only and could not be generalized to other populations.

Three dimensional hierarchy structures from self-assembly of quantum dots.

We have reported first example of 3D hierarchy structure from self-assembly of water-soluble QDs followed by chemical reaction control. After addition of ethylenediaminetetraacetic acid, dipotassium salt dehydrate (EDTA) into L-cysteine-stabilized CdTe QD solution, the color of solution was observed to become lighter and shallower, and finally white precipitates appeared. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) results confirm that the morphology transformation from zero dimensional (0D) QDs via two-dimensional (2D) nanoflakes to 3D microflowers occurs among those QD assemblies. Meanwhile, EDX results demonstrate that the as-formed QD-assemblies are not CdTe but CdS. The turnover of chemistry nature from CdTe to CdS after addition of EDTA is mainly due to the oxidation of Te followed by a series of chemical reactions. The photoluminescence (PL) spectroscopy and confocal laser scanning microscopy (CLSM) results reveal that such 3D hierarchy structure of CdS QDs have good optical property.