Dual-Functional Capping Agent-Mediated Transformation of Silver Nanotriangles to Silver Nanoclusters for Dual-Mode Biosensing.

The localized surface plasmon resonance (LSPR) property, depending on the structure (morphology and assembly) of nanoparticles, is very sensitive to the environmental fluctuation. Retaining the colorimetric effect derived from the LSPR property while introducing new optical properties (such as fluorescence) that provide supplementary information is an effective means to improve the controllability in structures and reproducibility in optical properties. DNA as a green and low-cost etching agent has been demonstrated to effectively control the morphology and optical properties (the blue shift of the LSPR peak) of the plasmonic nanoparticles. Herein, taking silver nanotriangles (AgNTs) as a proof of concept, we report a novel strategy to induce precisely tunable LSPR and fluorescence-composited dual-mode signals by using mono-DNA first as an etching agent for etching the morphology of AgNTs and later as a template for synthesizing fluorescent silver nanoclusters (AgNCs). In addition, common templates for synthesizing AgNCs, such as l-glutathione and bovine serum albumin, were demonstrated to have the capability to serve as etching agents. More importantly, these biomolecules as dual-functional capping agents (etching agents and templates) follow the size-dependent rule: as the size of the thiolated biomolecule increases, the blue shift of the LSPR peak increases; at the same time, the fluorescence intensity increases. The enzyme that can change the molecular weight (size) of the biomolecular substrates (DNA, peptides, and proteins) through an enzymatic cleavage reaction was explored to regulate the LSPR and fluorescent properties of the resulting nanoparticles (by etching of AgNTs and synthesis of AgNCs), achieving excellent performance in detection of cancer-related proteases. This study can be expanded to other biopolymers to impact both fundamental nanoscience and applications and provide powerful new tools for bioanalytical biosensors and nanomedicine.

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancies. However, the underlying cellular mechanisms of circRNAs implicated in the pathogenesis of HCC remain unknown. In this study, we identified a functional RNA, hsa_circ_0000384 (circMRPS35), from public tumor databases using a set of computational analyses, and we further identified that circMRPS35 was highly expressed in 35 pairs of HCC from patients. Moreover, knockdown of the expression of circMRPS35 in Huh-7 and HCC-LM3 cells suppressed their proliferation, migration, invasion, clone formation, and cell cycle in vitro, and it suppressed tumor growth in vivo as well. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), regulating the expression of Syntaxin 3 (STX3), which modulated the ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Unexpectedly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC. These results demonstrated that circMRPS35 might be a novel mediator in HCC progress, and they raise the potential of a new biomarker for HCC diagnosis and prognosis, as well as a novel therapeutic target for HCC patients.

Controllable Synthesis, Formation Process, and Luminescence Performances of Diverse Yttrium Compounds with Hollow Structures.

Hollow spherical Y2O3 and YBO3 have been prepared by a facile template-directed strategy using phenol-formaldehyde (PF) resin spheres as templates. The PF@Y(OH)CO3 precursor can be fabricated by a simple precipitation route. The Y2O3 hollow spheres are obtained via a direct annealing process, and the hollow spherical YBO3 are fabricated via a hydrothermal route followed by an annealing process at the expense of the same PF@Y(OH)CO3 precursor. The whole synthesis procedure is performed in aqueous solution without any surfactant or catalyst. Moreover, YVO4 quasi-octahedral microcrystals with spherical holes are obtained. The formation mechanisms of the yttrium compounds with different morphologies have been discussed. By incorporating proper rare earth activator ions into the Y2O3, YBO3, and YVO4 hosts, the as-synthesized luminescent materials can exhibit eminent performances with both down-conversion and up-conversion luminescence. Furthermore, the as-fabricated light-emitting diode (LED) devices can emit dazzling characteristic emission light, which reveals that the phosphors have application potential in lighting and displays. This simple synthesis strategy may provide a new idea for the fabrication of inorganic compounds with perfect hollow structures and excellent properties.

Effects of sodium-glucose cotransporter 2 inhibitors on serum uric acid in patients with type 2 diabetes mellitus: A systematic review and network meta-analysis.

AIMS: The present study aims to determine the effects of sodium-glucose cotransporter 2 (SGLT-2) inhibitors on the serum uric acid (SUA) levels of patients with type 2 diabetes mellitus (T2DM) in Asia. METHODS: PubMed, CENTRAL, Embase and Cochrane Library databases were searched for randomized controlled trials of SGLT-2 inhibitors in patients with T2DM up to 15 July 2021, without language or date restrictions. RESULTS: In total, 19 high-quality studies (4218 participants) were included in the present network meta-analysis. All of the included SGLT-2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ipragliflozin, luseogliflozin and tofogliflozin) significantly decreased SUA levels compared with those of the control [total standard mean difference -0.965, 95% CI (-1.029, -0.901), p = .000, I2  = 98.7%] in patients with T2DM. Subgroup analysis and meta-regression showed that the combined analysis of different inhibitors might lead to heterogeneity of the results. Therefore, among the SGLT-2 inhibitors, the results of the subsequent network meta-analysis revealed that luseogliflozin and dapagliflozin ranked the highest in terms of lowering SUA levels among the SGLT-2 inhibitors. Moreover, the network meta-analysis declared that luseogliflozin (1 and 10 mg) and dapagliflozin (5 mg) led to a superior reduction in SUA in patients with T2DM. CONCLUSIONS: SGLT-2 inhibitors could significantly reduce SUA levels in patients with T2DM, particularly luseogliflozin (1 and 10 mg) and dapagliflozin (5 mg) possess the best effects. Therefore, SGLT-2 inhibitors look extremely promising as an antidiabetes treatment option in patients with T2DM with high SUA.

Differential Proteomic Profiles of Coronary Serum Exosomes in Acute Myocardial Infarction Patients with or Without Diabetes Mellitus: ANGPTL6 Accelerates Regeneration of Endothelial Cells Treated with Rapamycin via MAPK Pathways.

PURPOSE: Delayed re-endothelialization after coronary drug-eluting stent implantation is associated with an increased incidence of late in-stent thrombosis. Serum exosomes exhibit controversial effects on promoting endothelialization. This study aimed to compare the angiogenic effects of serum exosomes derived from patients with acute myocardial infarction (AMI) and AMI plus diabetes mellitus (DM) and to explore the underlying mechanisms. METHODS: Serum exosomes derived from patients in the control (Con-Exos), AMI (AMI-Exos), and AMI plus DM (AMI+DM-Exos) groups were isolated and identified using standard assays. CCK-8, wound healing, and tube formation assays were performed to detect the angiogenic abilities of serum exosomes on rapamycin-conditioned human umbilical vein endothelial cells (HUVECs). Differential proteomic profiles between AMI-Exos and AMI+DM-Exos were analyzed by mass spectrometry. The effects and potential mechanisms of exosomal angiopoietin-like 6 (ANGPTL6) were investigated. RESULTS: Functional assays indicated that compared with Con-Exos, AMI-Exos enhanced, whereas AMI+DM-Exos inhibited the cell proliferation, migration, and tube formation of rapamycin-conditioned HUVECs. Subsequently, 28 differentially expressed proteins between AMI-Exos and AMI+DM-Exos were identified, which were correlated with material transportation, immunity, and inflammatory reaction. Moreover, ANGPTL6 was highly enriched in AMI-Exos. Overexpression and knockdown of ANGPTL6 enhanced and inhibited angiogenesis, respectively. Furthermore, the effect of ANGPTL6 on angiogenesis was mediated via the activation of ERK 1/2, JNK, and p38 pathways. The inhibition of ERK 1/2 signaling markedly attenuated the migration abilities of overexpressing ANGPTL6. CONCLUSION: Diabetes impairs the regenerative capacities of serum exosomes. Exosomal ANGPTL6 contributes to endothelial repair and is a novel therapeutic target for enhanced stent endothelization.

Exosomes secreted from mesenchymal stem cells mediate the regeneration of endothelial cells treated with rapamycin by delivering pro-angiogenic microRNAs.

Delayed endothelial healing after drug eluting stent (DES) implantation is a critical clinical problem in treatment of coronary artery diseases. Exosomes exhibit proangiogenic potential in a variety of ischemic diseases. However, the association of exosomes with endothelial regeneration after DES implantation has been rarely reported. In this study, we aimed to investigate the therapeutic effects of mesenchymal stem cell (MSC)-derived exosomes on endothelial cells treated with rapamycin and explore the potential mechanisms of MSC-derived exosomes in promoting endothelial regeneration. Exosomes were isolated from MSCs by ultracentrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot assay. The in vitro effects of MSC-derived exosomes on the proliferation and migration of endothelial cells treated with rapamycin were evaluated by integrated experiment, cell counting kit-8, scratch, tube formation, and transwell assays. And the apoptosis of rapamycin-induced endothelial cells loaded with MSC-derived exosomes was detected using TUNEL and Annexin-V FITC and PI double-staining assays. The microRNA (miRNA) cargo of MSC-derived exosomes was identified by high-throughput RNA sequencing. Pro-angiogenic miRNAs and key pathways were further characterized. Our results indicated that MSC-derived exosomes could be ingested into umbilical vein endothelial cells (HUVECs) and significantly enhanced cell proliferation rate, migratory and tube-forming capabilities in vitro. MSC-derived exosomes also inhibited the apoptosis of HUVECs induced by rapamycin. A distinct class of exosomal miRNAs was further identified, including six miRNAs tightly related to neovasculogenesis. Silencing the expression of exosomal miRNA-21-5p and let-7c-5p attenuated the pro-proliferative and pro-migratory capacity of MSC-derived exosomes. Moreover, functional enrichment analysis indicated that metabolic pathways might contribute to reendothelialization. This study highlights a proregenerative effect of MSC-derived exosomes in vitro, which may be partly explained by the delivery of pro-angiogenic miRNAs to endothelial cells.

Enhanced Two-Photon Photochromism in Metasurface Perfect Absorbers.

Light switchable materials are essential to optoelectronic applications in photovoltaics, memories, sensors, and communications. Natural switchable materials suffer from weak absorption and slow response times, preventing their use in low-power, ultrafast applications. Integrating light switchable materials with metasurface perfect absorbers offers an innovative route to achieving desirable features for nanophotonic devices, such as directional emission, low-power and broadband operation, high radiative quantum efficiency, and large spontaneous emission rates. Here we show an enhanced two-photon photochromism based on a metasurface perfect absorber: film-coupled colloidal silver nanocubes. The photochromic molecules, spiropyrans, are sandwiched between the silver nanocubes and the gold substrate. With nearly 100% absorption and an accompanying large field enhancement in the molecular junction, the transformation of spiropyrans to merocyanines is observed under excitation with 792 nm laser light. Fluorescence lifetime measurements on the merocyanine form reveal that large Purcell enhancement in the film-coupled nanocubes leads to large enhancements of the spontaneous emission rate and a high quantum efficiency. An averaged incident power as low as 10 µW is enough to initiate the two-photon isomerization of spiropyran in the film-coupled nanocubes, and a power of 100nW is able to excite the merocyanines to emit fluorescence. The power consumption is orders of magnitude lower than bare spiropyran thin films on silicon and gold, which is highly desirable for the writing and reading processes relevant to optical data storage. By sweeping the plasmonic resonance of the film-coupled nanocubes, wavelength specificity is demonstrated, which opens up new possibilities for minimizing the cross talk between adjacent bits in nanophotonic devices.

Clarification of surface modes of a periodic nanopatch metasurface.

We study the angle-dependent optical reflectance spectrum of a metasurface consisting of a periodic array of film-coupled plasmonic nanopatch particles. The nanopatch metasurface exhibits a strong, angle-independent absorption resonance at a wavelength defined by the nanopatch geometry and relative density. When the nanopatches are arranged in a regular lattice, a second, sharp absorption dip is present that varies strongly as a function of the incidence angle. This second resonance is a collective effect involving the excitation of surface plasmon modes and relates to a Wood's anomaly. Using an analytical model, we compute the surface modes of the structure and confirm details about the various mechanisms that contribute to the reflection spectra. The measured reflectance spectra are in excellent agreement with both analytical calculations and full-wave numerical simulations.

Integrative view of 2-oxoglutarate/Fe(II)-dependent oxygenase diversity and functions in bacteria.

BACKGROUND: The 2-oxoglutarate/Fe(II)-dependent oxygenase (2OG oxygenase) superfamily is extremely diverse and includes enzymes responsible for protein modification, DNA and mRNA repair, and synthesis of secondary metabolites. METHODS: To investigate the evolutionary relationship and make functional inferences within this remarkably diverse superfamily in bacteria, we used a protein sequence similarity network and other bioinformatics tools to analyze the bacterial proteins in the superfamily. RESULTS: The network based on experimentally characterized 2OG oxygenases reflects functional clustering. Networks based on all of the bacterial 2OG oxygenases from the Interpro database indicate that only few proteins in this superfamily are functionally defined. The uneven distribution of the enzymes supports the hypothesis that horizontal gene transfer plays an important role in 2OG oxygenase evolution. A hydrophobic tyrosine residue binding the primary substrates at the N-termini is conserved. At the C-termini, the iron-binding, oxoglutarate-binding, and hydrophobic motifs are conserved and coevolved. Considering the proteins in the family are largely unexplored, we annotated them by the Pfam database and hundreds of novel and multi-domain proteins are discovered. Among them, a two-domain protein containing an N-terminal peroxiredoxin domain and a C-terminal 2OG oxygenase domain was characterized enzymatically. The results show that the enzyme could catalyze the reduction of peroxide using 2-oxoglutarate as an electron donor. CONCLUSIONS: Our observations suggest relatively low evolutionary pressure on the bacterial 2OG oxygenases and a straightforward electron transfer pathway catalyzed by the two-domain 2OG oxygenase. GENERAL SIGNIFICANCE: This work enables an expanded understanding of the diversity, evolution, and functions of bacterial 2OG oxygenases.

Algoriphagus aestuariicola sp. nov., isolated from estuary sediment.

A Gram-staining-negative and strictly aerobic bacterium, designated strain S2-A1T, was isolated from estuary sediment in South Korea. Cells of strain S2-A1T were oxidase- and catalase-positive rods without a gliding motility. Growth was observed at 15-40 °C (optimum, 37 °C), at pH 6.0-10.0 (optimum, pH 7.0-7.5) and in the presence of 0-4.0 % (w/v) NaCl (optimum, 0.5-1.0 %). The sole respiratory quinone was MK-7. iso-C15 : 0, summed feature 3 (comprising C16 : 1ω7c/C16 : 1ω6c) and summed feature 9 (comprising iso-C17 : 1ω9c/C16 : 0 10-methyl) were found as the major fatty acids (>5 % of the total fatty acids). The polar lipids of strain S2-A1T consisted of phosphatidylethanolamine, an unidentified aminophospholipid, three unidentified aminolipids and five unidentified lipids. The G+C content of the genomic DNA was 45.6 mol%. Strain S2-A1T was most closely related to Algoriphagus taeanensisHMC4223T with a 97.7 % 16S rRNA gene sequence similarity. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S2-A1T formed a tight phyletic lineage with members of the genus Algoriphagus. On the basis of phenotypic, chemotaxonomic and molecular features, strain S2-A1T clearly represents a novel species of the genus Algoriphagus, for which the name Algoriphagus aestuariicola sp. nov. is proposed. The type strain is S2-A1T (=KACC 18987T=JCM 31546T).

Roseovarius confluentis sp. nov., isolated from estuary sediment.

A Gram-stain-negative and strictly aerobic bacterium, designated strain SAG6T, was isolated from estuary sediment in South Korea. Cells of strain SAG6T were found to be oxidase- and catalase-positive rods with gliding motility. Cell growth was observed at 15-40 °C (optimum 30 °C), at pH 6.5-10.0 (optimum pH 7.0) and in the presence of 0.5-13.0 % (w/v) NaCl (optimum 2.0 %). Ubiquinone-10 was the only detected respiratory quinone and summed feature 8 (comprising C18 : 1ω7c/C18 : 1ω6c), C16 : 0, C18 : 1ω7c 11-methyl and C12 : 0 were the major fatty acids identified (>5 % of the total fatty acids). The polar lipids of strain SAG6T consisted of phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified aminolipid and two unidentified lipids. The G+C content of the genomic DNA was 66.3 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain SAG6T formed a tight phyletic lineage within the genus Roseovarius. Strain SAG6T was most closely related to Roseovarius indicus B108T with 97.6 % 16S rRNA gene sequence similarity. Based on phenotypic, chemotaxonomic and molecular features, strain SAG6T clearly represents a novel species of the genus Roseovarius, for which the name Roseovarius confluentis sp. nov. is proposed. The type strain is SAG6T (=KACC 18598T=JCM 31541T).

PARP Inhibitor for Neoadjuvant Therapy in HER2-Negative Breast Cancer: A Systematic Review and Meta-Analysis of Efficacy and Safety.

Poly-ADP ribose polymerase inhibitor (PARPi) is approved for HER2-negative advanced breast cancer with BRCA1/2 mutation. In recent years, many studies have explored the application of PARPi in neoadjuvant therapy, but failed to reach a unified conclusion. PubMed, Clinicaltrials.gov, Cochrane CENTRAL, Embase, and key oncological meetings for trials were searched for studies reporting neoadjuvant regimens with PARPi in HER2-negative breast cancer. Pathological complete response (pCR), residual cancer burden (RCB), breast-conservation surgery rate (BCSR), clinical response, and adverse events were extracted and pooled in a meta-analysis using the Mantel Haenszel random/fixed effects model. Subgroup analyses of pCR were conducted according to BRCA1/2 status, and hormone receptor (HR) status. Five studies (N = 1223) were included, the addition of PARPi to neoadjuvant regimens significantly increased pCR rates (HR 1.45, 95%CI 1.09-1.92, P = .01, I2 = 86%). In subgroup analysis, the addition of PARPi increased the pCR rate both in HR-positive (n = 383) and HR-negative (n = 431) subgroups, which showed a dominant effect of PARPi regardless of HR status (HR 2.07, 95%CI 1.33-3.23, P = .001, I2 = 0%; HR 1.85, 95%CI 1.39-2.26, P < .0001, I2 = 0%, respectively). However, when we performed a subgroup analysis based on the status of BRCA1/2, no further benefit for PARPi was found. Adverse reactions were generally tolerable. Other outcome indexes, including RCB, clinical response, BCSR, and PARPi did not show a clinical benefit. Regardless of BRCA1/2 status, PARPi in neoadjuvant therapy, can improve the pCR rate of HER2-negative breast cancer, especially in HR-positive patients. Thus, we should have performed larger randomized trials and provided a stronger evidence-based basis.

Mechanism interpretation of Guhan Yangshengjing for protection against Alzheimer's disease by network pharmacology and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Guhan Yangshengjing (GHYSJ) is an effective prescription for delaying progression of Alzheimer's disease (AD) based on the ancient Chinese medical classics excavated from Mawangdui Han Tomb. Comprising a combination of eleven traditional Chinese herbs, the precise protective mechanism through which GHYSJ acts on AD progression remains unclear and has significant implications for the development of new drugs to treat AD. AIM OF THE STUDY: To investigate the mechanism of GHYSJ in the treatment of AD through network pharmacology and validate the results through in vitro experiments. MATERIALS AND METHODS: Chemical composition-target-pathway network and protein-protein interaction network were constructed by network pharmacology to predict the potential targets of GHYSJ for the treatment of AD. The interaction relationship between active ingredients and targets was verified by molecular docking and molecular force. Furthermore, the chemical constituents of GHYSJ were analyzed by LC-MS and HPLC, the effects of GHYSJ on animal tissues were analyzed by H&E staining. An Aß-induced SH-SY5Y cellular model was established to validate the core pathways and targets predicted by network pharmacology and molecular docking. RESULTS: The results of the network pharmacology analysis revealed a total of 155 bioactive compounds capable of crossing the blood-brain barrier and interacting with 677 targets, among which 293 targets specifically associated with AD, which mainly participated in and regulated the amyloid aggregation pathway and PI3K/Akt signaling pathway, thereby treating AD. In addition, molecular docking analysis revealed a robust binding affinity between the principal bioactive constituents of GHYSJ and crucial targets implicated in AD. Our findings were further substantiated by in vitro experiments, which demonstrated that Liquiritigenin and Ginsenosides Rh4, crucial constituents of GHYSJ, as well as GHYSJ pharmaceutic serum, exhibited a significant down-regulation of BACE1 expression in Aß-induced damaged SH-SY5Y cells. This study provides valuable data and theoretical underpinning for the potential therapeutic application of GHYSJ in the treatment of AD and secondary development of GHYSJ prescription. CONCLUSION: Through network pharmacology, molecular docking, LC-MS, and cellular experiments, GHYSJ was initially confirmed to delay the progression of AD by regulating the expression of BACE1 in Amyloid aggregation pathway. Our observations provided valuable data and theoretical underpinning for the potential therapeutic application of GHYSJ in the treatment of AD.

Isophorone-based crystallization-induced-emission sensors detect proteome aggregation in live cells and tissues with breast cancer.

BACKGROUND: Protein misfolding and aggregation can lead to various diseases. Recent studies have shed light on the aggregated protein in breast cancer pathology, which suggests that it is crucial to design chemical sensors that visualize protein aggregates in breast cancer, especially in clinical patient-derived samples. However, most reported sensors are constrained in cultured cell lines. RESULTS: In this work, we present the development of two isophorone-based crystallization-induced-emission fluorophores for detecting proteome aggregation in breast cancer cell line and tissues biopsied from diseased patients, designated as A1 and A2. These probes exhibited viscosity sensitivity and recovered their fluorescence strongly at crystalline state. Moreover, A1 and A2 exhibit selective binding capacity and strong fluorescence for various aggregated proteins. Utilizing these probes, we detect protein aggregation in stressed breast cancer cells, xenograft mouse model of human breast cancer and clinical patient-derived samples. Notably, the fluorescence intensity of both probes light up in tumor tissues. SIGNIFICANCE: The synthesized isophorone-based crystallization-induced-emission fluorophores, A1 and A2, enable sensitive detection of protein aggregation in breast cancer cells and tissues. In the future, aggregated proteins are expected to become indicators for early diagnosis and clinical disease monitoring of breast cancer.

High hemoglobin glycation index is associated with increased risk of diabetes: A population-based cohort study in China.

Purpose: The hemoglobin glycation index (HGI) quantifies the mismatch between glycated hemoglobin A1c and average glycemia among individuals. Currently, it is unknown the potential role of HGI in exhaustively evaluating the progression of glucose metabolism/the risk of developing diabetes mellitus. Therefore, this study aimed to investigate the association between HGI and the risk of incident diabetes. Methods: A total of 7,345 participants aged at least 40 years and without diabetes were divided into three groups according to the tertile of their baseline HGI level and followed for a median of 3.24 years to track new-onset diabetes. Using multivariate Cox regression analyses, we explored the association between the HGI, both categorized and continuous, and incident diabetes. Results: During follow-up, 742 subjects (263 males and 479 females) developed diabetes mellitus. Higher HGI was associated with an increased risk of diabetes, even when adjusted for confounding factors, and every standard deviation increase in HGI was associated with a significant risk increase of 30.6% for diabetes (hazard ratio 1.306, 95% confidence interval 1.232-1.384). Conclusions: Participants with a higher HGI were at a higher risk of future diabetes, irrespective of their glycemic conditions. Consequently, HGI may be employed to identify individuals at high risk for diabetes.

The Inverse Association of Serum Magnesium with Papillary Thyroid Cancer in Thyroid Nodules: a Cross-Sectional Survey Based on Thyroidectomy Population.

Magnesium is considered to play a role in preventing cancer. However, the association between serum magnesium and papillary thyroid cancer (PTC) remains unknown. We retrospectively reviewed records of all patients who underwent thyroidectomy with thyroid nodules confirmed pathologically as benign nodule or PTC at our institution from January 2016 to December 2020. Data including demographic characteristics, laboratory tests, and pathological features were analyzed in 5709 adult patients eventually. The subjects with benign nodules had a higher mean serum magnesium level than those with PTC (P < 0.001), and the proportions of PTCs decreased across quartiles of serum magnesium within the normal range. After adjustment for confounders, patients with the lowest quartile of serum magnesium had a higher prevalence of PTC than those with the highest quartile (OR = 1.421, 95%CI: 1.125-1.795, P for trend = 0.005), and the risk of PTC was 0.863 (95%CI: 0.795-0.936) for a per-SD change in serum magnesium. The contribution of serum magnesium remained in subgroup analysis (P for interaction for all analyses > 0.05). Based on the ROC curve, the cut-off value of serum magnesium used to differentiate benign nodules from PTCs was 935 µmol/L. Combining serum magnesium with other clinical indicators can improve the efficacy of predicting PTC. Our results showed that lower serum magnesium within the normal range was associated with a greater risk of PTC among patients with thyroid nodules considering thyroidectomy. Serum magnesium may be an independent protective factor against PTC and provide additional information on the odds of malignancy in uncertain thyroid nodules in combination with other clinical factors.

Ultra-Small High-Entropy Alloy Nanoparticles: Efficient Nanozyme for Enhancing Tumor Photothermal Therapy.

High-entropy alloys nanoparticles (HEANPs) are receiving extensive attention due to their broad compositional tunability and unlimited potential in bioapplication. However, developing new methods to prepare ultra-small high-entropy alloy nanoparticles (US-HEANPs) faces severe challenges owing to their intrinsic thermodynamic instability. Furthermore, there are few reports on studying the effect of HEANPs in tumor therapy. Herein, the fabricated PtPdRuRhIr US-HEANPs act as bifunctional nanoplatforms for the highly efficient treatment of tumors. The US-HEANPs are engineered by the universal metal-ligand cross-linking strategy. This simple and scalable strategy is based on the aldol condensation of organometallics to form the target US-HEANPs. The synthesized US-HEANPs exhibit excellent peroxidase-like (POD-like) activity and can catalyze the endogenous hydrogen peroxide to produce highly toxic hydroxyl radicals. Furthermore, the US-HEANPs possess a high photothermal conversion effect for converting 808 nm near-infrared light into heat energy. In vivo and in vitro experiments demonstrated that under the synergistic effect of POD-like activity and photothermal action, the US-HEANPs can effectively ablate cancer cells and treat tumors. It is believed that this work not only provides a new perspective for the fabrication of HEANPs, but also opens the high-entropy nanozymes research direction and their biomedical application.

Recent progress of microfluidic technology for pharmaceutical analysis.

In recent years, the progress of microfluidic technology has provided new tools for pharmaceutical analysis and the proposal of pharm-lab-on-a-chip is appealing for its great potential to integrate pharmaceutical test and pharmacological test in a single chip system. Here, we summarize and highlight recent advances of chip-based principles, techniques and devices for pharmaceutical test and pharmacological/toxicological test focusing on the separation and analysis of drug molecules on a chip and the construction of pharmacological models on a chip as well as their demonstrative applications in quality control, drug screening and precision medicine. The trend and challenge of microfluidic technology for pharmaceutical analysis are also discussed and prospected. We hope this review would update the insight and development of pharm-lab-on-a-chip.

Nucleolar protein NOC4L inhibits tumorigenesis and progression by attenuating SIRT1-mediated p53 deacetylation.

SIRT1 is an NAD+-dependent deacetylase and plays an important role in the deacetylation of both histone and non-histone proteins. Many studies revealed that SIRT1 is upregulated in a variety of tumors and tightly associated with tumorigenesis and cancer progression, but the detailed underlying mechanism of the biological processes remains unclarified. In the present study, we found a nucleolar protein NOC4L, human ortholog of yeast Noc4p, which is essential for the nuclear export of the ribosomal 40S subunit and could bind to SIRT1 to inhibit SIRT1 mediated deacetylation of p53. NOC4L interacts with SIRT1 in variety of cells under nucleolar stress and directly interacts with SIRT1 in vitro. Furthermore, we determined the C-terminal of NOC4L and the catalytic domain of SIRT1 were required for their interaction. Overexpression of NOC4L did not change the protein levels of SIRT1 or p53, but increased the acetylation of p53 and promoted cell apoptosis. Additionally, NOC4L inhibited tumor cell proliferation in a p53-dependent manner and restrained tumor growth in a nude mice xenograft model. Clinically, colorectal cancer patients with the high expression of NOC4L had a better prognosis as TP53 was normally expressed, but no significant difference was observed in survival with mutant TP53. Taken together, our results identified a novel SIRT1 regulatory protein and broaden our understanding of the molecular mechanism of how nucleolar protein NOC4L regulates p53 under nucleolar stress. This research provides an insight into tumorigenesis and cell self-protection in the early stage of DNA damage.

A systematic review and meta-analysis of BRCA1/2 mutation for predicting the effect of platinum-based chemotherapy in triple-negative breast cancer.

INTRODUCTION: Platinum-based chemotherapy (PBC) remains the mainstay of treatments for triple-negative breast cancer (TNBC). TNBC is a heterogeneous group, the issue of whether BRCA1/2 mutation carriers have a particular sensitivity to platinum agents is inconclusive. We conducted a meta-analysis to explore the relationship between BRCA1/2 mutation and PBC susceptibility in individuals with TNBC, aiming to gain more information on the size of the benefit of PBC in BRCA1/2 mutation carriers. MATERIALS AND METHODS: All studies applying PBC with a subgroup of BRCA1/2 status were included. All endpoints, including pCR and RCB in the neoadjuvant phase, DFS in the adjuvant phase, ORR, PFS, and OS in the advanced phase, were assessed using HRs and 95% Cl. RESULTS: From the 22 studies included, there were 2158 patients with TNBC, with 392 (18%) bearing the BRCA1/2 gene mutation. Based on 13 studies applying neoadjuvant PBC, we discovered that BRCA1/2 mutation was substantially associated with a 17.6% increased pCR rate (HR 1.32, 95% CI 1.17-1.49, p < 0.00001; I2 = 51%). Same result was observed in RCB0/I index (HR 1.38, 95% CI 1.08-1.76, P = 0.009; I2 = 0%). The meta-analysis of 6 trials addressing advanced therapy revealed that ORR rates were significantly higher in patients with BRCA1/2 mutation (HR 1.91, 95% CI 1.48-2.47, p < 0.00001; I2 = 32%), as well as PFS(HR 1.13, 95% CI 0.81-1.57, P = 0.47; I2 = 0%) and OS (HR 1.89, 95% CI 1.22-2.92, P = 0.004; I2 = 0%). CONCLUSION: According to our meta-analysis of 22 trials in TNBC, BRCA1/2 mutation carriers were significantly more sensitive to PBC regimens, especially in neoadjuvant and advanced therapy.