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Colorectal cancer has the highest mortality rate of all digestive system diseases. Considering the debate about cytokines and biases that exist in traditional observational study designs, we performed a two-sample Mendelian randomization (MR) analysis to explore the association of circulating cytokines with CRC risk. In this study, we used cytokine genetic variants from a recently published genome-wide association study (GWAS) including 14,824 European-ancestry participants. Summary-level data for colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium. In addition, we conducted independent supplementary analyses using genetic variation data of colorectal cancer and cytokines from a large public GWAS in 2021. Among 91 circulating factors, we only found IL-12B to be significantly associated with CRC risk (odds ratio [OR]: 1.19; 95% confidence interval [CI]: 1.00-1.42; p = .046). We used 2021 data for analysis and found that higher Interleukin-12p70 levels (IL-12p70) were revealed to have a significant positive association with CRC risk (OR: 1.27; 95% CI: 1.13-1.43; p < 1.22 × 10-3). Moreover, CRC was suggestively correlated with an elevated level of vascular endothelial growth factor (VEGF) (OR: 1.17; 95% CI: 1.02-1.35; p = .026), macrophage colony-stimulating factor (M-CSF) (OR: 0.85; 95% CI: 0.76-0.96; p = .005), IL-13 (OR: 1.15; 95% CI: 1.02-1.30; p = .028), IL-10 (OR: 1.23; 95% CI: 1.01-1.49; p = .037), and IL-7 (OR: 1.19; 95% CI: 1.02-1.39; p = .024). Our MR studies support that one cytokine IL-12 is significantly associated with CRC risk and that five cytokines VEGF, M-CSF, IL-13, IL-10, and IL-7 are associated with CRC risk.
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Neoplasias Colorretais , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/sangue , Citocinas/sangue , Citocinas/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Fatores de Risco , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Masculino , Feminino , Interleucina-10/sangue , Interleucina-10/genéticaRESUMO
Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is the most aggressive form of DLBCL, with a significantly inferior prognosis due to resistance to the standard R-CHOP immunochemotherapy. Survival of ABC-DLBCL cells addicted to the constitutive activations of both canonical and noncanonical NF-κB signaling makes them attractive therapeutic targets. However, a pharmaceutical approach simultaneously targeting the canonical and noncanonical NF-κB pathway in the ABC-DLBCL cell is still lacking. Peptide-conjugated gold nanoclusters (AuNCs) have emerged unique intrinsic biomedical activities and possess a great potential in cancer theranostics. Here, we demonstrated a Au25 nanocluster conjugated by cell-penetrating peptides that can selectively repress the growth of ABC-DLBCL cells by inducing efficient apoptosis, more efficiently than glutathione (GSH)-conjugated AuNCs. The mechanism study showed that the cell-penetrating peptides enhanced the cellular internalization efficiency of AuNCs, and the selective repression in ABC-DLBCL cells is due to the inhibition of inherent constitutive canonical and noncanonical NF-κB activities by AuNCs. Several NF-κB target genes involved in chemotherapy resistance in ABC-DLBCL cells, including anti-apoptotic Bcl-2 family members and DNA damage repair proteins, were effectively down-regulated by the AuNC. The emerged novel activity of AuNCs in targeting both arms of NF-κB signaling in ABC-DLBCL cells may provide a promising candidate and a new insight into the rational design of peptide-conjugated Au nanomedicine for molecular targeting treatment of refractory lymphomas.
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Peptídeos Penetradores de Células , Linfoma Difuso de Grandes Células B , Nanopartículas Metálicas , NF-kappa B , Humanos , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/farmacologia , Linfócitos/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , NF-kappa B/metabolismo , Transdução de Sinais , Nanopartículas Metálicas/químicaRESUMO
Using a controlled optical bias and balanced geometry, we propose a new scheme for broadband terahertz detection by laser-gas interaction without high-voltage manipulation. Compared to the conventional optical bias scheme, the common noise is reduced and the dynamic range as well as the signal-to-noise ratio are doubled. It provides a simple alternative for coherent broadband terahertz detection. The influence of optical bias on terahertz waveform is also investigated, and the evolution of the terahertz-induced second harmonic with probe delay is further revealed. This new detection scheme for broadband terahertz will boost the application of terahertz time-domain spectroscopy for its miniaturization and integrability.
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Biochemical and structural studies have shown that the initiation of RNA polymerase II transcription proceeds in the following stages: assembly of the polymerase with general transcription factors and promoter DNA in a 'closed' preinitiation complex (PIC); unwinding of about 15 base pairs of the promoter DNA to form an 'open' complex; scanning downstream to a transcription start site; synthesis of a short transcript, thought to be about 10 nucleotides long; and promoter escape. Here we have assembled a 32-protein, 1.5-megadalton PIC derived from Saccharomyces cerevisiae, and observe subsequent initiation processes in real time with optical tweezers. Contrary to expectation, scanning driven by the transcription factor IIH involved the rapid opening of an extended transcription bubble, averaging 85 base pairs, accompanied by the synthesis of a transcript up to the entire length of the extended bubble, followed by promoter escape. PICs that failed to achieve promoter escape nevertheless formed open complexes and extended bubbles, which collapsed back to closed or open complexes, resulting in repeated futile scanning.
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RNA Polimerase II/química , RNA Polimerase II/metabolismo , Saccharomyces cerevisiae/enzimologia , Iniciação da Transcrição Genética , Pareamento de Bases/genética , DNA/genética , DNA/metabolismo , Pinças Ópticas , Regiões Promotoras Genéticas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Saccharomyces cerevisiae/genética , Fator de Transcrição TFIIH/metabolismoRESUMO
Recent evidence suggests that transcript elongation by RNA polymerase II (RNAPII) is regulated by mechanical cues affecting the entry into, and exit from, transcriptionally inactive states, including pausing and arrest. We present a single-molecule optical-trapping study of the interactions of RNAPII with transcription elongation factors TFIIS and TFIIF, which affect these processes. By monitoring the response of elongation complexes containing RNAPII and combinations of TFIIF and TFIIS to controlled mechanical loads, we find that both transcription factors are independently capable of restoring arrested RNAPII to productive elongation. TFIIS, in addition to its established role in promoting transcript cleavage, is found to relieve arrest by a second, cleavage-independent mechanism. TFIIF synergistically enhances some, but not all, of the activities of TFIIS. These studies also uncovered unexpected insights into the mechanisms underlying transient pauses. The direct visualization of pauses at near-base-pair resolution, together with the load dependence of the pause-entry phase, suggests that two distinct mechanisms may be at play: backtracking under forces that hinder transcription and a backtrack-independent activity under assisting loads. The measured pause lifetime distributions are inconsistent with prevailing views of backtracking as a purely diffusive process, suggesting instead that the extent of backtracking may be modulated by mechanisms intrinsic to RNAPII. Pauses triggered by inosine triphosphate misincorporation led to backtracking, even under assisting loads, and their lifetimes were reduced by TFIIS, particularly when aided by TFIIF. Overall, these experiments provide additional insights into how obstacles to transcription may be overcome by the concerted actions of multiple accessory factors.
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RNA Polimerase II/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Elongação da Transcrição Genética , Fatores de Transcrição TFII/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Ativação Enzimática , Reativadores Enzimáticos/metabolismo , Inosina Trifosfato/metabolismo , Cinética , Modelos Biológicos , Pinças Ópticas , RNA Polimerase II/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição TFII/genética , Fatores de Elongação da Transcrição/genéticaRESUMO
The db/db mouse is one of the most popular animal models for type 2 diabetes mellitus, but changes in the activities of important P450s and UGTs are still not completely clear. This study was designed to investigate the alterations of major hepatic cytochrome P450s and UDP-glucuronyltransferase enzymes in db/db mice. Mouse liver microsomes (MLMs) were obtained from male db/db mice and their wild type littermates. After incubation of the substrates separately with MLMs, the samples were pooled and analysed by high-throughput liquid chromatography-tandem mass spectrometry system for the simultaneous study of nine phase I metabolic reactions and three glucuronidation conjugation reactions to determine the activity of the metabolic enzymes. Compared with normal controls, the Clint estimate for testosterone-6ß-hydroxylation was lower (46%) (p < 0.05), while the Vmax and Clint estimates for propofol O-glucuronidation were 5-fold higher (p < 0.01) in the liver microsomes from db/db mice. There was no significant difference in phase I metabolic reactions of phenacetin-O-deethylation, coumarin-7-hydroxylation, bupropion-hydroxylation, omeprazole-5-hydroxylation, dextromethorphan-O-demethylation, tolbutamide-4-hydroxylation, chlorzoxazone-6-hydroxylation and midazolam-1-hydroxylation and in glucuronidation reactions of estradiol 3-O-glucuronidation, and 3-azido-3-deoxythymidine glucuronidation. The data suggest that, in db/db mice, the activity of Cyp3a11, catalysing testosterone-6ß-hydroxylation, decreased, while the activity of UGT1a9, catalysing propofol O-glucuronidation, increased. Copyright © 2016 John Wiley & Sons, Ltd.
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Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucuronosiltransferase/metabolismo , Animais , Modelos Animais de Doenças , Hidroxilação , Masculino , Camundongos , Camundongos Mutantes , Microssomos Hepáticos/metabolismo , Midazolam/metabolismo , Propofol/metabolismo , Testosterona/metabolismoRESUMO
INTRODUCTION: Anastomotic leakage (AL) is defined as the failure of complete healing or disruption of the anastomosis subsequent to rectal cancer surgery, resulting in the extravasation of intestinal contents into the intra-abdominal or pelvic cavity. It is a serious complication of rectal cancer surgery, accounting for a considerable increase in morbidity and mortality. The use of fluorescence imaging technology in surgery allows surgeons to better evaluate blood perfusion. However, the conclusions of some existing studies are not consistent, so a consensus on whether the near-infrared indocyanine green (NIR-ICG) imaging system can reduce the incidence of AL is needed. METHODS: This POSTER trial is designed as a multicentre, prospective, randomised controlled clinical study adhering to the "population, interventions, comparisons, outcomes (PICO)" principles. It is scheduled to take place from August 2019 to December 2024 across eight esteemed hospitals in China. The target population consists of patients diagnosed with rectal cancer through pathological confirmation, with tumours located≤10 cm from the anal verge, eligible for laparoscopic surgery. Enrolled patients will be randomly assigned to either the intervention group or the control group. The intervention group will receive intravenous injections of ICG twice, with intraoperative assessment of anastomotic blood flow using the near-infrared NIR-ICG system during total mesorectal excision (TME) surgery. Conversely, the control group will undergo conventional TME surgery without the use of the NIR-ICG system. A 30-day follow-up period postoperation will be conducted to monitor and evaluate occurrences of AL. The primary endpoint of this study is the incidence of AL within 30 days postsurgery in both groups. The primary outcome investigators will be blinded to the application of ICG angiography. Based on prior literature, we hypothesise an AL rate of 10.3% in the control group and 3% in the experimental group for this study. With a planned ratio of 2:1 between the number of cases in the experimental and control groups, and an expected 20% lost-to-follow-up rate, the initial estimated sample size for this study is 712, comprising 474 in the experimental group and 238 in the control group. ETHICS AND DISSEMINATION: This study has been approved by Ethics committee of Beijing Friendship Hospital, Capital Medical University (approval number: 2019-P2-055-02). The results will be disseminated in major international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04012645.
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Fístula Anastomótica , Verde de Indocianina , Laparoscopia , Neoplasias Retais , Humanos , Verde de Indocianina/administração & dosagem , Neoplasias Retais/cirurgia , Neoplasias Retais/diagnóstico por imagem , Laparoscopia/métodos , Estudos Prospectivos , Fístula Anastomótica/prevenção & controle , Corantes , Feminino , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Masculino , China , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Adulto , Pessoa de Meia-IdadeRESUMO
Peptide-protected gold nanoclusters (AuNCs), possessing exceptional biocompatibility and remarkable physicochemical properties, have demonstrated intrinsic pharmaceutical activity in immunomodulation, making them a highly attractive frontier in the field of nanomedicine exploration. Autoimmune hepatitis (AIH) is a serious autoimmune liver disease caused by the disruption of immune balance, for which effective treatment options are still lacking. In this study, we initially identified glutathione (GSH)-protected AuNCs as a promising nanodrug candidate for AIH alleviating in a Concanavalin A (Con A)-induced mice model. However, to enhance treatment efficiency, liver-targeted delivery needs to be improved. Therefore, human serum albumin (HSA)-encapsulated AuNCs were constructed to achieve enhanced liver targeting and more potent mitigation of Con A-induced elevations in plasma aspartate transaminase (AST), alanine transaminase (ALT), and liver injury in mice. In vivo and in vitro mechanism studies indicated that AuNCs could suppress the secretion of IFN-γ by Con A-stimulated T cells and subsequently inhibit the activation of the JAK2/STAT1 pathway and eventual hepatocyte apoptosis induced by IFN-γ. These actions ultimately protect the liver from immune cell infiltration and damage caused by Con A. These findings suggest that bio-protected AuNCs hold promise as nanodrugs for AIH therapy, with their liver targeting capabilities and therapeutic efficiency being further improved via rational surface ligand engineering.
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To date, earlier diagnosis of Alzheimer's disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aß) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aß plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aß plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aß plaque formation.
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Doença de Alzheimer , Encéfalo , Fator de Crescimento do Tecido Conjuntivo , Camundongos Transgênicos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Animais , Humanos , Camundongos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Ouro/química , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Nanopartículas Metálicas/química , Modelos Animais de Doenças , Peptídeos beta-Amiloides/metabolismo , Feminino , Masculino , Imagem Multimodal/métodos , Biomarcadores/metabolismo , Imagem Óptica/métodosRESUMO
BACKGROUND: Accurate evaluation of the response to preoperative treatment enables the provision of a more appropriate personalized therapeutic schedule for locally advanced rectal cancer (LARC), which remains an enormous challenge, especially neoadjuvant immunotherapy plus chemoradiotherapy (nICRT). METHODS: This prospective, multicenter cohort study enrolled patients with LARC from 6 centers who received nICRT. The dynamic variation in the gut microbiome during nICRT was evaluated. A species-level gut microbiome prediction (SPEED) model was developed and validated to predict the pathological complete response (pCR) to nICRT. FINDINGS: A total of 50 patients were enrolled, 75 fecal samples were collected from 33 patients at different time points, and the pCR rate reached 42.4% (14/33). Lactobacillus and Eubacterium were observed to increase after nICRT. Additionally, significant differences in the gut microbiome were observed between responders and non-responders at baseline. Significantly higher abundances of Lachnospiraceaebacterium and Blautiawexlerae were found in responders, while Bacteroides, Prevotella, and Porphyromonas were found in non-responders. The SPEED model showcased a superior predictive performance with areas under the curve of 98.80% (95% confidence interval [CI]: 95.67%-100%) in the training cohort and 77.78% (95% CI: 65.42%-88.29%) in the validation cohort. CONCLUSIONS: Programmed death 1 (PD-1) blockade plus concurrent long-course CRT showed a favorable pCR rate and is well tolerated in microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) patients with LARC. The SPEED model can be used to predict the pCR to nICRT based on the baseline gut microbiome with high robustness and accuracy, thereby assisting clinical physicians in providing individualized management for patients with LARC. FUNDING: This research was funded by the China National Natural Science Foundation (82202884).
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BACKGROUND: Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1- and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function. METHODS AND RESULTS: We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulin resistance. miR-223(-/-) mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell-mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow-derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic proinflammatory pathways and enhances the alternative antiinflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization. CONCLUSION: For the first time, this study demonstrates that miR-223 acts to inhibit Pknox1, suppressing proinflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance.
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Adipócitos/imunologia , Tecido Adiposo/imunologia , Inflamação/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , Obesidade/imunologia , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Transplante de Medula Óssea , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Polaridade Celular/genética , Polaridade Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Gorduras na Dieta/farmacologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Proteínas de Homeodomínio/metabolismo , Imunofenotipagem , Resistência à Insulina/imunologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Células Mieloides/citologia , Células Mieloides/imunologia , Valor Preditivo dos Testes , RNA Interferente Pequeno/genéticaRESUMO
OBJECTIVE: To establish a method to determine lead and Isotope Ratios in whole blood by inductively coupled plasma mass spectrometry (ICP-MS). METHODS: The whole blood samples was removed protein by 5% nitric acid , Online join thallium (Tl) as internal standard substance, used lyophilized bovine blood lead and cadmium standard material (GBW09139h and GBW09140h) for quality control of blood lead concentrations. Lead isotope standard substances (GBW04426) is used to determine the correction factor, lead isotope ratios will lead isotope standard reference material NIST SRM981 by icp-ms with samples for testing. RESULTS: Optimize the detection method, detection of blood lead and lead isotope, and the method of linear range r >0.9999, GBW09139h and GBW09140h test results are within the scope of quality control. NIST SRM981 isotope determination precision RSD<1%, NIST SRM981 test results and the certificate of value close to. CONCLUSION: The method is simple and convenient data is reliable, can meet the total lead (pb) in blood and former isotope simultaneous determination.
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Radioisótopos de Chumbo , Chumbo , Espectrometria de Massas/métodos , Animais , Bovinos , Chumbo/análise , Chumbo/sangue , Radioisótopos de Chumbo/análise , Radioisótopos de Chumbo/sangueRESUMO
We relate the model of vorticity wave interaction to Krein collision, PT-symmetry breaking, and the formation of exceptional points in shear flow instabilities. We show that the dynamical system of coupled vorticity waves is a pseudo-Hermitian system with nonreciprocal coupling terms. Krein signatures of the eigenvalues are illustrated as the signs of the action of the vorticity waves. Interaction between positive-action and negative-action vorticity waves then corresponds to the Krein collision between eigenvalues with opposite Krein signatures, the spontaneous breaking of PT symmetry, and the formation of exceptional points. The control parameter of the PT-symmetry-breaking bifurcation is the ratio between frequency detuning and coupling strength of the vorticity waves. The critical behavior near the exceptional points is described as a transition between phase-locking and phase-slip dynamics of the vorticity waves. The phase-slip dynamics correspond to nonmodal, transient growth of perturbations in the regime of unbroken PT symmetry, and the phase-slip frequency Ωâ|k-k_{c}|^{1/2} shares the same critical exponent with the phase rigidity of system eigenvectors.
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Owing to their structural designability and tuneable properties, supramolecular metal-organic complexes have recently emerged as promising candidates for the sensing and detection of molecules and anions. Herein, we synthesised three tripyrazolate-linked [M6L2] metallocages with the formulas [(bpyPd)6L2](NO3)6 (1), [(dmbpyPd)6L2](NO3)6 (2), and [(phenPd)6L2](NO3)6 (3) (H3L = tris(4-(5-(trifluoromethyl)-1H-pyrazol-3-yl)phenyl)amine, bpy = 2,2'-bipyridine, dmbpy = 4,4'-dimethylbipyridine, phen = 1,10-phenanthroline). Crystallography revealed that metal-directed coordination and the bidentate chelate behaviour of the ligand induced the self-assembly of supramolecular metal-organic cages. Notably, these cages were employed as turn-on fluorescence sensors for SO2 and its derivative (HSO3-) through a disassembly mechanism. Cages 1, 2, and 3 showed a highly selective and sensitive detection of HSO3- over other common anions in aqueous solutions and of SO2 gas over other common gasses, with an excellent anti-interference ability. These metallocages were subsequently applied as sensors in environmental and biological samples. This study not only enriches the ongoing research on metal-organic supramolecular materials but also facilitates the future preparation of stimuli-responsive supramolecular coordination complexes.
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Luminescent supramolecular metallacycles have attracted great interest as a new promising class of sensing substrates. In this work, two tetraphenylethene (TPE)-based diimidazole and dipyrazole ligands with the aggregation-induced emission (AIE) feature were designed for the construction of supramolecular tetragonal metallacycles 1-4 with two 90° mononuclear [(bpy)M]2+ or dinuclear [(bpy)2M2]4+ acceptors (bpy = 2,2'-dipyridine; M = Pd, Pt), in which the fluorescence can be quenched to an "off" state due to the ligand-to-metal charge transfer (LMCT). Metallacycle 1 was utilized as a fluorescence sensor for phosphate (PO43-) detection in aqueous solution by means of disassembly, leading to the release of the ligand. Additionally, the metallacycle can be regenerated through self-assembly via the introduction of Pd(II) acceptors. PO43- was detected using TPE-based metallacycles over a wide concentration range, with a detection limit as low as 2.1 × 10-8 M. Furthermore, sensor 1 also presented the semiquantitative visual detection ability for PO43- in the test paper mode via fluorescence changes. The aforementioned studies not only enhance the current research on fluorescent materials but also offer a strategy for the creation of stimuli-responsive supramolecular coordination complexes.
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Programmed cell death protein (PD-1) is an important immunosuppressive molecule, which can inhibit interaction between PD-1 and its ligand PD-L1, further enhancing the T cell response and anti-tumor activity, which is called immune checkpoint blockade. Immunotherapy, represented by immune checkpoint inhibitors, has opened up a new era of tumor treatment and is gradually being applied to colorectal cancer recently. Immunotherapy was reported could achieve a high objective response rate (ORR) for colorectal cancer with high microsatellite instability (MSI), thus opening up a new era of colorectal cancer immunotherapy. Along with the increasing use of PD1 drugs in colorectal cancer, we should pay more attention to the adverse effects of these immune drugs while seeing the hope. Immune-related adverse events (irAEs) caused by immune activation and immune homeostasis during anti-PD-1/PD-L1 therapy can affect multi-organ and even be fatal in serious cases. Therefore, understanding irAEs is essential for their early detection and appropriate management. In this article, we review the irAEs that occur during the treatment of colorectal cancer patients with PD-1/PD-L1 drugs, analyze the current controversies and challenges, and point out future directions that should be explored, including exploring efficacy predictive markers and optimizing the paradigm of individualized immunotherapy.
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Correction for 'Self-assembly of tripyrazolate-linked [M6L2] cages for the selective sensing of HSO3- and gaseous SO2 by turn-on fluorescence' by Peipei Wang et al., Dalton Trans., 2023, https://doi.org/10.1039/d3dt00083d.
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An effective disaster prevention map ensures public safety and efficient evacuation during emergencies. Emergency evacuation information design in Taiwan is in its nascent stages. This study focuses on individuals' understanding, behavior, and decision-making during disaster prevention to devise suitable disaster prevention map norms. We examined the Emergency Planning Zone's existing disaster prevention methods and surveyed the community to understand their disaster prevention concepts and needs. We conducted two experiments: the first tested the comprehension of existing disaster prevention maps and identified their issues, while the second evaluated a redesigned map based on Experiment 1's findings. We discovered that all age groups agree on needing accurate, fast information and diverse evacuation route options. Experiment 1 revealed disproportionate assembly point icons on the existing map, leading to navigation difficulties. The map also failed to mark landmarks, road names, and blocked intersections accurately. The redesigned map in Experiment 2 addressed these issues, showing that improving map information design aids recognition and memory, and bridges wayfinding behavior gaps in people with different spatial abilities. We suggest marking evacuation routes on maps, placing corresponding signs on-site, and locating assembly points near landmarks for easier navigation.
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PURPOSE: Transanal total mesorectal excision (taTME) is a promising surgical procedure for middle and low rectal cancer; however, it is linked to significant morbidity. This study aimed to determine the incidence of postoperative surgical complications and anastomotic leakage following taTME and to identify their associated risk factors. METHODS: The prospective clinical data of 114 patients, who underwent taTME and primary anastomosis for mid-low rectal cancer between November 2016 and June 2022, were retrospectively analyzed. Univariate and multivariate analyses were performed to identify clinical characteristics and risk factors for predicting surgical complications and anastomotic leakage. RESULTS: Surgical complications occurred in 40 (35.1%) patients within the first 30 days following surgery. Based on the Clavien-Dindo classification, minor complications (Clavien-Dindo grades I + II) accounted for 30.7%, while major complications (Clavien-Dindo grades III + IV) accounted for only 4.4%. None of the patients died within 30 days. The incidence of anastomotic leakage was 15.8%: 4.4% as grade A (5 cases), 9.6% as grade B (11 cases), and 1.8% as grade C (2 cases). Preoperative T3-4 was identified as an independent risk factor for surgical complications (p = 0.031) by multivariate analysis. American Society of Anesthesiology score ≥ 3 (P = 0.021) and incomplete total mesorectal excision specimens (P = 0.030) were significantly associated with the risk of anastomotic leakage. CONCLUSIONS: In this study, the incidence of surgical complications and anastomotic leakage in taTME aligned with previously reported rates. Preoperative T3-4 was significantly associated with surgical complications. American Society of Anesthesiology score ≥ 3 and incomplete TME specimens independently increased the risk of anastomotic leakage.
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Laparoscopia , Neoplasias Retais , Cirurgia Endoscópica Transanal , Humanos , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Reto/cirurgia , Incidência , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Retais/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Fatores de Risco , Cirurgia Endoscópica Transanal/métodos , Laparoscopia/métodosRESUMO
Immune-mediated skin diseases have a high prevalence and seriously affect patients' quality of life. Gold compounds have been considered promising therapeutic agents in dermatology, but the high incidence of adverse reactions have limited their clinical application. There is a great need to develop more effective and less toxic gold-based drugs. Gold nanoclusters fabricated by using peptides (pep-AuNCs) have appeared as potential biomedical nanomaterials because of their excellent biocompatibility, ease of fabrication and unique physicochemical properties. Glutathione (GSH) is an endogenous tripeptide and has been used for lightening the skin color. Therefore, we fabricated a well-defined gold nanocluster with GSH as an example to explore the immunomodulatory effect of AuNCs on a TNF-α-treated human keratinocyte cell line (HaCaT) in vitro, the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritant contact dermatitis (ICD) model and the oxazolone (OXA)-induced psoriatic model in vivo. The results indicated that topically applied AuNCs successfully attenuated the severity of ICD and psoriasis-like lesions. In vitro and in vivo, AuNCs effectively inhibited the abnormal activation of the NF-κB pathway and the consequent overexpression of proinflammatory cytokines in keratinocytes. In particular, the transactivation of IL-17A, the most important cytokine in psoriasis pathology, was effectively inhibited by AuNCs treatment. In addition, AuNCs did not show any obvious cytotoxicity in HaCaT cells at doses even up to 100 µM and did not induce any irritation in the healthy skin and major organs, which indicated their favorable biosafety. These results indicate that biocompatible pep-AuNCs might be a promising gold-based nanomedicine for the treatment of inflammatory skin diseases.