Injectable Therapeutic Hydrogel with H2O2 Self-supplying and GSH Consumption for Synergistic Chemodynamic/Low-temperature Photothermal Inhibition of Postoperative Tumor Recurrence and Wound Infection.

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO2@Au hydrogel system (CuO2@Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO2@Au Gel is construced by embedding therapeutic CuO2@Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO2@Au in CuO2@Au Gel is capable of self-supplying H2O2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO2@Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery. This article is protected by copyright. All rights reserved.

Palladium-Catalyzed Heck/Suzuki Tandem Reaction of (Z)-1-Iodo-1,6-dienes and Organoboronic Acids.

The Heck/Suzuki tandem reaction has emerged as an essential strategy for the synthesis of complex molecules. Herein, an efficient palladium-catalyzed Heck/Suzuki tandem reaction of (Z)-1-iodo-1,6-dienes with organoboronic acids is described, providing various tetrahydropyridines in good to excellent yields under mild reaction conditions. The key to the success of this approach is the avoidance of the intramolecular second Heck insertion occurring prior to the transmetalation step. In addition, the asymmetric version of this reaction is investigated to deliver chiral tetrahydropyridine in excellent yield with promising enantioselectivity.

Evolution of a tidal channel network in the Yellow River Delta, China, and simulation of optimization scenarios.

Tidal channel networks, which characterize all river deltas, control the exchange of water and nutrients (hydrological connectivity) between the ocean and the delta area. Therefore, a tidal channel network in optimal conditions ensures the maintenance of the diversity and stability of the deltaic ecosystem. However, the developmental status of channel networks in the Yellow River Delta, China, has not been clearly determined. Here, we selected a typical tidal channel network in this delta that showed different spatial patterns (e.g., connectivity attributes) in the past three decades and explored its evolution using entropy as an index of connectivity. Seven scenarios were set up to determine the optimal status of the tidal channel network by optimizing its structure. The optimization effect was evaluated by comparing the connectivity attributes of the channel network before and after optimization. The results showed that the network experienced two obviously different developmental phases: an evolution before 2005 and a regression after 2005. Mann-Kendall analysis indicated that the channel network achieved dynamic stability before 2014 and became unstable thereafter. The simulations conducted to optimize the system showed that adding outlets changed the current patterns of the network' structural and functional connectivity. As the optimization proceeded, structural connectivity increased while functional connectivity decreased, and the tidal channel network tended to be dynamically stable. Our study elucidated the quantitative relationship between outlet number and stability within tidal channel networks, providing reference information that could be incorporated into future projects for the restoration and management of river deltas.

HNF4A as a potential target of PFOA and PFOS leading to hepatic steatosis: Integrated molecular docking, molecular dynamic and transcriptomic analyses.

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are indeed among the most well known and extensively studied Per- and polyfluoroalkyl substances (PFASs), and increasing evidence confirm their effects on human health, especially liver steatosis. Nonetheless, the molecular mechanisms of their initiation of hepatic steatosis is still elusive. Therefore, potential targets of PFOA/PFOS must be explored to ameliorate its adverse consequences. This research aims to investigate the molecular mechanisms of PFOA and PFOS-induced liver steatosis, with emphasis on identifying a potential target that links these PFASs to liver steatosis. The potential target that causes PFOA and PFOS-induced liver steatosis have been explored and determined based on molecular docking, molecular dynamics (MD) simulation, and transcriptomics analysis. In silico results show that PFOA/PFOS can form a stable binding conformation with HNF4A, and PFOA/PFOS may interact with HNF4A to affect the downstream conduction mechanism. Transcriptome data from PFOA/PFOS-induced human stem cell spheres showed that HNF4A was inhibited, suggesting that PFOA/PFOS may constrain its function. PFOS mainly down-regulated genes related to cholesterol synthesis while PFOA mainly up-regulated genes related to fatty acid ß-oxidation. This study explored the toxicological mechanism of liver steatosis caused by PFOA/PFOS. These compounds might inhibit and down-regulate HNF4A, which is the molecular initiation events (MIE) that induces liver steatosis.

Prurigo Nodularis onset during secukinumab treatment of psoriasis: a case report.

BACKGROUND: Secukinumab has been approved by the U.S. FDA and the European Medicines Agency for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis with the documented adverse effects. Here we reported in one case that a new symptom, Prurigo Nodularis (PN), developed during the programmed dosing of secukinumab. CASE INTRODUCTION: A 22-years-old male with a 6-month history of severe plaque psoriasis vulgaris was presented to the dermatology clinic two weeks after the fifth serial weekly doses of secukinumab, for the reason of the outbreaks of multiple erythematous papules and pruritus nodules on the trunk and extremities. Physical examination showed that psoriatic rash were under effective control with the previous targeted therapy of secukinumab for plaque psoriasis vulgaris, but new dermatologic condition was spotted with multiple edematous red firm papules on the trunk and extremities, in the form of soy or hemispherical nodules, red in color, firm to touch, with some ulcerated crusts visible at tops, but negative Auspitz sign. Pathological examination confirmed these papules as PN. CONCLUSION: This case report is shared to inform clinicians about an unannounced adverse effect of the secukinumab in the treatment of psoriasis, and it is recommended that patients be carefully informed of the possible risk of PN before starting treatment.

Development and validation of a novel T cell proliferation-related prognostic model for predicting survival and immunotherapy benefits in melanoma.

BACKGROUND: T cell plays a crucial role in the occurrence and progression of Skin cutaneous melanoma (SKCM). This research aims to identify the actions of T cell proliferation-related genes (TRGs) on the prognosis and immunotherapy response of tumor patients. METHOD: The clinical manifestation and gene expression data of SKCM patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. T cell proliferation-related molecular subtypes were identified utilizing consensus clustering. Subsequently, Cox and Lasso regression analysis was conducted to identify six prognostic genes, and a prognostic signature was constructed. A series of experiments, such as qRT-PCR, Western blotting and CCK8 assay, were then conducted to verify the reliability of the six genes. RESULTS: In this study, a grading system was established to forecast survival time and responses to immunotherapy, providing an overview of the tumoral immune landscape. Meanwhile, we identified six prognostic signature genes. Notably, we also found that C1RL protein may inhibit the growth of melanoma cell lines. CONCLUSION: The scoring system depending on six prognostic genes showed great efficiency in predicting survival time. The system could help to forecast prognosis of SKCM patients, characterize SKCM immunological condition, assess patient immunotherapy response.

Human SCARB2 Acts as a Cellular Associator for Helping Coxsackieviruses A10 Infection.

Coxsackievirus A10 (CVA10) causes hand, foot, and mouth disease (HFMD) and herpangina, which can result in severe neurological symptoms in children. CVA10 does not use the common enterovirus 71 (EV71) receptor, human SCARB2 (hSCARB2, scavenger receptor class B, member 2), for infection but instead uses another receptor, such as KREMEN1. Our research has shown that CVA10 can infect and replicate in mouse cells expressing human SCARB2 (3T3-SCARB2) but not in the parental NIH3T3 cells, which do not express hSCARB2 for CVA10 entry. Knocking down endogenous hSCARB2 and KREMEN1 with specific siRNAs inhibited CVA10 infection in human cells. Co-immunoprecipitation confirmed that VP1, a main capsid protein where virus receptors for attaching to the host cells, could physically interact with hSCARB2 and KREMEN1 during CVA10 infection. It is the efficient virus replication following virus attachment to its cellular receptor. It resulted in severe limb paralysis and a high mortality rate in 12-day-old transgenic mice challenged with CVA10 but not in wild-type mice of the same age. Massive amounts of CVA10 accumulated in the muscles, spinal cords, and brains of the transgenic mice. Formalin inactivated CVA10 vaccine-induced protective immunity against lethal CVA10 challenge and reduced the severity of disease and tissue viral loads. This is the first report to show that hSCARB2 serves as an associate to aid CVA10 infection. hSCARB2-transgenic mice could be useful in evaluating anti-CVA10 medications and studying the pathogenesis induced by CVA10.

Domino Sequences Involving Stereoselective Hydrazone-Type Heck Reaction and Denitrogenative [1,5]-Sigmatropic Rearrangement.

Although the Heck reactions of alkene partners with various electrophiles have achieved great success, the variant focused on carbon═heteroatom counterparts still remains elusive. Herein, we report a Pd(0)-catalyzed asymmetric intramolecular hydrazone-type Heck reaction of N-[(Z)-3-iodoallyl]-aminoacetaldehyde and hydrazine hydrate (NH2NH2-H2O), wherein the required hydrazone is in situ generated via an acid-promoted condensation. A key strategic advantage of this Heck paradigm is that the resultant Heck product allylic diazene rapidly undergoes stereospecific denitrogenative [1,5]-sigmatropic rearrangement, eventually furnishing a domino sequence toward 3-substituted tetrahydropyridine (THP) with high enantioselectivity. The substrate-induced diastereoselective version has also been realized, exclusively giving cis-2,5-disubstituted THPs. The utility of this sequence is demonstrated by the formal synthesis of multiple valuable bioactive targets, including 3-ethylindoloquinolizine, preclamol, and niraparib.

Pd(0)-Catalyzed Asymmetric 7-Endo Hydroacyloxylative Cyclization of 1,6-Enyne Enabled by an Anion Ligand-Directed Strategy.

Despite diversity in reaction mechanisms, the palladium-catalyzed cyclization of 1,6-enyne generally proceeds in a 5-exo manner. Herein, we report the development of a Pd(0)-catalyzed hydroacyloxylative cyclization of 1,6-enyne in either 7-endo-trig or 6-exo-trig fashion when paired with an appropriate dihaloacetic acid reactant, such as F2HCCO2H and Cl2HCCO2H. Using the combination of Pd2(dba)3 and a chiral phosphine ligand, the hydroacyloxylative cyclization of 1,6-enyne bearing a 1,1-disubstituted alkene moiety readily gives highly enantiopure seven-membered heterocycles while the reaction of those having a 1,2-disubstituted alkene affords six-membered rings with moderate enantioselectivity. Preliminary experimental studies suggest a reaction mechanism featuring an unusual E-to-Z vinyl-Pd(II) isomerization and alkene trans-oxypalladation, which is proven to be governed by the rationally selected carboxylate.

Prediction of the Endocrine disruption profile of fluorinated biphenyls and analogues: An in silico study.

Fluorinated biphenyls and their analogues (FBAs) are considered new persistent organic pollutants, but their endocrine-disrupting effects are still unknown. To fill this gap, the binding probability of 44 FBAs to different nuclear hormone receptors (NHRs) was predicted using Endocrine Disruptome. And molecular similarity and network toxicology analysis were used to strengthen the docking screening. The docking results showed that FBAs could have high binding potential for various NHRs, such as estrogen receptors ß antagonism (ERß an), liver X receptors α (LXRα), estrogen receptors α (ERα), and liver X receptors ß (LXRß). The similarity analysis found that the degree of overlap of the NHR repertoire was related to the Tanimoto coefficient of FBAs. Network toxicology verified a part of docking screening results and identified endocrine-disrupting pathways worthy of attention. This study found out potential endocrine-disrupting FBAs and their vulnerable, and developed a workflow that would leverage in silico approaches including molecular docking, similarity, and network toxicology for risk prioritization of potential endocrine-disrupting compounds.

Pd0 -Catalyzed Asymmetric Carbonitratation Reaction Featuring an H-Bonding-Driven Alkyl-PdII -ONO2 Reductive Elimination.

Reductive elimination of alkyl-PdII -O is a synthetically useful yet underdeveloped elementary reaction. Here we report that the combination of an H-bonding donor [PyH][BF4 ] and AgNO3 additive under toluene/H2 O biphasic system can enable such elementary step to form alkyl nitrate. This results in the Pd0 -catalyzed asymmetric carbonitratations of (Z)-1-iodo-1,6-dienes with (R)-BINAP as the chiral ligand, affording alkyl nitrates up to 96 % ee. Mechanistic studies disclose that the reaction consists of oxidative addition of Pd0 catalyst to vinyl iodide, anion ligand exchange between I- and NO3 - , alkene insertion and SN 2-type alkyl-PdII -ONO2 reductive elimination. Evidences suggest that H-bonding interaction of PyH⋅⋅⋅ONO2 can facilitate dissociation of O2 NO- ligand from the alkyl-PdII -ONO2 species, thus enabling the challenging alkyl-PdII -ONO2 reductive elimination to be feasible.

Synthesis of Furans via Rhodium(III)-Catalyzed Cyclization of Acrylic Acids with α-Diazocarbonyl Compounds.

An efficient protocol for the synthesis of furans through Rh(III)-catalyzed vinyl C-H activation from acrylic acids and α-diazocarbonyl compounds has been developed. The reaction features broad functional group tolerance and affords a series of furans in moderate to good yields. Moreover, no additives such as copper or silver salts are required. Some control experiments are performed to give insight into the mechanism of this cascade transformation and the decarbonylation process is involved in the formation of the furan product.

Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy.

The development of chemo/photothermal nanotherapeutic systems with excellent photothermal performance, stable drug loading, tumor targeting and strong membrane penetration still remains a challenge. To address this problem, herein a rod-like nanocomposite system (AuNR@FA-PR/PEG) forming from folic acid (FA) terminated carboxylated cyclodextrin (CD) pseudopolyrotaxane (FA-PR) and polyethylene glycol (PEG) modifying gold nanorods (AuNR) was reported. Cisplatin (CDDP) was loaded in AuNR@FA-PR/PEG via coordination bonds to prepare a rod-like pH-responsive nanosystem (AuNR@FA-PR/PEG/CDDP) with chemotherapy/photothermal therapy. The rod-like morphology of AuNR@FA-PR/PEG was characterized by transmission electron microscope. In vitro drug release experiments showed the pH-responsive of AuNR@FA-PR/PEG/CDDP. In vivo real-time imaging assays proved AuNR@FA-PR/PEG/CDDP could rapidly enrich in the tumor area and stay for a long time because of folate targeting and their rod-like morphology. In vivo photothermal imaging assays showed AuNR@FA-PR/PEG/CDDP excellent photothermal performance, the average temperature of tumor region could reach 63.5 °C after 10 min irradiation. In vitro and in vivo experiments also demonstrated that the combined therapy of chemotherapy and photothermal therapy had an outstandingly synergistic effect and improved the therapeutic efficacy comparing with chemotherapy and photothermal therapy alone. Therefore, the prepared rod-like AuNR@FA-PR/PEG/CDDP will provide a new strategy for the effective treatment of cancer.

Synthesis of Pyranones: Ru-Catalyzed Cascade Reaction via Vinylic C-H Addition to Glyoxylate.

The efficient synthesis of pyranones is presented by a three-component cascade reaction from readily available acrylic acids, ethyl glyoxylate, and p-toluenesulfonamide under ruthenium catalysis. For the first time, the nucleophilic addition of the vinylic C-H bond of acrylic acids across aldehyde is achieved, and the intramolecular cyclization as well as subsequent second insertion to aldehyde form the substituted butenolides. The elimination of sulfonamides occurs at higher temperature to give the pyranones.

Precisely NIR-II-activated and pH-responsive cascade catalytic nanoreactor for controlled drug release and self-enhanced synergetic therapy.

Mesoporous polydopamine (MPDA) and MPDA-based nanosystems have been widely used in the field of photothermal therapy (PTT) and drug delivery. However, synthesis of the corresponding nanoplatforms for efficient PTT and controlled drug release simultaneously in the second near infrared (NIR-II) region remains a great challenge. Herein, a NIR-II and pH dual-responsive HMPDA@Cu2-xSe cascade catalytic nanoplatform was constructed by assembling hollow mesoporous polydopamine (HMPDA) with ultra-small Cu2-xSe, which could compensate the inadequate NIR-II-induced PTT effect of HMPDA and enhance the efficacy of chemodynamic therapy (CDT) simultaneously under NIR-II laser irradiation. Meanwhile, doxorubicin (DOX) and glucose oxidase (GOx) were encapsulated into the synthesized HMPDA@Cu2-xSe using the photothermal-induced phase change material (PCM) tetradecyl (1-TD) as a gatekeeper to achieve the controlled release of the cargo. Under 1064 nm laser, the generated heat could cause 1-TD melting, resulting in the release of large amounts of DOX and GOx. The released GOx could further catalyze glucose to H2O2 and gluconic acid, which in turn promoted the effects of PTT/CDT and the release of drugs. In vitro and in vivo experiments showed that the synthesized HMPDA@Cu2-xSe-DOX-GOx@PCM (HMPC-D/G@PCM) nanosystem exhibited a significant tumor cell inhibition effect by combining different treatment modes. Thus, this smart nanoplatform with multiple stimuli-activated cascade reactions provided a new idea for designing effective multi-modal combination therapy for tumors.

Rh-Catalyzed Coupling of Acrylic/Benzoic Acids with α-Diazocarbonyl Compounds: An Alternative Route for α-Pyrones and Isocoumarins.

A coupling of acrylic acids/benzoic acids with α-diazocarbonyl compounds has been realized by a combined catalytic system of rhodium catalyst and Zn(OAc)2 additive. The presence of Zn(OAc)2 obviously accelerates the C(sp2)-H activation and destructed the formation of carboxylic ester that is formed via a nucleophilic O-H insertion to metal carbenoid. The procedure featured mild reaction conditions and broad substrate scope, providing a straightforward approach to the synthesis of α-pyrones and isocoumarins without the transformation of carboxylic acids to the corresponding amides.

A multifunctional nanoamplifier with self-enhanced acidity and hypoxia relief for combined photothermal/photodynamic/starvation therapy.

Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT) have been potential noninvasive therapeutic modality with high efficiency, however, there still exist some intrinsic limitations that impede their clinical applications. Herein, taking the advantages of the synergistic effect and high reactivity of manganese dioxide (MnO2) nanosheets and glucose oxidase (GOx), multifunctional MPDA@MnO2-MB-GOx nanoamplifier was constructed for enhanced PTT, PDT, and starvation therapy. In tumor microenvironment (TME), MnO2 nanosheets on the surface of mesoporous polydopamine (MPDA) could react with endogenous hydrogen peroxide (H2O2) and generate oxygen (O2) to relieve tumor hypoxia, thus enhancing the efficacy of PDT and GOx catalysis. Glucose consumption under the catalysis of GOx will enhance the acidity of TME and increase intracellular H2O2 concentration, which in turn promotes the production of O2 by MnO2 nanosheets, thus forming efficient cascade reaction and maximizing the efficacy of the functional agents. Furthermore, the heat generated by MPDA under the irradiation of 808 nm laser can accelerate chemical reactions, thus further enhancing synergistic therapeutic efficacy. In vitro/vivo results emphasize that enhanced cancer cell death and tumor inhibition are gained by modulating unfavorable TME with the functional nanosystem, which highlights the promise of the synthesized MPDA@MnO2-MB-GOx nanomaterial to overcome the limitations of phototherapy.

Prediction of the endocrine-disrupting ability of 49 per- and polyfluoroalkyl substances: In silico and epidemiological evidence.

The toxic effects of per- and polyfluoroalkyl substances (PFASs) on humans are mediated by nuclear hormone receptors (NHRs). However, data on the interaction of PFASs and NHRs is limited. Endocrine Disruptome, an inverse docking tool, was used in this study to simulate the docking of 49 common PFASs with 14 different types of human NHRs. According to the findings, 25 PFASs have a high or moderately high probability of binding to more than five NHRs, with androgen receptor (AR) and mineralocorticoid receptor (MR) being the most likely target NHRs. Molecular docking analyses revealed that the binding modes of PFASs with the two NHRs were similar to those of their corresponding co-crystallized ligands. PFASs, in particular, may disrupt the endocrine system by binding to MR. This finding is consistent with epidemiological research that has linked PFASs to MR-related diseases. Our findings may contribute to a better understanding of the health risks posed by PFASs.

Cobalt-Catalyzed Vinylic C-H Addition to Formaldehyde: Synthesis of Butenolides from Acrylic Acids and HCHO.

A carboxyl-assisted C-H functionalization of acrylic acids with formaldehyde to give butenolides is described. It is the first time that the addition of an inert vinylic C-H bond to formaldehyde has been achieved via cobalt-catalyzed C-H activation. The unique reactivity of the cobalt species was observed when compared with related Rh or Ir catalysts. γ-Hydroxymethylated butenolides were produced by the treatment of Na2CO3 after the catalytic reaction in one pot.

Value of ddPCR in the Preoperative Diagnosis of Solitary Pulmonary Nodules Based on the Observation of Virtual Reality Images of Smart Medical Treatment.

At present, lung cancer ranks the first cause of tumor death in the world, and malignant tumors in the SPN detected by imaging account for 5-40%, most of which are peripheral lung cancer. The recovery of the solitary nodules in the lung after treatment has also been paid attention to. In order to explore the correlation of solitary pulmonary nodule (SPN) with microvessel density (MVD), vascular parameters, and vascular ratio under virtual reality images of smart medical treatment and evaluate the differentiation of SPN by ddPCR under virtual reality image observation diagnosis value, this article collects relevant information by investigating patients, investigating relevant literature, interviewing professionals, and constructing a case template, using a comprehensive quantitative and qualitative analysis method to create a damage assessment matrix. Experimental results prove that there are significant differences in the microvascular architecture within the SPN in the benign, inflammatory, and malignant groups. The correlation between ddPCR and vascular parameters (especially the ratio of luminal vessels) under the virtual reality image observation of smart medical treatment is better than other detection methods, and its accuracy is about 10% higher. Based on the observation of smart medical virtual reality images, ddPCR can be used as an index for noninvasive evaluation of tumor angiogenesis, which is helpful for the differential diagnosis of SPN.