Combination of Fruquintinib and Anti-PD-1 for the Treatment of Colorectal Cancer.

Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti-PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti-PD-1 treatment. Then the effect of fruquintinib plus anti-PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti-PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti-PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti-PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.

Dynamic evolutionary metamodel analysis of the vulnerability of complex systems.

Because the collapse of complex systems can have severe consequences, vulnerability is often seen as the core problem of complex systems. Multilayer networks are powerful tools to analyze complex systems, but complex networks may not be the best choice to mimic subsystems. In this work, a cellular graph (CG) model is proposed within the framework of multilayer networks to analyze the vulnerability of complex systems. Specifically, cellular automata are considered the vertices of a dynamic graph-based model at the microlevel, and their links are modeled by graph edges governed by a stochastic model at the macrolevel. A Markov chain is introduced to illustrate the evolution of the graph-based model and to obtain the details of the vulnerability evolution with low-cost inferences. This CG model is proven to describe complex systems precisely. The CG model is implemented with two actual organizational systems, which are used on behalf of the typical flat structure and the typical pyramid structure, respectively. The computational results show that the pyramid structure is initially more robust, while the flat structure eventually outperforms it when being exposed to multiple-rounds strike. Finally, the sensitivity analysis results verify and strengthen the reliability of the conclusions.

Rapidly Tuning the PID Controller Based on the Regional Surrogate Model Technique in the UAV Formation.

The leader-follower structure is widely used in unmanned aerial vehicle formation. This paper adopts the proportional-integral-derivative (PID) and the linear quadratic regulator controllers to construct the leader-follower formation. Tuning the PID controllers is generally empirical; hence, various surrogate models have been introduced to identify more refined parameters with relatively lower cost. However, the construction of surrogate models faces the problem that the singular points may affect the accuracy, such that the global surrogate models may be invalid. Thus, to tune controllers quickly and accurately, the regional surrogate model technique (RSMT), based on analyzing the regional information entropy, is proposed. The proposed RSMT cooperates only with the successful samples to mitigate the effect of singular points along with a classifier screening failed samples. Implementing the RSMT with various kinds of surrogate models, this study evaluates the Pareto fronts of the original simulation model and the RSMT to compare their effectiveness. The results show that the RSMT can accurately reconstruct the simulation model. Compared with the global surrogate models, the RSMT reduces the run time of tuning PID controllers by one order of magnitude, and it improves the accuracy of surrogate models by dozens of orders of magnitude.

Dipicolinic acid enhances kiwifruit resistance to Botrytis cinerea by promoting phenolics accumulation.

BACKGROUND: Kiwifruit is highly susceptible to fungal pathogens, such as Botrytis cinerea, which reduce crop production and quality. In this study, dipicolinic acid (DPA), which is one of the main components of Bacillus spores, was evaluated as a new elicitor to enhance kiwifruit resistance to B. cinerea. RESULTS: DPA enhances antioxidant capacity and induces the accumulation of phenolics in B. cinerea-infected 'Xuxiang' kiwifruit. The contents of the main antifungal phenolics in kiwifruit, including caffeic acid, chlorogenic acid and isoferulic acid, increased after DPA treatment. DPA enhanced H2 O2 levels after 0 and 1 days, which promoted catalase (CAT) and superoxide dismutase (SOD) activities, reducing long-term H2 O2 levels. DPA promoted the up-regulation of several kiwifruit defense genes, including CERK1, MPK3, PR1-1, PR1-2, PR5-1 and PR5-2. Furthermore, DPA at 5 mM inhibited B. cinerea symptoms in kiwifruit (95.1% lesion length inhibition) more effectively than the commercial fungicides carbendazim, difenoconazole, prochloraz and thiram. CONCLUSIONS: The antioxidant properties of DPA and the main antifungal phenolics of kiwifruit were examined for the first time. This study uncovers new insights regarding the potential mechanisms used by Bacillus species to induce disease resistance. © 2023 Society of Chemical Industry.

Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation.

BACKGROUND: The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear. METHODS: The antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated. RESULTS: We found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8+ T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8+ T cells in xenograft mice and colorectal cancer organoids. CONCLUSION: Our data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.

Multifunctional MXene/Chitosan-Coated Cotton Fabric for Intelligent Fire Protection.

Multifunctional intelligent fireproof cotton fabrics are urgently demanded in the era of the Internet of Things. Herein, a novel high fire safety cotton fabric (denoted as MXene/CCS@CF) with temperature sensing, fire-warning, piezoresistivity, and Joule heating performance was developed by coating MXene nanosheet and carboxymethyl chitosan (CCS) via an eco-friendly layer-by-layer assembly method. Benefiting from the thermoelectric characteristic and high conductivity of MXene nanosheet, MXene/CCS@CF exhibited accurate wide-range temperature sensing performance. When being burned, it could repeatedly trigger the fire-warning system in less than 10 s. More importantly, MXene/CCS@CF showed outstanding flame retardancy because of the synergistic carbonization between MXene and CCS. The limiting oxygen index of MXene/CCS@CF was as high as 45.5%, and the char length was only 33 mm after the vertical burning test. Meanwhile, its peak heat release rate reduced more than 66%. Besides, the obtained fabric could detect a variety of human motions. Moreover, the controllable Joule heating performance enabled the fabric to be used in extreme cold weather. This work provides a facile approach to fabricating a next-generation high fire safety cotton fabric, showing promising applications in firefighting, home automation, and smart transportation.

Combination therapy with PD-1/PD-L1 blockade in non-small cell lung cancer: strategies and mechanisms.

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has been approved as the standard-of-care for the treatment of non-small cell lung cancer (NSCLC). Yet, the population of patients who benefit from the treatment remains modest, some of whom would get relapsed and progressed eventually. Combination therapy has emerged as an effective way to broaden beneficiaries from PD-1/PD-L1 immunotherapy and overcome or delay the resistance. In this review, we discuss the PD-1/PD-L1 blockade in combination with conventional chemotherapy, targeted therapy or immunotherapy. Meanwhile, we illustrate their underlying mechanisms in regulating the process of the cancer-immunity cycle, providing the rationale for the PD-1/PD-L1 blockade-based combination therapy. The challenges of combination regimens are also addressed.

CXCR6 is required for antitumor efficacy of intratumoral CD8+ T cell.

BACKGROUND: Increasing infiltration of CD8+ T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8+ T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases. METHODS: Combination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6-/- mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6+CD8+ T cells. Transgenic Cxcr6-/- OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response. RESULTS: We identified that CXCR6 was exclusively expressed on intratumoral CD8+ T cell. CXCR6+CD8+ T cells were more immunocompetent, and chimeras with specific deficiency on CD8+ T cells showed weaker antitumor activity. In addition, Cxcr6-/- mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6+CD8+ T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression. CONCLUSIONS: This study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8+ T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.

Application of Vinamidinium Salt Chemistry for a Palladium Free Synthesis of Anti-Malarial MMV048: A "Bottom-Up" Approach.

MMV390048 (1) is a clinical compound under investigation for antimalarial activity. A new synthetic route was developed which couples two aromatic fragments while forming the central pyridine ring over two steps. This sequence takes advantage of raw materials used in the existing etoricoxib supply chain and eliminates the need for palladium catalysts, which were projected to be major cost-drivers.

Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials.

A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

Alzheimer's Disease Brain Network Classification Using Improved Transfer Feature Learning with Joint Distribution Adaptation.

Alzheimer's disease significantly affects the quality of life of patients. This paper proposes an approach to identify Alzheimer's disease based on transfer learning using functional MRI images, which is especially useful when the training dataset is small. Transfer learning improves the performance of the classifier with the help of an auxiliary dataset, which may be obtained from a different population group and/or machine. First, we used the joint distribution adaptation method to project the source and target domain samples into a new feature space, and then we built a classifier that works well in both the source and target domains but emphasizes the target domain. In the classifier, we assigned larger weights to the target domain samples and minimized the weighted loss in classifying the samples in both domains. Experimental results verify the effectiveness of our proposed approach and, with the help of the auxiliary samples, the classification accuracy of our target dataset has been greatly improved.

Dendritic Cell Targeting Peptide-Based Nanovaccines for Enhanced Cancer Immunotherapy.

Immunotherapy emerges as an effective avenue for tumor elimination and has many advantages compared with traditional surgery, radiotherapy, and chemotherapy. Tumor vaccines play an important role in cancer immunotherapy, while the application of tumor vaccines in clinical usage is limited because only limited response can be induced by primary tumor antigens. Accordingly, it is a key point to activate T-cell response with some novel tumor vaccines. Here, we applied phage display biopanning and screened a peptide (TY) that could combine with bone-marrow-derived-dendritic-cells (BMDCs) specifically and spleenic DCs. Then we developed mesoporous silica nanoparticles (MSN-TY/OVA/CpG), with peptide TY and OVA/CpG to target and activate DCs, respectively. Our results showed that the nanoparticles (NPs) could be specifically absorbed by DC in vitro, which enhanced the maturation and activation of DCs in vitro and in vivo. The in vitro study demonstrated the efficiency of nanoparticles in antigen uptake by BMDCs and in the activation of antigen-specific cytotoxic CD8+ T cells. Moreover, MSN-TY/OVA/CpG could activate antigen-specific CD8+ T cells and elicited the cytotoxic T lymphocyte (CTL) priming in naive C57BL/6J mice. Therapeutic application of MSN-TY/OVA/CpG enhanced the activation of DCs and the introducing of CD8+ T cell-mediated immune response to promote tumor elimination, prolong survival of tumor-bearing mice, and cause less systemic toxicity. All these results showed that the targeted nanovaccines could deliver antigen into DCs and activate cancer immunotherapy.

In silico design and bioevaluation of selective benzotriazepine BRD4 inhibitors with potent antiosteoclastogenic activity.

The bromodomain (BRD) and extra-terminal domain (BET) protein family bind to acetylated histones on lysine residues and act as epigenetic readers. Recently, the role of this protein family in bone loss has been gaining attention. Earlier studies have reported that benzotriazepine (Bzt) derivatives could be effective inhibitors of BET proteins. In this study, using in silico tools we designed three Bzt analogs (W49, W51, and W52). By docking, molecular simulations, and chemiluminescent Alpha Screen binding assay, we show that the studied analogs were selective at inhibiting BRD4 when compared to BRD2. Furthermore, we tested the effectiveness of these analogs on osteoclast formation and function. Among the examined analogs, Bzt-W49 and Bzt-W52 were found to be the most potent inhibitors of osteoclastogenesis without cytotoxicity in murine RAW264.7 osteoclast progenitors. Both the compounds also inhibited osteoclast formation without affecting cell viability in human CD14+ monocytes. Moreover, owing to attenuated osteoclastogenesis, actin ring formation and bone resorptive function of osteoclasts were severely perturbed. In conclusion, these results suggest that the novel BRD4-selective Bzt analogs designed in this study could be explored further for developing therapeutics against bone loss diseases characterized by excessive osteoclast activity.

Association between prothrombin gene polymorphisms and hereditary thrombophilia in Xinjiang Kazakhs population.

To assess the association between polymorphisms of prothrombin gene and hereditary thrombophilia in Xinjiang Kazakhs population. Through cross-sectional investigation, permanent Kazakh population of Ili Kazakh Autonomous Prefecture was selected as the study object to measure their antithrombin III (AT-III), protein C, protein S activity and activated C protein resistance value, thus defining the situation of the crowd's hereditary thrombophilia. Sequenom Massarray detection technology was used to conduct a genotype test of the six sites selected by the case and control groups. Haploview software was used to perform linkage disequilibrium analysis of the six sites, and the impact of the interaction between genetic variations and environment on hereditary thrombophilia was researched by the use of sum model. A total of 1005 Kazakh volunteers participated in the test (332 men and 673 women), average age (41.13 ±â€Š11.50) years; the prevalence of hereditary thrombophilia in Xinjiang Kazakh population was 31.0%, and the prevalence of AT-III deficiency, protein C deficiency, protein S deficiency and activated protein C resistance was 16.4, 14.9, 20.6 and 7.8%, respectively. The difference in allele frequency of the hereditary thrombophilia patient group at rs3136447 and rs5896 sites was statistically significant (P = 0.0483 and P = 0.0302, respectively). rs5896 and rs2070852 had high linkage disequilibrium (r = 0.99), and constituted a single-domain block 1. The rs3136447 and the rs5896 polymorphisms located in the region of the prothrombin gene may be associated with hereditary thrombophilia in the Xinjiang Kazakhs population. There is additive interactive effect of rs5896 polymorphism (CT + TT) and smoke on hereditary thrombophilia.

Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors.

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) and ROCK2 (IC(50) = 670 nM), whereas compound 24 was more selective for ROCK2 (IC(50) = 100 nM) over ROCK1 (IC(50) = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

SKLB1206, a novel orally available multikinase inhibitor targeting EGFR activating and T790M mutants, ErbB2, ErbB4, and VEGFR2, displays potent antitumor activity both in vitro and in vivo.

Anti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such as gefitinib and erlotinib, is limited by the development of drug-resistant mutations, including the gatekeeper T790M mutation and upregulation of alternative signaling pathways. Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success. Here, we report a novel reversible EGFR inhibitor, SKLB1206, which has potent activity against EGFR with gefitinib-sensitive and -resistant (T790M) mutations. In addition, SKLB1206 has also considerable inhibition potency against some other related oncokinases, including ErbB2, ErbB4, and VEGF receptor 2 (VEGFR2). SKLB1206 exhibited highly antiproliferative activity against a range of EGFR-mutant cell lines, including gefitinib-sensitive and -resistant cell lines, and EGFR or ErbB2-overexpressing cell lines. SKLB1206 also showed a potent antiangiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 showed complete tumor regression in gefitinib-sensitive HCC827 and PC-9 xenograft models and showed a considerable antitumor effect on the gefitinib-resistant H1975 model as well as other EGFR/ErbB2-overexpressing or -dependent tumor models including A431, LoVo, and N87 established in athymic mice. SKLB1206 also showed a very good oral bioavailability (50.1%). Collectively, these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR-activating/resistance mutations or EGFR/ErbB2 overexpressed.

An efficient and general route to gem-difluoromethylenated alpha,beta-unsaturated delta-lactones: high enantioselective synthesis of gem-difluoromethylenated goniothalamins.

An efficient and general strategy to gem-difluoromethylenated alpha,beta-unsaturated delta-lactones in high yields from various aldehydes (including aliphatic, aromatic, alpha,beta-unsaturated, and sterically hindered aldehydes) has been developed. This methodology was successfully applied for the preparation of two enantiomers of gem-difluoromethylenated goniothalamins (S)-1 and (R)-1. gem-Difluoropropargylation of cinnamaldehyde followed by the resolution of resulting homopropargylic alcohols mediated by lipase from Pseudomonas (AK) gave alcohols (R)-6 and (S)-6. Selective hydrogenation of the triple bond of (S)-6 and (R)-6 to double bond with Lindlar catalyst in the presence of quinoline afforded the expected product (S)-8 and (R)-8, respectively. Deprotection of (S)-8 and (R)-8 followed by oxidation of the resulting 1,5-diols with catalytic 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and excess bis-acetoxyiodobenzene (BAIB) provided the target molecules gem-difluoromethylenated goniothalamins (S)-1 and (R)-1 in high yields, respectively.