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Abstract As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Here we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.

Abstract 53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the ‘leaky’ DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

Purpose: To investigate anatomical and dosimetric changes during volumetric modulated arc therapy (VMAT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) after induction therapy (IT) and explore characteristics of patients with notable variations. Materials and methods: From July 2021 to June 2023, 60 LA-NPC patients undergoing VMAT after IT were retrospectively recruited. Adaptive computed tomography (aCT), reconstructed from weekly cone-beam computed tomography(CBCT), facilitates recontouring and planning transplantation. Volume, dice similarity coefficients, and dose to target volumes and organs at risk(OARs) on planning CT(pCT) and aCT were compared to identify changing patterns. Multivariate logistic regression was used to investigate risk factors. Results: The volumes of PGTVnasopharynx (PGTVp), PGTVnode (PGTVn), ipsilateral and contralateral parotid glands decreased during VMAT, with reductions of 2.25 %, 6.98 %, 20.09 % and 18.00 %, respectively, at 30 fractions from baseline (P

Abstract Vaccine‐based therapeutics for cancers face several challenges including lack of immunogenicity and tumor escape pathways for single antigen targets. It has been reported that radiotherapy has an in situ vaccine effect that provides tumor antigens following irradiation, helping to activate antigen‐presenting cells (APCs). Herein, a new vaccine approach is developed by combining genetically engineered irradiated tumor cell debris (RTD) and hyaluronic acid (HA), termed HA@RTD. A cancer cell line is developed that overexpresses granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). A hydrogel was developed by covalent conjugation of HA with RTD proteins that acted as a potent vaccine system, the effects which were probed with T cell receptor sequencing. The engineered vaccine activated antitumor immunity responses and prevented tumor growth in mice even with a single immunization. HA@RTD vaccine efficacy was also assessed in therapeutic settings with established tumors and in combination with immune checkpoint blockade.

Abstract Reciprocal interactions between the tumor microenvironment (TME) and cancer cells play important roles in tumorigenesis and progression of glioma. Glioma-associated macrophages (GAMs), either of peripheral origin or representing brain-intrinsic microglia, are the majority population of infiltrating immune cells in glioma. GAMs, usually classified into M1 and M2 phenotypes, have remarkable plasticity and regulate tumor progression through different metabolic pathways. Recently, research efforts have increasingly focused on GAMs metabolism as potential targets for glioma therapy. This review aims to delineate the metabolic characteristics of GAMs within the TME and provide a summary of current therapeutic strategies targeting GAMs metabolism in glioma. The goal is to provide novel insights and therapeutic pathways for glioma by highlighting the significance of GAMs metabolism.

Abstract Immunotherapy has revolutionized the treatment of cancer. However, its efficacy remains to be optimized. There are at least two major challenges in effectively eradicating cancer cells by immunotherapy. Firstly, cancer cells evade immune cell killing by down-regulating cell surface immune sensors. Secondly, immune cell dysfunction impairs their ability to execute anti-cancer functions. Radiotherapy, one of the cornerstones of cancer treatment, has the potential to enhance the immunogenicity of cancer cells and trigger an anti-tumor immune response. Inspired by this, we fabricate biofunctionalized liposome-like nanovesicles (BLNs) by exposing irradiated-cancer cells to ethanol, of which ethanol serves as a surfactant, inducing cancer cells pyroptosis-like cell death and facilitating nanovesicles shedding from cancer cell membrane. These BLNs are meticulously designed to disrupt both of the aforementioned mechanisms. On one hand, BLNs up-regulate the expression of calreticulin, an “eat me” signal on the surface of cancer cells, thus promoting macrophage phagocytosis of cancer cells. Additionally, BLNs are able to reprogram M2-like macrophages into an anti-cancer M1-like phenotype. Using a mouse model of malignant pleural effusion (MPE), an advanced-stage and immunotherapy-resistant cancer model, we demonstrate that BLNs significantly increase T cell infiltration and exhibit an ablative effect against MPE. When combined with PD-1 inhibitor (α-PD-1), we achieve a remarkable 63.6% cure rate (7 out of 11) among mice with MPE, while also inducing immunological memory effects. This work therefore introduces a unique strategy for overcoming immunotherapy resistance.

Summary: Obesity is a global health challenge with limited therapeutic solutions. Here, we demonstrate the engineering of an energy-dissipating hybrid tissue (EDHT) in the body for weight control. EDHT is constructed by implanting a synthetic gel matrix comprising immunomodulatory signals and functional cells into the recipient mouse. The immunomodulatory signals induce the host stromal cells to create an immunosuppressive niche that protects the functional cells, which are overexpressing the uncoupling protein 1 (UCP1), from immune rejection. Consequently, these endogenous and exogenous cells co-develop a hybrid tissue that sustainedly produces UCP1 to accelerate the host’s energy expenditure. Systematic experiments in high-fat diet (HFD) and transgenic (ob/ob) mice show that EDHT efficiently reduces body weight and relieves obesity-associated pathological conditions. Importantly, an 18-month observation for safety assessment excludes cell leakage from EDHT and reports no adverse physiological responses. Overall, EDHT demonstrates convincing efficacy and safety in controlling body weight.

Abstract By integrating land use and transportation systems, transit-oriented development (TOD) focuses on transit and land development, development potential, and the balance between transportation and land use. The TOD level assessment not only helps optimize existing TODs but also guides TOD planning. Based on previous literature, methods for assessing TOD around rail transit stations can be roughly divided into three categories: TOD index, the node-place model, and the data envelopment analysis (DEA) model. The TOD index aggregates indicators from different dimensions into a single value for evaluation. The node-place model emphasizes transportation, land use, and the balance between them, as well as expansion factors. And the DEA model is suitable for situations without input indicator weights or consideration of different units of measurement. TOD indicators are the basis of the evaluation, and in both the TOD index and node-place models, indicator weights are mostly determined by using subjective methods. Furthermore, a limited number of studies to date have pre-evaluated the implementation of TOD at rail stations under construction or in planning. This paper aims to assess the level of TOD areas at the rail transit station level, which can help in constructing the evaluation index system, selecting TOD stations, and optimizing them.

Abstract Background Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. It is an aggressive tumor characterized by rapid proliferation, diffuse tumor morphology, and poor prognosis. Unfortunately, current treatments, such as surgery, radiotherapy, and chemotherapy, are unable to achieve good outcomes. Therefore, there is an urgent need to explore new treatment targets. A detailed mechanistic exploration of the role of the nuclear pore transporter KPNB1 in GBM is lacking. This study demonstrated that KPNB1 regulated GBM progression through a transcription factor YBX1 to promote the expression of post-protrusion membrane protein NLGN3. This regulation was mediated by the deubiquitinating enzyme USP7. Methods A tissue microarray was used to measure the expression of KPNB1 and USP7 in glioma tissues. The effects of KPNB1 knockdown on the tumorigenic properties of glioma cells were characterized by colony formation assays, Transwell migration assay, EdU proliferation assays, CCK-8 viability assays, and apoptosis analysis using flow cytometry. Transcriptome sequencing identified NLGN3 as a downstream molecule that is regulated by KPNB1. Mass spectrometry and immunoprecipitation were performed to analyze the potential interaction between KPNB1 and YBX1. Moreover, the nuclear translocation of YBX1 was determined with nuclear-cytoplasmic fractionation and immunofluorescence staining, and chromatin immunoprecipitation assays were conducted to study DNA binding with YBX1. Ubiquitination assays were performed to determine the effects of USP7 on KPNB1 stability. The intracranial orthotopic tumor model was used to detect the efficacy in vivo. Results In this study, we found that the nuclear receptor KPNB1 was highly expressed in GBM and could mediate the nuclear translocation of macromolecules to promote GBM progression. Knockdown of KPNB1 inhibited the progression of GBM, both in vitro and in vivo. In addition, we found that KPNB1 could regulate the downstream expression of Neuroligin-3 (NLGN3) by mediating the nuclear import of transcription factor YBX1, which could bind to the NLGN3 promoter. NLGN3 was necessary and sufficient to promote glioma cell growth. Furthermore, we found that deubiquitinase USP7 played a critical role in stabilizing KPNB1 through deubiquitination. Knockdown of USP7 expression or inhibition of its activity could effectively impair GBM progression. In vivo experiments also demonstrated the promoting effects of USP7, KPNB1, and NLGN3 on GBM progression. Overall, our results suggested that KPNB1 stability was enhanced by USP7-mediated deubiquitination, and the overexpression of KPNB1 could promote GBM progression via the nuclear translocation of YBX1 and the subsequent increase in NLGN3 expression. Conclusion This study identified a novel and targetable USP7/KPNB1/YBX1/NLGN3 signaling axis in GBM cells.

Abstract Background The development of radioresistance seriously hinders the efficacy of radiotherapy in lung cancer. However, the underlying mechanisms by which radioresistance occurs are still incompletely understood. The N6-Methyladenosine (m6A) modification of RNA is involved in cancer progression, but its role in lung cancer radioresistance remains elusive. This study aimed to identify m6A regulators involved in lung cancer radiosensitivity and further explore the underlying mechanisms to identify therapeutic targets to overcome lung cancer radioresistance. Methods Bioinformatic mining was used to identify the m6A regulator IGF2BP2 involved in lung cancer radiosensitivity. Transcriptome sequencing was used to explore the downstream factors. Clonogenic survival assays, neutral comet assays, Rad51 foci formation assays, and Annexin V/propidium iodide assays were used to determine the significance of FBW7/IGF2BP2/SLC7A5 axis in lung cancer radioresistance. Chromatin immunoprecipitation (ChIP)-qPCR analyses, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP)-qPCR analyses, RNA pull-down analyses, co-immunoprecipitation analyses, and ubiquitination assays were used to determine the feedback loop between IGF2BP2 and SLC7A5 and the regulatory effect of FBW7/GSK3β on IGF2BP2. Mice models and tissue microarrays were used to verify the effects in vivo. Results We identified IGF2BP2, an m6A “reader”, that is overexpressed in lung cancer and facilitates radioresistance. We showed that inhibition of IGF2BP2 impairs radioresistance in lung cancer both in vitro and in vivo. Furthermore, we found that IGF2BP2 enhances the stability and translation of SLC7A5 mRNA through m6A modification, resulting in enhanced SLC7A5-mediated transport of methionine to produce S-adenosylmethionine. This feeds back upon the IGF2BP2 promoter region by further increasing the trimethyl modification at lysine 4 of histone H3 (H3K4me3) level to upregulate IGF2BP2 expression. We demonstrated that this positive feedback loop between IGF2BP2 and SLC7A5 promotes lung cancer radioresistance through the AKT/mTOR pathway. Moreover, we found that the ubiquitin ligase FBW7 functions with GSK3β kinase to recognize and degrade IGF2BP2. Conclusions Collectively, our study revealed that the m6A “reader” IGF2BP2 promotes lung cancer radioresistance by forming a positive feedback loop with SLC7A5, suggesting that IGF2BP2 may be a potential therapeutic target to control radioresistance in lung cancer.

ObjectiveInvestigate the impact of combined computerized cognitive training and occupational therapy on individuals with mild cognitive impairment (MCI).MethodsWe randomly assigned 118 MCI patients into two groups: a combined intervention group (n = 37) and a control group (n = 81), the latter receiving standard nursing care. The intervention group additionally underwent 12 weeks of computerized cognitive training and occupational therapy. Blind assessors evaluated cognitive performance, anxiety, depression, and daily living activities before the intervention, post-intervention, and at a 3-month follow-up.ResultsRepeated-measures analysis of variance showed that the sMoCA scores, HAMA scores, and ADL scores of the experimental group at T2 (post-intervention) and T3 (3-month follow-up) were higher than those of the control group, and the difference was statistically significant (p

In this paper, we work on the discrete modified Leslie type predator-prey model with Holling type II functional response. The existence and local stability of the fixed points of this system are studied. According to bifurcation theory and normal forms, we investigate the codimension 1 and 2 bifurcations of positive fixed points, including the fold, 1:1 strong resonance, fold-flip and 1:2 strong resonance bifurcations. In particular, the discussion of discrete codimension 2 bifurcation is rare and difficult. Our work can be seen as an attempt to complement existing research on this topic. In addition, numerical analysis is used to demonstrate the correctness of the theoretical results. Our analysis of this discrete system revealed quite different dynamical behaviors than the continuous one.

The decomposition of biodegradable composite carbon sources generates a large amount of biodegradable microplastics, which may not only furnish microbial denitrification, but might also pose potential environmental risks. In the present study, the effects of different dosages of a biodegradable composite carbon source on the microbial communities, the nitrogen metabolic pathways and the antibiotic resistome were explored through Illumina MiSeq sequencing analysis and metagenomic analysis. The results of partial least-square discriminant analysis (PLS-DA) and analysis of similarity (ANOSIM) demonstrated that the response of the bacterial community to a biodegradable composite carbon source was more obvious than the fungal community. The application of biodegradable microplastics diminished the complexity of the microbial communities to some extent and obviously stimulated denitrification. Antibiotics resistance gene (ARG) dispersal was not evidently accelerated after the addition of biodegradable composite carbon source. Lysobacter, Methylobacillus, Phyllobacterium, Sinorhizobium, Sphingomonas from Proteobacteria and Actinomadura, Agromyces, Gaiella and Micromonospora from Actinobacteria were the major ARG hosts. Overall, the addition of a biodegradable composite carbon source shaped microbial communities and their antibiotic resistance profiles in this study.

Radiotherapy (RT) serves as the primary treatment for solid tumors. Its potential to incite an immune response against tumors both locally and distally profoundly impacts clinical outcomes. However, RT may also promote the accumulation of immunosuppressive cytokines and immunosuppressive cells, greatly impeding the activation of antitumor immune responses and substantially limiting the effectiveness of RT. Therefore, regulating post-RT immunosuppression to steer the immune milieu toward heightened activation potentially enhances RT’s therapeutic potential. Cytokines, potent orchestrators of diverse cellular responses, play a pivotal role in regulating this immunosuppressive response. Identifying and promptly neutralizing early released immunosuppressive cytokines are a crucial development in augmenting RT’s immunomodulatory effects. To this end, we conducted a screen of immunosuppressive cytokines following RT and identified macrophage colony-stimulating factor (MCSF) as an early up-regulated and persistent immune suppressor. Single-cell sequencing revealed that the main source of up-regulated MCSF derived from tumor cells. Mechanistic exploration revealed that irradiation-dependent phosphorylation of the p65 protein facilitated its binding to the MCSF gene promoter, enhancing transcription. Knockdown and chemical inhibitor experiments conclusively demonstrated that suppressing tumor cell-derived MCSF amplifies RT’s immune-activating effects, with optimal results achieved by early MCSF blockade after irradiation. Additionally, we validated that MCSF acted on macrophages, inducing the secretion of a large number of inhibitory cytokines. In summary, we propose a novel approach to enhance the immune activation effects of RT by blocking the MCSF-CSF1R signaling pathway early after irradiation.

ABSTRACTRadiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.

Abstract Background We aimed to evaluate the correlation between the pathological changes and multi-parameter MRI characteristics of liver regeneration (LR) in a standard partial hepatectomy (PH) rat model. Methods Seventy Sprague–Dawley rats were randomly divided into two groups: MR scan group (n = 14) and pathologic analysis (PA) group (n = 56). All 14 rats in the MR group underwent liver T1 mapping, T2 mapping, and diffusion kurtosis imaging before and the 1st, 2nd, 3rd, 5th, 7th, 14th, and 21st day after 70% hepatectomy. Seven rats in the PA group were euthanized at each time point to determine Ki-67 indices, hepatocyte size (HTS), steatosis grade, and inflammation score. Results Liver T1 and T2 values increased to maximum on day 2 (P

Stem-like tumor cells (SLTCs) are thought to be the cellular entity responsible for clinical recurrence and subsequent metastasis. Inhibiting or killing SLTCs can effectively reduce recurrence and metastasis, yet little has been done to clear SLTCs because they are usually resistant to chemotherapy, radiotherapy, and even immunotherapy. In this study, we established SLTCs by low-serum culture and confirmed that the low-serum-cultured tumor cells were in a quiescent state and resistant to chemotherapy, showing features of SLTCs, consistent with the reported data. We demonstrated that SLTCs had high levels of reactive oxygen species (ROS). Based on the finding that radiated tumor cell-derived microparticles (RT-MPs) contained ROS, we used RT-MPs to kill SLTCs. We found that RT-MPs could further increase ROS levels and kill SLTCs in vivo and in vitro partially by ROS carried by the RT-MPs themselves, providing a new method for eliminating SLTCs.

Abstract Extracellular vesicles (EVs), spherical biological vesicles, mainly contain nucleic acids, proteins, lipids and metabolites for biological information transfer between cells. Microparticles (MPs), a subtype of EVs, directly emerge from plasma membranes, and have gained interest in recent years. Specific cell stimulation conditions, such as ultraviolet and X-rays irradiation, can induce the release of MPs, which are endowed with unique antitumor functionalities, either for therapeutic vaccines or as direct antitumor agents. Moreover, the size of MPs (100–1000 nm) and their spherical structures surrounded by a lipid bilayer membrane allow MPs to function as delivery vectors for bioactive antitumor compounds, with favorable phamacokinetic behavior, immunostimulatory activity and biological function, without inherent carrier-specific toxic side effects. In this review, the mechanisms underlying MP biogenesis, factors that influence MP production, properties of MP membranes, size, composition and isolation methods of MPs are discussed. Additionally, the applications and mechanisms of action of MPs, as well as the main hurdles for their applications in cancer management, are introduced. Graphical Abstract

Abstract Background Honeysuckle is a time‐honored herb with anticancer activity in traditional Chinese medicine. Recently, accumulating reports are suggesting that the microRNAs in this medicinal plant not only play a physiological role in their original system, but also can be transmitted to another species as potential therapeutic components. In the numerous bioactive investigations, the anti-tumor effects of these microRNAs in the magical herb are rarely studied, especially the special miR2911, a honeysuckle-encoded atypical microRNA, with high stability during the boiling process and unique biological activity to target TGF-β1 mRNA. Methods Luciferase assay was conducted to test the ability of miR2911 to target TGF-β1 mRNA. ELISA was performed to determine the expression level of TGF-β1 of mouse colorectal adenocarcinoma CT26 cells when treated with miR2911 and tumor tissue in Sidt1 +/+ and Sidt1 −/− mice. qRT-PCR was performed to examine the level of expression of miR2911. Tumor-bearing wild and nude mice were employed to evaluate the anti-tumor effect of honeysuckle and miR2911 in vivo. Tumor tissue necrosis was observed by H&E staining. Besides, the infiltration of T lymphocytes across solid tumors was tested by immunostaining staining. Results Our results showed that honeysuckle slowed the development of colon cancer down. Further research showed that miR2911 could bind strongly to TGF-β1 mRNA and down-regulate the expression of TGF-β1 and had a high stability under boiling and acid condition. Moreover, SIDT1 mediated dietary miR2911 inter-species absorption. And we found that miR2911 had a similar anticancer effect as honeysuckle. Mechanistically, miR2911 reversed the tumor-promoting effect of TGF-β1 by an increase of T lymphocytes infiltration, resulting in slowing the colon cancer process in immunocompetent mice. Consistent with this inference, the anti-tumor effect of miR2911 was revealed to be abolished in T cell immune deficiency mice. Conclusion Taken together, honeysuckle-derived miR2911 showed an anti-tumor effect in colon cancer through targeting TGF-β1 mRNA. The down-regulation of TGF-β1 promoted T lymphocytes infiltration, and accordingly impeded the colon tumor development.

The use of rice and millet has been uncovered at a few archaeological sites associated with the Shuangdun Culture (ca. 7.3–6.8 ka BP) in the middle catchment of the Huai River, China. Nevertheless, the consumption of rice, millet, and other types of plant foods at other contemporaneous sites in the same region still needs supporting information from more case studies. This article examines pottery sherds (n = 21) excavated from another representative Shuangdun Culture site at Houjiazhai with starch grain analysis. Varied types of pottery vessels contain starch remains from rice (Oryza sativa), foxtail millet (Setaria italica), broomcorn millet (Panicum miliaceum), Job’s tears (Coix lacryma-jobi), Triticeae, roots of snake gourd (Trichosanthes kirilowii), lotus root (Nelumbo nucifera), Chinese yam (Dioscorea panthainca), lily bulbs (Lilium sp.), acorns (Quercus sp.), and beans (Vigna sp. or/and Vicia sp.). Further quantitative analysis of the starch data indicates that cereals, including rice and millet, were predominantly consumed in the pottery vessels. Changes and continuities of culinary practices are also present at Houjiazhai, which are reflected in the different pottery assemblages as well as the utilized plant species in different occupation phases at the site. Combining previous studies, this article also reveals the differences and similarities of the past population in choosing their plant food resources during the period of Shuangdun Culture in the middle catchment of the Huai River, China.

Cancer immunotherapy, which suppresses cancer progression by activating the anti-cancer immunity of patients, shows utility in treating multiple types of cancers. Immunogenic cell death (ICD) induced by most clinical treatment modalities plays a critical role in promoting cancer immunotherapy by releasing tumor-associated antigens and neoantigens and exposing “danger signals” to stimulate immune cells. This comment article presents the different roles of nanoparticles in various treatment modalities of cancers, including chemotherapy, radiotherapy, photodynamic and photothermal therapies, and therapy with radiated tumor cell-released nanoparticles, which often activate anti-cancer immunological effects by inducing ICD of cancer cells, and highlights the challenges and opportunities of ICD-related cancer immunotherapy in the clinic.

The middle and lower Huai River Valley, located between the Yangtze and Yellow Rivers, was a key transitional zone for the northward spread of rice and southward migration of millet agriculture in central-eastern China during the Holocene. Knowing when millets spread here, how they were combined with rice in mixed farming, the reasons for their spread, and the temporal variation of cropping patterns is of crucial significance to the development of our understanding of ancient adaptation strategies adopted by human societies in response to climatic and cultural changes. Focusing on crops, phytolith analyses of the soil samples, in tandem with radiocarbon dating from the Wanbei site, reveal evidence of a multicropping pattern of combining rice (Oryza sative), broomcorn millet (Panicum miliaceum), and foxtail millet (Setaria italica) during the Dawenkou culture period between 5720 and 4426 cal. BP in the middle and lower Huai River Valley, China. The data show that rice was always the principal crop of the pattern, and that domesticated rice was developed during the early and middle Dawenkou culture periods. However, its domestication rate became lower during the late Dawenkou culture period. Broomcorn millet and foxtail millet with domesticated traits appeared only in lower proportions of the total produced throughout the period. The proportions of rice and foxtail millet increased slightly, while the proportions of broomcorn millet decreased over time. Finally, the formation of the multicropping pattern at Wanbei may have been primarily influenced by both the warm and wet climatic environment and the cultural exchange and communication between the Haidai region and the middle and lower Huai River Valley during the Dawenkou culture period. The findings in this paper may not only contribute to mapping the spatiotemporal route for the northward expansion of rice agriculture and southward spread of millet agriculture, but also assist in understanding the human adaptation strategies employed in eastern China during the Holocene.

PurposeTo determine whether intravoxel incoherent motion (IVIM) parameters correlate with liver regeneration and function recovery after partial hepatectomy (PH) in rats with carbon tetrachloride (CCl4)-induced liver fibrosis.MethodsSixty-two adult Sprague-Dawley rats were divided into the control group and the fibrosis group with CCl4 injection for 8 weeks. At the end of the 8th week, all rats received left lateral lobe liver resection. Within each group, IVIM imaging (n = 10/group) and histologic and biochemical analyses (n = 3/group/time point) were performed pre- and post-PH (on days 1, 2, 3, 5, 7, 14, and 21). Differences in liver IVIM parameters and correlation between IVIM parameters and Ki-67 indices, hepatocyte diameter, alanine transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) values were analyzed.ResultsPost-PH, liver true diffusion coefficient (D) values decreased and pseudodiffusion coefficient (D*) and perfusion fraction (PF) values increased, then recovered to pre-PH levels gradually in both fibrosis and control rats. PF in fibrosis group were significantly higher than in controls from 3 to 21 days (P < 0.05). In fibrosis rats, both Ki-67 indices and hepatocyte diameters increased, and a strong correlation was found between PF and Ki-67 indices (r = −0.756; P = 0.03), D* and PF values and ALT, AST, and TBil values (r = −0.762 to −0.905; P < 0.05). In control rats, only hepatocyte diameters increased, and all IVIM parameters correlated well with hepatocyte diameters, ALT, AST and TBil values (r = 0.810 to −1.000; P < 0.05).ConclusionThe regeneration pattern in fibrotic liver tissue was different compared with control livers. IVIM parameters can monitor liver regeneration and functional recovery non-invasively after PH.

Cancer cell radioresistance is the primary cause of the decreased curability of non–small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53–interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.

Abstract Background Small cell lung cancer (SCLC) is a highly aggressive lung cancer subtype with poor survival and limited treatment options. Sequencing results have revealed gene mutations associated with SCLC, however, the correlation between the genomic alterations and clinical prognosis of SCLC is yet unclear. Methods Targeted next-generation sequencing of 62 cancer related genes was performed on 53 SCLC samples. The correlations between clinical outcomes and genomic alterations were analyzed. Results 38/62 (61.3%) candidate genes harbored some alterations, while all the SCLC samples carried at least 3 gene mutations. The most common nonsynonymous mutations included ERBB2 (95.9%), CREBBP (95.9%), and TP53 (77.6%). The median nonsynonymous tumor mutation burden (TMB) was 21.7 mutations/Mb (rang, 9.3–55.9). High TMB (> 21 mutations/Mb) was good prognostic factor in overall survival (OS) (21.7 vs. 10.4 months, P = 0.012). Multivariate analysis showed that high TMB was an independent prognostic factor. The overall survival (OS) of patients carrying KIAA1211 mutation was significantly longer than those with wild-type KIAA1211 (P

Extracellular vesicles are small membrane particles derived from various cell types. EVs are broadly classified as ectosomes or small extracellular vesicles, depending on their biogenesis and cargoes. Numerous studies have shown that EVs regulate multiple physiological and pathophysiological processes. The roles of small extracellular vesicles in cancer growth and metastasis remain to be fully elucidated. As endogenous products, small extracellular vesicles are an ideal drug delivery platform for anticancer agents. However, several aspects of small extracellular vesicle biology remain unclear, hindering the clinical implementation of small extracellular vesicles as biomarkers or anticancer agents. In this review, we summarize the utility of cancer-related small extracellular vesicles as biomarkers to detect early-stage cancers and predict treatment outcomes. We also review findings from preclinical and clinical studies of small extracellular vesicle-based cancer therapies and summarize interventional clinical trials registered in the United States Food and Drug Administration and the Chinese Clinical Trials Registry. Finally, we discuss the main challenges limiting the clinical implementation of small extracellular vesicles and recommend possible approaches to address these challenges.

Fear is a response to impending threat that prepares a subject to make appropriate defensive responses, whether to freeze, fight, or flee to safety. The neural circuits that underpin how subjects learn about cues that signal threat, and make defensive responses, have been studied using Pavlovian fear conditioning in laboratory rodents as well as humans. These studies have established the amygdala as a key player in the circuits that process fear and led to a model where fear learning results from long-term potentiation of inputs that convey information about the conditioned stimulus to the amygdala. In this review, we describe the circuits in the basolateral amygdala that mediate fear learning and its expression as the conditioned response. We argue that while the evidence linking synaptic plasticity in the basolateral amygdala to fear learning is strong, there is still no mechanism that fully explains the changes that underpin fear conditioning.

A series of acid hydrolysis lignin-g-poly-(acrylic acid) (AHL-g-PAA) composites was prepared by grafting acid hydrolysis lignin on the surface of the polyacrylic acid network. The results of structure analysis revealed that AHL-g-PAA had been grafted. The surface morphologies of the hydrogels were improved, as shown by scanning electron microscopy observation. The AHL-g-PAA hydrogel had high water absorption and it possessed sensitivity to external pH stimulus. This study also revealed that the adsorption capacity of AHL-g-PAA was 235 mg/g for Pb(II) ions. The adsorption kinetics data could be described by the pseudo-second-order model, and the adsorption isotherm agrees well with the Langmuir model.

For the controlled release of pesticides, a novel composite porous hydrogel (LBPAA) was prepared based on lignin and polyacrylic acid for use as the support frame of a pore structure for water delivery. The LBPAA was analyzed to determine its water-swelling and slow release properties. The controlled release properties of LBPAA were evaluated through experiments in relation to the cumulative release of pesticides, with particular emphasis on environmental effects and release models. The porous LBPAA hydrogel showed improved properties compared to polyacrylic acid, and could therefore be considered an efficient material for application in controlled release systems in agriculture.

Background. To analyze the therapeutic effects of corneal debridement combined with intrastromal voriconazole in recalcitrant fungal keratitis. Methods. This is a retrospective study. Fourteen patients with recalcitrant fungal keratitis were treated by corneal debridement combined with intrastromal voriconazole (50 μg/0.1 ml). This paper reviews and analyzes the patients’ basic state, surgical intervention, medicinal treatment, and outcomes. Results. The mean sizes of infiltration and ulcer were (5.54 ± 1.32)mm and (3.46 ± 1.03)mm, respectively, and the mean depth was (315.43 ± 57.72)μm. Twelve of the patients had satellite lesion, and 2 suffered hypopyon. After intrastromal voriconazole, the size of infiltration decreased significantly to (4.32 ± 1.10)mm (P

Near-field ultrasonic phased array theory is researched and utilized in the carbon-fiber wing box to identify the damage in the structure. Near-field ultrasonic phased array based structural health monitoring is researched to overcome the limitation of the far-field ultrasonic phased array in monitoring scope. The time delay of the theory and the process of the damage identification method are researched in detail. The recognition result is shown in a mapped image. The proposed method is applied in carbon fiber-reinforced polymer (CFRP) wing box to monitor the load in the structure. The experimental results show that the near-field ultrasonic phased array based structural health monitoring method is effective to identify the load position in the structure.