Search

Abstract Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

Abstract Immunotherapy, particularly with immune checkpoint inhibitors, has significantly transformed cancer treatment. Despite its success, many patients struggle to respond adequately or sustain long‐lasting clinical improvement. A growing consensus has emerged that radiotherapy (RT) enhances the response rate and overall efficacy of immunotherapy. Although combining RT and immunotherapy has been extensively investigated in preclinical models and has shown promising results, establishing itself as a dynamic and thriving area of research, clinical evidence for this combination strategy over the past five years has shown both positive and disappointing results, suggesting the need for a more nuanced understanding. This review provides a balanced and updated analysis of the combination of immunotherapy and RT. We summarized the preclinical mechanisms through which RT boosts antitumor immune responses and mainly focused on the outcomes of recently updated clinical trials, including those that may not have met expectations. We investigated the optimization of the therapeutic potential of this combined strategy, including key challenges, such as fractionation and scheduling, lymph node irradiation, and toxicity. Finally, we offered insights into the prospects and challenges associated with the clinical translation of this combination therapy, providing a realistic perspective on the current state of research and potential future directions.

Abstract Background 5-fluorouracil (5-FU) is conventionally used in chemotherapy for colon adenocarcinomas. Acquired resistance of 5-FU remains a clinical challenge in colon cancer, and efforts to develop targeted agents to reduce resistance have not yielded success. Protosappanin B (PSB), the main component of Lignum Sappan extract, is known to exhibit anti-tumor effects. However, whether and how PSB could improve 5-FU resistance in colon cancer have not yet been established. In this study, we aimed to explore the effects and underlying mechanisms of PSB in 5-FU-induced chemoresistance in colon adenocarcinoma. Methods Forty-seven paired colon cancer tissue samples from patients who received 5-FU chemotherapy were collected as clinical samples. Two 5-FU resistant colon cancer cell lines were established for in vitro experiments. Reverse transcription-quantitative PCR (RT-qPCR) was performed to determine the mRNA and microRNA (miRNA) expression levels in colon adenocarcinoma tissues and cell lines. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were performed to evaluate cell proliferation and apoptosis, respectively. Results LINC00612 was highly expressed in colon adenocarcinoma samples and 5-FU resistant colon cancer cells. LINC00612 knockdown enhances 5-FU chemosensitivity in 5-FU resistant cells. Notably, PSB treatment attenuated LINC00612 expression in 5-FU resistant colon adenocarcinoma cells. Moreover, PSB treatment reversed the increase in LINC00612-induced 5-FU resistance. Mechanistically, LINC00612 specifically bound to miR-590-3p, which promoted 5-FU resistance in colon adenocarcinoma cells and attenuated the inhibitory effect of LINC00612 on GOLPH3 expression. Conclusion PSB attenuates 5-FU chemoresistance in colon adenocarcinoma by regulating the LINC00612/miRNA-590-3p/GOLPH3 axis. Graphical Abstract

Background: Gastric cancer is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Triphenyl phosphate (TPP) is a prevalent flame retardant, but its health implications remain to be thoroughly understood. Objective: To explore the link between TPP exposure and gastric cancer by examining gene expression patterns and developing a predictive model. Methods: Gene expression data were sourced from The Cancer Genome Atlas (TCGA) and the Comparative Toxicogenomics Database (CTD). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were employed for analysis. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to obtain phosphate flame retardant-related scores. A predictive model was constructed through differential analysis, univariate COX regression, and LASSO regression. Molecular docking was performed to assess protein interactions with TPP. Results: ssGSEA identified scores related to phosphate flame retardants in gastric cancer, which had a strong association with immune-related traits. Several genes associated with TPP were identified and used to develop a prognostic model that has clinical significance. Molecular docking showed a high binding affinity of TPP with MTTP, a gene related to lipid metabolism. Pathway analysis indicated that TPP exposure contributes to gastric cancer through lipid metabolic processes. Conclusion: The study establishes a potential correlation between TPP exposure and gastric cancer onset, pinpointing key genes and pathways involved. This underscores the significance of environmental factors in gastric cancer research and presents a potential diagnostic tool for clinical application.

The aim of this study is to address the issue of difficulty in evaluating the combined sewer overflow (CSO) pollution effectively, especially for the monitoring of overflow from non-standard thin-plate weirs (NTPWs). In order to construct a discharge calculation mathematical model (DCMM) of NTPWs in an urban combined sewer overflow system (UCSOS), which can be used to construct a real-time monitoring and early warning system, a physical model constructed firstly for obtaining hydraulic characteristic sets under three flow conditions (free, submerged, pressurized flow). Then, the coefficient function expressions are obtained under three flow conditions through genetic algorithm (GA) fitting, and a DCMM of UCSOS is established subsequently. The results indicate that DCMM exhibits high accuracy, with mean relative error (MRE) at 0.0326, root mean square error (RMSE) at 1.569, and Nash–Sutcliffe efficiency (NSE) coefficient at 0.9387. The DCMM can not only evaluate the discharge capacity under different flow conditions, but also be used to realize reliable and convenient discharge monitoring. Although the DCMM constructed in this case is not universal, the modeling method of combining physical models with GA is an effective new approach to evaluate the discharge capacity of NTPW, which also holds value for application in other cities. HIGHLIGHTS We obtained data by conducting physical model experiments and used GA algorithm to fit expressions of the coefficient function under three flow conditions respectively to constructed the DCMM.; The DCMM can not only evaluate the discharge capacity under different flow conditions, but also be used to realize reliable and convenient discharge monitoring for NTPWs.; A real-time monitoring and early warning system based on the DCMM is constructed to meets the issue of difficulty in evaluating the combined sewer overflow pollution.;

Abstract Background S100A8 and S100A9 are members of Ca2+-binding EF-hand superfamily, mainly expressed by macrophages and neutrophils. Limited by the poor stability of homodimers, they commonly exist as heterodimers. Beyond acting as antibacterial cytokines, S100A8/A9 is also associated with metabolic and autoimmune diseases such as obesity, diabetes, and rheumatoid arthritis. While the involvement of S100A8/A9 in breast cancer development has been documented, its prognostic significance and the precise regulatory mechanisms remain unclear. Methods S100A8/A9 protein in breast cancer samples was evaluated by immunohistochemistry staining with tumor tissue microarrays. The serum S100A8 concentration in patients was measured by enzyme-linked immunosorbent assay (ELISA). The S100A8 secreted by breast cancer cells was detected by ELISA as well. Pooled analyses were conducted to explore the relationships between S100A8/A9 mRNA level and clinicopathological features of breast cancer patients. Besides, the effects of S100A8/A9 and DACH1 on patient outcomes were analyzed by tissue assays. Finally, xenograft tumor assays were adopted to validate the effects of DACH1 on tumor growth and S100A8/A9 expression. Results The level of S100A8/A9 was higher in breast cancer, relative to normal tissue. Increased S100A8/A9 was related to poor differentiation grade, loss of hormone receptors, and Her2 positive. Moreover, elevated S100A8/A9 predicted a worse prognosis for breast cancer patients. Meanwhile, serum S100A8 concentration was upregulated in Grade 3, basal-like, and Her2-overexpressed subtypes. Additionally, the results of public databases showed S100A8/A9 mRNA level was negatively correlated to DACH1. Stable overexpressing DACH1 in breast cancer cells significantly decreased the generation of S100A8. The survival analysis demonstrated that patients with high S100A8/A9 and low DACH1 achieved the shortest overall survival. The xenograft models indicated that DACH1 expression significantly retarded tumor growth and downregulated S100A8/A9 protein abundance. Conclusion S100A8/A9 is remarkedly increased in basal-like and Her2-overexpressed subtypes, predicting poor prognosis of breast cancer patients. Tumor suppressor DACH1 inhibits S100A8/A9 expression. The combination of S100A8/A9 and DACH1 predicted the overall survival of breast cancer patients more preciously.

BackgroundThe interaction between environmental endocrine-disrupting chemicals, such as Bisphenol A (BPA), and their influence on cancer progression, particularly regarding the GOLPH3 gene in colorectal cancer, remains unclear.MethodsWe performed an integrated analysis of transcriptional profiling, clinical data, and bioinformatics analyses utilizing data from the Comparative Toxicogenomics Database and The Cancer Genome Atlas. The study employed ClueGO, Gene Set Enrichment Analysis, and Gene Set Variation Analysis for functional enrichment analysis, alongside experimental assays to examine the effects of BPA exposure on colorectal cancer cell lines, focusing on GOLPH3 expression and its implications for cancer progression.ResultsOur findings demonstrated that BPA exposure significantly promoted the progression of colorectal cancer by upregulating GOLPH3, which in turn enhanced the malignant phenotype of colorectal cancer cells. Comparative analysis revealed elevated GOLPH3 protein levels in cancerous tissues versus normal tissues, with single-cell analysis indicating widespread GOLPH3 presence across various cell types in the cancer microenvironment. GOLPH3 was also associated with multiple carcinogenic pathways, including the G2M checkpoint. Furthermore, our investigation into the colorectal cancer microenvironment and genomic mutation signature underscored the oncogenic potential of GOLPH3, exacerbated by BPA exposure.ConclusionThis study provides novel insights into the complex interactions between BPA exposure and GOLPH3 in the context of colorectal cancer, emphasizing the need for heightened awareness and measures to mitigate BPA exposure risks. Our findings advocate for further research to validate these observations in clinical and epidemiological settings and explore potential therapeutic targets within these pathways.

BackgroundCervical cancer poses a significant global threat to women’s health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of the disease. Given the immunosuppressive microenvironment in cervical cancer, it is imperative to explore novel perspectives. In this regard, STING agonists have emerged as promising candidates.MethodsThe expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Prognostic analysis of STING downstream genes (CCL5, CXCL9, CXCL10) and immune infiltration analysis were conducted using Kaplan-Meier Plotter, ESTIMATE, and deconvo_CIBERSOR. Single-cell RNA-seq (scRNA-seq) analysis was conducted to evaluate the potential of MSA-2 in cervical cancer treatment employing SingleR, chi-squared test, and Gene Set Enrichment Analysis (GSEA). Cellular interaction analysis utilized the CellChat package to assess the potentiation of cellular interaction following MSA-2 administration. Murine tumor models involving U14 and TC-1, were conducted, and the IF of tissue was subsequently conducted to assess the tumor microenvironment status after treatment.ResultsPrognosis in cervical cancer correlated with elevated expression of STING downstream genes, indicating prolonged survival and reduced recurrence. These genes positively correlated with immune infiltration, influencing stromal scores, immune scores, and estimate scores. Specific immune cell populations, including CD8+ T cells, M1-type macrophages, NK cells, and T follicular helper cells, were associated with STING downstream genes. scRNA-seq in a classic immune-excluded model revealed that MSA-2 exerts priming and activating functions on vital components within TME, and intensifies their intercellular communications. The in vivo assay ultimately demonstrated that MSA-2, either as a standalone treatment or in combination with anti-PD-1, effectively suppressed the growth of subcutaneous cervical tumors. Moreover, the combination strategy significantly augmented efficacy compared to anti-PD-1 monotherapy by eliciting a robust antitumor immune response.ConclusionThis study highlights the pivotal role of the STING pathway and the potential of MSA-2 in reshaping the immune microenvironment in cervical cancer. Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

Abstract Background Oxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora. Methods In this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora’s role in HGWD for chronic OIPN by pain scoring and related pathological analysis. Results HGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis. Conclusions HGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.

Abstract Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, negatively expresses estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is the main form of treatment for patients with TNBC, the effectiveness of chemotherapy for TNBC is still limited. The search for more effective therapies is urgent. Multiple targeted therapeutic strategies have emerged according to the specific molecules and signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, epidermal growth factor receptor inhibitors, Notch inhibitors, poly ADP-ribose polymerase inhibitors, and antibody–drug conjugates. Moreover, immune checkpoint inhibitors, for example, pembrolizumab, atezolizumab, and durvalumab, are widely explored in the clinic. We summarize recent advances in targeted therapy and immunotherapy in TNBC, with the aim of serving as a reference for the development of individualized treatment of patients with TNBC in the future.

Abstract Background Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance. Methods We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment. Results Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity. Conclusion Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.

Dietary factors play a crucial role in irritable bowel syndrome (IBS) pathogenesis. Therefore, the dietary contraindications for patients with IBS require further supplementation. Recent investigations have revealed that ginger consumption may pose a risk of aggravating the symptoms and incidence of IBS; however, the specific mechanism remains unknown. In this study, we developed experimental IBS and intestinal organoid differentiation screening models to elucidate the mechanisms underlying the ginger-mediated exacerbation of IBS symptoms. Subsequently, we used a knockout approach combined with click chemistry as well as virus infection to identify the toxic components of ginger and the target mechanism. Our results showed that a daily intake of 90 to 300 mg/kg ginger (equivalent to a human daily dose of 0.6 to 2 g per person) may pose a risk of exacerbating IBS symptoms. Furthermore, a component derived from 6-gingerol (ginger’s main ingredient) through in vivo gastric acid and heat processing inhibited the formation of the eIF3 transcription initiation complex by covalently binding to the Cys58 site of eIF3A, a key factor regulating intestinal crypt stem cell differentiation, further reducing the goblet cell number and related mucus layer thickness and increasing lipopolysaccharide infiltration and low-grade inflammation in the ileum crypts, thereby exacerbating the symptoms of IBS in mice. Our study suggests that dietary ginger aggravates IBS and provides safety evaluation methods for the proper use of foods in specific populations.

The unique climate, topography and soil conditions of Anhui Province in China are the main causes of drought, which is one of the limiting factors of economic and social development. Characterized by low data requirement, strong operability and flexibility, the conventional ‘assessment based on comprehensive index’ (ACI) is used to assess the drought risk, the index obtained by which can only represent the relative risk level among the objects and has no spatiotemporal characteristic. Therefore, a new method based on the iterative transformation of spatiotemporal vector (DRST) is proposed to solve this defect. The main conclusions are as follows: (1) The drought risk matrices obtained by DRS and DRT cannot quantify the drought risk level of subregions in each year absolutely. (2) The drought risk values obtained by DRST can be used to compare the drought risk from temporal and spatial dimensions at the same time, and both the drought-affected regions and the drought risk level are consistent with the statistical data. The new method expands the subsequent utilization space of the ‘assessment index’. For example, the allocation of drought-resistant resources (water resources, drought-resistant funds, etc.) can be determined according to these indexes. HIGHLIGHTS The conventional ‘assessment of comprehensive index’ method can only represent the relative risk level among the objects.; The drought risk based on the iterative transformation of ‘spatiotemporal vector’ (new method) can be compared from temporal and spatial dimensions at the same time.; The new method expands the subsequent utilization space of the ‘assessment index’.;

Abstract Breast cancer is the most common malignancy and the second leading cause of cancer-related death in women. Recent studies have indicated that aberrant activation of Rho GTPases relates to the malignant properties of breast cancer cells. As the guanine nucleotide exchange factor of Rho GTPases, the role of ECT2 (epithelial cell transforming 2) in breast cancer is still unclear. Tissue microarrays and multiple public databases were utilized to investigate the relationship between ECT2 level and clinical-pathological features of breast cancer patients. Kaplan Meier-plotter online tool and tissue microarray with survival information were used to investigate the predictive value for breast cancer. Here, we found increased ECT2 level was highly associated with advanced TNM stage, poor differentiation, and loss of hormone receptors of breast cancer. Gene expression profile showed that ECT2 level was closely correlated to cell-proliferation-associated pathways. Integration analysis using public databases and tissue microarray indicated that high ECT2 was an adverse prognostic factor for breast cancer patients. We believe the ECT2 level might be a valuable complement for commercially available predictors such as the 21 genes test. Furthermore, ECT2 would be a novel target for drug development for breast cancer.

Abstract Background Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance. Methods The dose-dependent effect of MSA-2 on STING signaling was determined by interferon-β level. The maturation and function of dendritic cell (DC) were measured by flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, and cytokine/chemokine detection. The synergistic effect between MSA-2 and YM101 was assessed by one-way MLR. The macrophage activation was measured by flow cytometry and cytokine/chemokine detection. The in vivo antitumor activity of MSA-2 combined with YM101 was explored in syngeneic murine tumor models. After treatments, the alterations in the tumor microenvironment (TME) were detected by flow cytometry, immunohistochemistry staining, immunofluorescence staining, RNA-seq, and single-cell RNA-seq (scRNA-seq). Results MSA-2 could promote the maturation and antigen presentation capability of murine DC. In the one-way MLR assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the TME. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes. Conclusion Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.

Abstract The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs.

In this study, the CrCoNi medium-entropy alloys (MEA) were processed by asymmetric rolling (298 K) and asymmetric cryorolling (ACR) (173 K and 83 K), respectively. During the rolling process, as the strain increased (from 50% to 80% reduction), the dislocation distribution inhomogeneity intensified. Meanwhile, the variation of twinning in different systems was more prominent. The cryogenic temperature promoted the inhomogeneity of the structure in the CrCoNi MEA, allowing dislocation cells and dislocation tangling zones to generate at lower strains. And the twinning susceptibility to temperature was more notable than that to strain. Secondary twins, and high-density stacking faults were found in the 173 K ACR CrCoNi MEA at low strain. And tertiary twins were found in the 83 K ACR CrCoNi MEA. It can be found from the experimental results that the improvement effect of the cryogenic environment during rolling on the mechanical properties of the CrCoNi MEA was greater than that of the increase in reduction (50%–80%). Asymmetric cryorolling shows a more efficient strengthening influence on CrCoNi MEA subjected to smaller deformation.

Due to the different design standards of urban drainage and water conservancy facilities, numerous coordination and linkage issues arise when confronting extreme rainfall. In this paper, three clustering methods were used to cluster rainfall events, and the results demonstrate that the dynamic time warping-hierarchical clustering algorithm (DTW-HCA) effectively captures the temporal similarity of time series. Then, the Pilgrim and Cordery rainfall distribution method was utilized to extract the characteristics of eight clusters of rainfall events, and eight kinds of rainfall patterns were obtained. Last, after importing the rainfall patterns into the MIKE model of Qingshan Lake to conduct flood simulations, the impacts of different rainfall patterns on municipal systems and water conservancy systems were assessed by the depth and area of urban waterlogging, as well as the water levels and discharge of rivers. Based on this, three rainfall patterns are proposed as a designed rainfall pattern (DRP), an extreme rainfall pattern for urban drainage facilities verification (ERPUDFV) and an extreme rainfall pattern for water conservancy facilities verification (ERPWCFV), which aim to provide a reference basis for designing region-specific extreme rainfall patterns, as well as the verification of urban drainage and water conservancy facilities.

We measure electron transport through point contacts in an electron gas in AlGaAs/GaAs heterostructures and graphene for a range of temperatures, magnetic fields, and electron densities. We find a magnetoconductance peak around B=0. With increasing temperature, the width of the peak increases monotonically, while its amplitude first increases and then decreases. For GaAs point contacts the peak is particularly sharp at relatively low temperatures T≈1.5K: the curve rounds on a scale of a few tens of microteslas, hinting at length scales of several millimeters for the corresponding scattering processes. We propose a model based on the transition between different transport regimes with increasing temperature: from ballistic transport to few electron-electron scatterings to hydrodynamic superballistic flow to hydrodynamic Poiseuille-like flow. The model is in qualitative and, in many cases, quantitative agreement with the experimental observations.

Aiming at the problem that the change of motor parameters in actual operation will significantly reduce the control accuracy of the motor, this paper proposes a sensorless control method of permanent magnet synchronous motor based on an adaptive back-EMF observer. Firstly, in the sensorless vector control algorithm, the mathematical model of the permanent magnet synchronous motor based on the coordinate axis transformation is established, online identification of permanent magnet synchronous motor flux linkage, and the adaptive back EMF observer is constructed. The parameters update the motor model to achieve accurate control of the rotor position and speed of the permanent magnet synchronous motor. Then the back-EMF observer and the adaptive back-EMF observer are verified in the simulation environment. Then the simulation model of the back-EMF observer and the adaptive back-EMF observer is carried out, and the comparison analysis is made. Finally, a permanent magnet synchronous motor control platform is built in the laboratory, and the method proposed in this paper is verified. The results show that, under the condition that the permanent magnet synchronous motor parameters change, the online identification of the parameters and the accurate speed of the permanent magnet synchronous motor can be realized control.

Abstract Cancer immunotherapy has made remarkable progress in the past decade. Bispecific antibodies (BsAbs) have acquired much attention as the next generation strategy of antibody-target cancer immunotherapy, which overwhelmingly focus on T cell recruitment and dual receptors blockade. So far, BsAb drugs have been proved clinically effective and approved for the treatment of hematologic malignancies, but no BsAb have been approved in solid tumors. Numerous designed BsAb drugs for solid tumors are now undergoing evaluation in clinical trials. In this review, we will introduce the formats of bispecific antibodies, and then update the latest preclinical studies and clinical trials in solid tumors of BsAbs targeting EpCAM, CEA, PMSA, ErbB family, and so on. Finally, we discuss the BsAb-related adverse effects and the alternative strategy for future study.

Abstract Macrophages are heterogeneous cells that present as different functional phenotypes due to their plasticity. They can be classified into two categories, namely M1- and M2-like macrophages, which are involved in processes as diverse as anti-tumor activity and immunosuppressive tumor promotion. Tumor-associated macrophages (TAMs) are defined as being of an M2-type and are considered as the active component in tumor microenvironment. TAMs are involved in multiple processes of tumor progression through the expression of cytokines, chemokines, growth factors, protein hydrolases and more, which lead to enhance tumor cell proliferation, angiogenesis, and immunosuppression, which in turn supports invasion and metastasis. It is assumed that the abundance of TAMs in major solid tumors is correlated to a negative patient prognosis. Because of the currently available data of the TAMs’ role in tumor development, these cells have emerged as a promising target for novel cancer treatment strategies. In this paper, we will briefly describe the origins and types of TAMs and will try to comprehensively show how TAMs contribute to tumorigenesis and disease progression. Finally, we will present the main TAM-based therapeutic strategies currently available.

Transforming growth factor-β (TGF-β) signaling regulates multiple physiological processes, such as cell proliferation, differentiation, immune homeostasis, and wound healing. Besides, TGF-β plays a vital role in diseases, including cancer. Accumulating evidence indicates that TGF-β controls the composition and behavior of immune components in the tumor microenvironment (TME). Advanced cancers leverage TGF-β to reshape the TME and escape immune surveillance. TGF-β-mediated immune evasion is an unfavorable factor for cancer immunotherapy, especially immune checkpoint inhibitors (ICI). Numerous preclinical and clinical studies have demonstrated that hyperactive TGF-β signaling is closely associated with ICI resistance. It has been validated that TGF-β blockade synergizes with ICI and overcomes treatment resistance. TGF-β-targeted therapies, including trap and bispecific antibodies, have shown immense potential for cancer immunotherapy. In this review, we summarized the predictive value of TGF-β signaling and the prospects of TGF-β-targeted therapies for cancer immunotherapy.

Background Agents blocking programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have been approved for triple-negative breast cancer (TNBC). However, the response rate of anti-PD-1/PD-L1 is still unsatisfactory, partly due to immunosuppressive factors such as transforming growth factor-beta (TGF-β). In our previous pilot study, the bispecific antibody targeting TGF-β and murine PD-L1 (termed YM101) showed potent antitumor effect. In this work, we constructed a bispecific antibody targeting TGF-β and human PD-L1 (termed BiTP) and explored the antitumor effect of BiTP in TNBC.Methods BiTP was developed using Check-BODYTM bispecific platform. The binding affinity of BiTP was measured by surface plasmon resonance, ELISA, and flow cytometry. The bioactivity was assessed by Smad and NFAT luciferase reporter assays, immunofluorescence, western blotting, and superantigen stimulation assays. The antitumor activity of BiTP was explored in humanized epithelial-mesenchymal transition-6-hPDL1 and 4T1-hPDL1 murine TNBC models. Immunohistochemical staining, flow cytometry, and bulk RNA-seq were used to investigate the effect of BiTP on immune cell infiltration.Results BiTP exhibited high binding affinity to dual targets. In vitro experiments verified that BiTP effectively counteracted TGF-β-Smad and PD-L1-PD-1-NFAT signaling. In vivo animal experiments demonstrated that BiTP had superior antitumor activity relative to anti-PD-L1 and anti-TGF-β monotherapy. Mechanistically, BiTP decreased collagen deposition, enhanced CD8+ T cell penetration, and increased tumor-infiltrating lymphocytes. This improved tumor microenvironment contributed to the potent antitumor activity of BiTP.Conclusion BiTP retains parent antibodies’ binding affinity and bioactivity, with superior antitumor activity to parent antibodies in TNBC. Our data suggest that BiTP might be a promising agent for TNBC treatment.

Fish in natural and cultivated environments can be challenged by starvation. However, inducing starvation in a controlled manner cannot only reduce feed consumption but also reduces aquatic eutrophication and even improves farmed fish quality. This study investigated the effects of starvation on the muscular function, morphology, and regulatory signaling in javelin goby (Synechogobius hasta) by evaluating the biochemical, histological, antioxidant, and transcriptional changes in the musculature of S. hasta subjected to 3, 7, and 14 days fasting. The muscle glycogen and triglyceride levels in S. hasta were gradually reduced under starvation, reaching their lowest at the end of the trial (P

We consider the symmetric difference of two graphs on the same vertex set [n], which is the graph on [n] whose edge set consists of all edges that belong to exactly one of the two graphs. Let F be a class of graphs, and let MF(n) denote the maximum possible cardinality of a family G of graphs on [n] such that the symmetric difference of any two members in G belongs to F. These concepts have been recently investigated by Alon et al. [SIAM J. Discrete Math., 37 (2023), pp. 379-403] with the aim of providing a new graphic approach to coding theory. In particular, MF(n) denotes the maximum possible size of this code. Existing results show that as the graph class F changes, MF(n) can vary from n to 2(1+0(1))(2n). We study several phase transition problems related to MF(n) in general settings and present a partial solution to a recent problem posed by Alon et al. [ABSTRACT FROM AUTHOR]

Aluminum matrix composites (AMCs) reinforced by 1.5 and 3 wt% FeCoCrNi high-entropy alloy particles (HEAp) were obtained by a stir casting process. The AMCs strip was further prepared by room temperature rolling (RTR, 298 K) and cryorolling (CR, 77 K). The mechanical properties of the AMCs produced by RTR and CR were studied. The effect of a microstructure on mechanical properties of composites was analyzed by scanning electron microscopy (SEM). The results show that CR can greatly improve the mechanical properties of the HEAp/AMCs. Under 30% rolling reduction, the ultimate tensile strength (UTS) of the RTR 1.5 wt% HEAp/AMCs was 120.3 MPa, but it increased to 139.7 MPa in CR composites. Due to the volume shrinkage effect, the bonding ability of CR HEAp/AMCs reinforcement with Al matrix was stronger, exhibiting higher mechanical properties.

In this paper, a novel tunable DBR laser based on novel cascaded gratings is proposed for chirp management in high-speed direct modulation applications. The cascaded gratings, i.e., a tilted π phase-shift grating followed by a normal uniform Bragg grating, can provide a narrow-band reflection spectrum with a sharp falling slope on the longer wavelength side, so that the optical spectrum shaping and the detuned-loading effects can be enhanced. Simulation results indicate that the wavelength tuning range of the laser is about 10 nm and the 3-dB modulation bandwidth reaches up to 25 GHz. By simply adjusting the phase current and thus changing the detuned frequency, the extinction ratio and the frequency chirp can be optimized, which is helpful to improve the dispersion tolerance and reduce the dispersion power penalty.

High-purity (99.999%) nickel with lamellar-structure grains (LG) was obtained by room-temperature rolling and cryorolling in this research, and then annealed at different temperatures (75 °C, 160 °C, and 245 °C). The microstructure was characterized by transmission electron microscopy. The grain growth mechanism during annealing of the LG materials obtained via different processes was studied. Results showed that the LG high-purity nickel obtained by room-temperature rolling had a static discontinuous recrystallization during annealing, whereas that obtained by cryorolling underwent static and continuous recrystallization during annealing, which was caused by the seriously inhibited dislocation recovery in the rolling process under cryogenic conditions, leading to more accumulated deformation energy storage in sheets.

As a newly identified manganese transport protein, ZIP14 is highly expressed in the small intestine and liver, which are the two principal organs involved in regulating systemic manganese homeostasis. Loss of ZIP14 function leads to manganese overload in both humans and mice. Excess manganese in the body primarily affects the central nervous system, resulting in irreversible neurological disorders. Therefore, to prevent the onset of brain manganese accumulation becomes critical. In this study, we used Zip14−/− mice as a model for ZIP14 deficiency and discovered that these mice were born without manganese loading in the brain, but started to hyper-accumulate manganese within 3 weeks after birth. We demonstrated that decreasing manganese intake in Zip14−/− mice was effective in preventing manganese overload that typically occurs in these animals. Our results provide important insight into future studies that are targeted to reduce the onset of manganese accumulation associated with ZIP14 dysfunction in humans.

ZIP8 is a newly identified metal transporter. In human patients, mutations in ZIP8 result in severe manganese deficiency, suggesting a critical role for ZIP8 in regulating systemic manganese homeostasis. In mice, the deletion of ZIP8 recapitulates the symptoms of patients with ZIP8 mutations. However, further studies using mouse models to examine ZIP8′s function were hindered by the lack of suitable antibodies to detect endogenous ZIP8 protein. In this study, we report the design, generation, and validation of a polyclonal antibody against mouse ZIP8. We have demonstrated that the newly generated antibody can be reliably used in immunoblotting analysis to detect endogenous ZIP8 protein in mouse tissues. The successful generation and validation of anti-mouse ZIP8 antibody provide opportunities to further examine the function and regulation of this metal transporter. In addition, our study may provide valuable insights into the future development of antibodies targeting polytopic membrane proteins.

CoCrNi equiatomic medium entropy alloy sheets were prepared by asymmetric rolling, cryorolling, and asymmetric cryorolling. The asymmetric cryorolled samples exhibited a noteworthy ultra-fine-grain heterogeneous lamella structure. The microstructure and corresponding hardness obtained by different rolling processes and subsequent annealing are compared. It can be seen from the results that the cryogenic deformation temperature had a stronger effect on the mechanical properties of the medium entropy alloys (MEA), compared with the shear strain caused by the asymmetric cryorolling. The effect of annealing temperature on texture components and volume fractions of the specially rolled samples was also analyzed. The result revealed that the recrystallized MEA exhibited similar texture components and the corresponding volume fraction, which indicated that the rolling process had limited influence on the formation of annealing texture. The recrystallized texture after annealing retained the deformation texture and twin related orientations appeared. Asymmetric rolled MEA showed strong random composition than symmetric rolled MEA regardless of rolling temperature. The recrystallized textures of the species obtained by the three rolling processes did not exhibit a significant dependence on the annealing temperature.

The metal transporters ZIP14 and ZnT10 play key physiological roles in maintaining manganese (Mn) homeostasis. However, in vivo regulation of these two transporters by Mn is not understood. Here, we examined how dietary Mn intake regulates ZIP14 and ZnT10 by feeding mice a low-Mn diet, a control diet, or a high-Mn diet for 6 weeks. Inductively coupled plasma mass spectrometry was used to measure Mn and iron (Fe) levels. ZIP14 and ZnT10 protein levels were measured by western blot analysis. While mice on the high-Mn diet exhibited significantly higher levels of Mn in the blood, liver, and brain, the low-Mn diet group did not display matching reductions, indicating that high Mn intake is more effective in disrupting Mn homeostasis in mice. Additionally, Fe levels were only slightly altered, suggesting independent transport mechanisms for Mn and Fe. In the high-Mn diet group, ZIP14 and ZnT10 were both upregulated in the liver, as well as in the small intestine, indicating a coordinated role for these transporters in Mn excretion. Unexpectedly, this upregulation only occurred in male mice, with the exception of hepatic ZIP14, providing new insight into mechanisms behind widely observed sex differences in Mn homeostasis.