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BackgroundImproving system coordination is a pivotal strategy and a critical pathway for social governance. Chinese society is currently facing a significant challenge in aligning the allocation of health resources with economic development. Evaluating the level of coordinated development within the system can provide valuable insights to support the construction of a more coordinated China and foster high-quality development.MethodsBased on a systematically constructed indicator framework, our study selected data from five eastern provinces of China to establish a ten-year panel dataset covering the period from 2011 to 2020. The comprehensive evaluation index and the relative development degree were employed to comprehensively evaluate the development level of the system. The coupling coordination degree model was applied to analyze the coupling coordination relationship and spatiotemporal evolution trend of the two systems. Additionally, the fixed effects model was used to identify the driving factors behind the coordinated development of the two systems.ResultsFrom 2011 to 2020, the comprehensive indices of health resource allocation and economic development in the five eastern provinces of China exhibited a consistent year-on-year increase, and the relative development degree experienced two critical values of 0.8 and 1.2, which changed from the lagging allocation of health resources to the lagging economic development. The system coordination index generally ranged between 0.35 and 0.90, with the coordination phase undergoing a transition from an antagonistic stage to a coordinated stage. The coordination type also gradually shifted from mild imbalance to good coordination. Furthermore, the levels of economic development, economic structure, technological investment, as well as the allocation of health human and material resources, all serve as critical drivers in enhancing the coordinated development of the system.ConclusionThe coordinated development of eastern China’s provinces produces substantial spillover effects, and the realization of a Healthy China initiative must strategically harness their radiative and demonstrative effects. Achieving a superior level of coordination requires urgent efforts to rectify the existing deficiencies in the distribution of grassroots healthcare resources. Furthermore, cultivating innovative drivers of economic growth and enhancing the capacity for economic support are critical to ensuring high-quality and sustainable development.

BackgroundSystem coordination is an effective way to achieve high-quality development, and the debate on the interaction between health investment and economic development is still ongoing. To strengthen previous research and offer feasible advice and references for relevant stakeholders, we provide empirical evidence for exploring intersystem coordination and enhancement pathways using data from China.MethodsBased on the data published by the National Bureau of Statistics of China, the current status of the interaction and coordination between health investment and economic development in China was measured by calculating the comprehensive evaluation index, relative development degree, and coupling coordination degree. Subsequently, a fuzzy-set qualitative comparative analysis method was introduced to explore pathways for enhancing system interaction and coordination.ResultsThere are obvious inter-provincial and regional differences between health investment and economic development in China. Provinces in the west and north are lagging in economic development, while provinces in the east and south are lagging in health investment. There is a clear synergy between health investment and economic development, and there is still much room for improving the degree of coupling coordination between systems. The five conditional configurations derived from the fuzzy-set qualitative comparative analysis yield three pathways for enhancing system coordination: a health expenditure-driven path, an economic development-driven path, and a balanced health investment and economic development-driven path.ConclusionHealth expenditure is sufficient for high coordination, and the level and equity of investment in health expenditure should be improved. The gross regional product is a necessary and sufficient condition for high coordination, and consideration must be given to strengthening the regional economic support capacity. Health investment and economic development can drive the coordinated development of the system in a balanced way. This enlightens us to give full play to the positive synergy between health investment and economic development based on promoting the benign interaction of subsystems.

Background Interleukin-18 (IL-18), or interferon (IFN)-γ-inducing factor, potentiates T helper 1 and natural killer cell activation as well as CD8+ T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part due to the expression of the decoy receptor, IL-18 binding protein (IL-18BP). A series of IL-18 variants that are devoid of IL-18BP binding, termed DR18 (decoy-resistant IL-18), was developed via directed evolution. We tested DR18 using oncolytic adenovirus (oAd) as a platform for delivery in syngeneic mouse tumor models.Methods oAd harboring wild-type IL-18 or DR18 (oAdDR18) was constructed by inserting IL-18 mutant into modified oAd backbone with Ad5/3 chimeric fiber. The delivery effect and IFN-γ induction were determined by ELISA. The antitumor efficiency of oAdDR18 was tested in CT26, B16BL6 and 4T1 tumor-bearing mice, or athymic nude mice and compared with recombinant DR18 protein (rDR18). 4T1 lung metastasis model was used to evaluate the antitumor efficiency of local and distant tumors. Antitumor memory and synergistic effect with an anti-programmed cell death protein-1 (PD-1) antibody was evaluated. The phenotypes of the immune cells in tumor microenvironment were analyzed by flow cytometry and immunohistochemistry.Results Mice received oAdDR18 maintained stable production of IL-18 and IFN-γ compared with those received rDR18. Intratumoral delivery of oAdDR18 significantly reduced tumor growth across several tumor models, but not in the athymic nude mouse model. Mice that had tumor remission showed antitumor memory. The antitumor effect was associated with intratumor infiltration of CD4+ and CD8+ T cells. DR18 delivered by oAd demonstrated long-lasting and enhanced antitumor activities against local and distant tumors compared with that received rDR18 or wild-type IL-18 delivered by oAd (oAdwtIL-18). oAdDR18 treatment also reduced 4T1 lung metastasis. In addition, combination of this virotherapy with immune checkpoint inhibitors (ICIs)like the anti-PD-1 antibody further enhanced the antitumor activity as compared with respective monotherapy.Conclusions oAdDR18 demonstrates enhanced antitumor activities through the induction of stronger local and system immunities and modulation of the tumor microenvironment compared with those of oAdwtIL-18 and rDR18. A combination of oncolytic virotherapy with cytokine engineering would lead to cytokine-based therapeutics for cancer and other diseases.

Both physiotherapy and medicine play essential roles in the treatment of epilepsy. The purpose of this research was to evaluate the efficacy of the combined therapy with focus ultrasound stimulation (FUS) and gastrodin (GTD) on seizures in a mouse model. Kainic acid-induced seizure mice were divided into five groups randomly: sham, FUS, saline + sham, GTD + sham and GTD + FUS. The results showed that combined therapy with ultrasound stimulation and gastrodin can significantly reduce the number and duration of seizures in GTD + FUS group. 9.4T magnetic resonance imaging and histologic staining results revealed the underlying mechanism of the combined therapy may be that ultrasound stimulation increases cell membrane permeability to increase GTD concentration in brain. In addition, we verified the safety of FUS combined with GTD therapy. This research provides a new strategy for neurological disorders combining treatment of physical neuromodulation and medicine.

Abstract Neuroinflammation is considered to be a significant mechanism contributing to depression. Several studies have reported that A1 astrocytes were highly prevalent in human neuroinflammatory and neurodegenerative diseases. However, the precise mechanism by which A1 astrocytes contribute to depression remains unclear. Clinical studies have suggested a correlation between TNF-α, an activator of A1 astrocytes, and the severity of depression. Based on these findings, we hypothesized that TNF-α might worsen depression by activating A1 astrocytes. Our previous studies indicated that Rhodomyrtone (Rho) has the potential to improve depression-like behavior in mice. However, the exact mechanism for this effect has not been fully elucidated. Importantly, it was reported that Rho alleviated skin inflammation in a mouse model of psoriasis by inhibiting the expression of TNF-α. Based on this finding, we hypothesized that rhodomyrtone may exert antidepressant effects by modulating the TNF-α pathway. However, further research is required to investigate and validate these hypotheses, shedding light on the relationships between neuroinflammation, A1 astrocytes, TNF-α, and depression. By obtaining a deeper understanding of the underlying mechanisms, these findings could lead to the development of novel antidepressant strategies that target the TNF-α pathway in the context of neuroinflammation. In vivo, based on the established chronic unpredictable mild stress (CUMS) mouse depression model, we characterized the mechanism of TNF-α and Rho during depression by using several behavioral assays, adeno-associated virus(AAV) transfection, western blotting, immunofluorescence, and other experimental methods. In vitro, we characterized the effect of Rho on inflammation in TNF-α-treated primary astrocytes. TNFR1 expression was significantly increased in the hippocampus of depression-like mice, with increased astrocytes activation and neuronal apoptosis. These processes were further enhanced with increasing levels of TNF-α in the cerebrospinal fluid of mice. However, this process was attenuated by knockdown of TNFR1 and infliximab (Inf; a TNF-α antagonist). Injection of rhodomyrtone decreased the expressions of TNFR1 and TNF-α, resulting in significant improvements in mouse depression-like behaviors and reduction of astrocyte activation. TNF-α could be involved in the pathophysiological process of depression, through mediating astrocytes activation by binding to TNFR1. By blocking this pathway, Rho may be a novel antidepressant.

Abstract Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Background Stroke is a significant global health issue, ranking as the second leading cause of death and the third leading cause of death and disability combined. This study aimed to examine the changes and differences in stroke burden from 1990 to 2019 in China and various global socio-demographic index (SDI) regions. Methods Data were obtained from the Global Burden of Diseases Study 2019, which included the incidence, prevalence, mortality, disability-adjusted life years (DALY), years of life with disability (YLD), and years of life lost (YLL) of stroke. The change trend of stroke burden was assessed based on age-standardised rates per 100 000 person-years and estimated annual percentage changes. The average annual rate of change in stroke burden was analysed using the average annual percentage change from 1990 to 2019. Pearson correlation analysis was used to explore the strength and direction of the correlation between stroke burden and SDI. Results Regions with high SDI showed the largest decline in age-standardised incidence, death, DALY, YLD, and YLL rates of stroke from 1990 to 2019. China experienced the largest increase in age-standardised prevalence and YLD rates of stroke from 1990 to 2019. There were significant differences in the average annual percent change in stroke burden among the majority of SDI regions. The burden for stroke at the national level was inversely correlated with SDI, despite some exceptions (Incidence: R = -0.417, P < 0.001; prevalence: R = -0.297, P < 0.001; mortality: R = -0.510, P < 0.001; DALY: R = -0.550, P < 0.001; YLD: R = -0.125, P = 0.075; YLL: R = -0.569, P < 0.001). Conclusions There were significant differences in the stroke burden across different regions with varying SDI levels from 1990 to 2019. The age-standardised prevalence rate and attributable disability burden of stroke remain substantial in different SDI regions, making it a major contributor to the overall disease burden. The severe burden of stroke highlights the importance of primary and secondary stroke-prevention strategies. Therefore, future strategies to prevent and reduce the burden of stroke should be formulated and implemented according to the SDI of each country. [ABSTRACT FROM AUTHOR]

Abstract Background Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma‐associated HLH (LA‐HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA‐HLH in the elderly population. Methods We retrospectively analyzed a multicenter cohort of elderly patients with LA‐HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed. Results A total of 173 elderly patients with LA‐HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B‐cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p 1407 U/L), and a higher creatinine level (>96.8 μmol/L) were independent predictors of decreased overall survival and 60‐day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60‐day survival of elderly patients with LA‐HLH. Conclusions LA‐HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA‐HLH.

Nanomedicine‐induced cancer cell death has become a prominent area of research in the life sciences field in recent years. The concept of cuproptosis was first proposed in 2022. Copper homeostasis in organisms is tightly regulated by protein transporters and molecular chaperones. Disruptions in copper homeostasis can adversely affect mitochondrial respiration and disrupt other physiological processes, leading to cytotoxicity. Therefore, researchers have designed and refined copper‐based nanomaterials to induce cuproptosis and assess their effects on cancer treatment. While several reviews on cuproptosis exist, they primarily delve into its molecular mechanisms. This review begins with elucidating the metabolism and homeostasis of copper in the body. Subsequently, the latest advancements in copper nanomaterial‐induced cuproptosis for cancer treatment and antimicrobial purposes is summarized. Finally, a comprehensive summary and outlook on the subject is provided. The goal with this review is to assist researchers in gaining a deeper understanding of the interaction between nanomaterials and cuproptosis, thereby offering new perspectives for designing novel nanomaterials to induce cuproptosis.

Abstract There are limited studies on mutation profiling for Peripheral T‐cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next‐generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0–7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression‐free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262–9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000–101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses.

BackgroundFamilial 46, XY Disorder of Sexual Development (DSD) was discovered in a Ph+, BCR::ABL1P210+ Acute Lymphoblastic Leukemia (ALL) female with RCBTB2::LPAR6 fusion gene. Siblings developing 46, XY DSD are extremely rare. Patients with 46, XY DSD have much higher rates of gonadal cancers. Nevertheless, the incidence of hematologic malignancies in patients with DSDs has received little attention. RCBTB2::LPAR6 is a rarely reported fusion gene in ALL.Case presentationHerein, we report a rare case of a newly diagnosed Ph+, BCR::ABL1P210+ ALL patient who was 77 years old and female by social sex. Whole Exome Sequencing (WES) and RNA sequencing revealed TET2 and NF1 mutations in addition to a rarely reported RCBTB2::LPAR6 fusion gene and 17 other genes with uncertain clinical significance. The patient was surprisingly found to have a male karyotype. On ultrasound, neither the uterus nor the ovaries were discernible. A detailed family and marital history revealed that the patient had undergone surgery at an early age for an unexplained inguinal mass. She had slow pubertal development, scanty menstruation, and few overtly feminine characteristics. She had three marriages, but none succeeded in getting pregnant. The patient had never sought therapy for infertility due to the inaccessibility of medical treatment and a lack of medical knowledge. Her sister, 73 years old and female by social sex, who had amenorrhea in adolescence and was unable to conceive, had the same experience. To our surprise, she also had a male karyotype.ConclusionsDue to the absence of long-term social attention and follow-up, studies on the incidence of hematologic malignancies in patients with 46, XY DSD are incredibly uncommon. Siblings developing 46, XY DSD is extremely rare. We report the oldest patient diagnosed with 46, XY DSD. There have not yet been any reports of familial 46, XY DSD with a concurrent diagnosis of Ph+BCR::ABL1P210+ALL with a rarely reported RCBTB2::LPAR6 fusion gene.

Burdock (Arctium lappa L.), which belongs to the Compositae family, possesses significant medicinal and nutritional value. Burdock root is abundant in proteins and essential amino acids. In this study, proteins from burdock roots were extracted by alkali extraction and acid sedimentation, and the optimal conditions for protein extraction from burdock roots and protein characteristics were explored. The optimal conditions for protein extraction with a yield rate of 9.03% were 40°C extraction temperature, pH 8.0, a solid–liquid ratio of 1:25 (g/mL), and extraction time of 65 minutes. Single-factor and orthogonal tests on the extraction rate of burdock proteins under different conditions found that the extraction rate of protein from burdock roots were influenced by pH, extraction temperature, solid–liquid ratio, and extraction time, in this order. The solubility and gelation properties of burdock protein were similar to those of soybean protein; however, burdock protein demonstrated 1.2 times the oil absorption capacity and half the water retention capacity of soybean protein. Analysis of the amino acid contents of burdock protein revealed that burdock root contains significant essential and non-essential amino acids, with valine content being the highest.

Background: The operation rate for different involved arteries and the manifestation of vessel involvement of patients with Takayasu arteritis undergoing open or endovascular operations remain unclear. We aimed to investigate the clinical characteristics, vessel involvement, angiographic classification and operations information in a large cohort of patients with Takayasu arteritis undergoing open or endovascular operations at a single centre in China. Methods: From January 2017 to October 2022, a total of 153 consecutive patients undergoing open or endovascular operations were recruited from the Department of Vascular Surgery of Beijing Hospital. The demographic characteristics, clinical presentations, pattern of vascular involvement and operation information were collected and analysed. Results: The majority of patients were female (128/153, 83.7%). The most common vascular finding was hypertension (66.7%). The subclavian (74.2%), carotid (70.1%) and renal (68.9%) arteries were the most commonly involved arteries. Type V (40.5%) was the most common angiographic classification pattern. A total of 296 open or endovascular operations were performed, including 73 percutaneous transluminal angioplasties (PTAs), 50 stent placements and 173 bypass graft operations. Patients with renal (83.3%) or carotid (65.2%) artery involvement had markedly higher rates of undergoing operations. Conclusions: The subclavian and carotid arteries, as well as the type V (40.5%) pattern, exhibited the highest frequency of involvement among patients with Takayasu arteritis who underwent open or endovascular operations. Variations in angiographic features can result in differences in clinical manifestations and significantly impact the possibility and modality of operations.

Abstract Background The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T‐cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy. Methods In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi‐squared test and Kruskal–Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors. Results Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56‐negative status (p

Abstract Sepsis is defined as a life-threatening organ dysfunction caused by excessive formation of reactive oxygen species (ROS) and dysregulated inflammatory response. Previous studies have reported that shikonin (Shik) possess prominent anti-inflammatory and antioxidant effects and holds promise as a potential therapeutic drug for sepsis. However, the poor water solubility and the relatively high toxicity of shikonin hamper its clinical application. To address this challenge, we constructed Zn2+-shikonin nanoparticles, hereafter Zn-Shik-PEG NPs, based on an organic-inorganic hybridization strategy of metal-polyphenol coordination to improve the aqueous solubility and biosafety of shikonin. Mechanistic studies suggest that Zn-Shik-PEG NPs could effectively clear intracellular ROS via regulating the Nrf2/HO-1 pathway, meanwhile Zn-Shik-PEG NPs could inhibit NLRP3 inflammasome-mediated activation of inflammation and apoptosis by regulating the AMPK/SIRT1 pathway. As a result, the Zn-Shik-PEG NPs demonstrated excellent therapeutic efficacies in lipopolysaccharide (LPS) as well as cecal ligation puncture (CLP) induced sepsis model. These findings suggest that Zn-Shik-PEG NPs may have therapeutic potential for the treatment of other ROS-associated and inflammatory diseases.

Abstract Verticillium dahliae is a soil-borne hemibiotrophic fungal pathogen that threatens cotton production worldwide. In this study, we assemble the genomes of two V. dahliae isolates: the more virulence and defoliating isolate V991 and nondefoliating isolate 1cd3-2. Transcriptome and comparative genomics analyses show that genes associated with pathogen virulence are mostly induced at the late stage of infection (Stage II), accompanied by a burst of reactive oxygen species (ROS), with upregulation of more genes involved in defense response in cotton. We identify the V991-specific virulence gene SP3 that is highly expressed during the infection Stage II. V. dahliae SP3 knock-out strain shows attenuated virulence and triggers less ROS production in cotton plants. To control the disease, we employ polyethyleneimine-coated MXene quantum dots (PEI-MQDs) that possess the ability to remove ROS. Cotton seedlings treated with PEI-MQDs are capable of maintaining ROS homeostasis with enhanced peroxidase, catalase, and glutathione peroxidase activities and exhibit improved tolerance to V. dahliae. These results suggest that V. dahliae trigger ROS production to promote infection and scavenging ROS is an effective way to manage this disease. This study reveals a virulence mechanism of V. dahliae and provides a means for V. dahliae resistance that benefits cotton production.

Pulmonary hypertension (PH) is a malignant disease with progressive increase of pulmonary vascular pressure, which eventually leads to right heart failure. More and more evidences show that immune cells and inflammation play an important role in the occurrence and development of PH. In the context of pulmonary vascular diseases, immune cells migrate into the walls of the pulmonary vascular system. This leads to an increase in the levels of cytokines and chemokines in both the bloodstream and the surrounding tissues of the pulmonary vessels. As a result, new approaches such as immunotherapy and anti-inflammatory treatments are being considered as potential strategies to halt or potentially reverse the progression of PH. We reviewed the potential mechanisms of immune cells, cytokines and chemokines in PH development. The potential relationship of vascular cells or bone morphogenetic protein receptor 2 (BMPR2) in immune regulation was also expounded. The clinical application and future prospect of immunotherapy were further discussed.

Abstract Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary. There are two main isoforms of PRL: 23‐kDa PRL (named full‐length PRL) and vasoinhibins (including 5.6–18 kDa fragments). Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization, including endothelial cell proliferation and migration, protease production, and apoptosis. However, their effects on vascular function and cardiovascular diseases are different or even contrary. In addition to the structure, secretion regulation, and signal transduction of PRL/vasoinhibins, this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.

MicroRNAs (miRNAs) are versatile regulators of pulmonary arterial remodeling in idiopathic pulmonary arterial hypertension (IPAH). We herein aimed to characterize miRNAs in peripheral blood mononuclear cell (PBMC) and plasma exosomes, and investigate specific miRNA expression in pulmonary artery cells and lung tissues in IPAH. A co-dysregulated miRNA was identified from the miRNA expression profiles of PBMC and plasma exosomes in IPAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the potential function of differentially expressed miRNAs. Real-time quantitative reverse transcription polymerase chain reaction was used to validate the expression of specific miRNAs in hypoxia-induced pulmonary microvascular endothelial cells (PMECs), pulmonary artery smooth muscle cells (PASMCs), pericyte cells (PCs), and lung tissues of patients with IPAH and rats. Finally, the miRNA-mRNA mechanisms of miR-122-5p were predicted. MiR-122-5p was the only co-upregulated miRNA in PBMC and plasma exosomes in patients with IPAH. Functional analysis of differentially expressed miRNAs revealed associations with the GO terms “transcription, DNA-templated,” “cytoplasm,” and “metal ion binding” in both PBMC and plasma exosomes, KEGG pathway MAPK signaling in PBMC, and KEGG-pathway human papillomavirus infection in plasma exosomes. Hypoxic PMECs and PCs, lung tissue of patients with IPAH, and rats showed increased expression of miR-122-5p, but hypoxic PASMCs showed decreased expression. And miR-122-5p mimics and inhibitor affected cell proliferation. Finally, miR-122-5p was found to potentially target DLAT (in lung tissue) and RIMS1 (in PMECs) in IPAH. According to the dual-luciferase assay, miR-122-5p bound to DLAT or RIMS1. In studies, DLAT imbalance was associated with cell proliferation and migration, RIMS1 is differentially expressed in cancer and correlated with cancer prognosis. Our findings suggest that the miR-122-5p is involved in various biological functions in the adjacent vascular wall cells in IPAH.

Waldenstrom’s macroglobulinemia (WM) is a rare and indolent B-cell lymphoma. To investigate the type and survival of hematologic secondary malignancies (SMs) in Chinese patients with WM, we retrospectively reviewed the characteristics of 102 patients with WM from February 2002 to May 2023 in our center. Four men and two women were diagnosed with hematologic SMs. Of the six patients with hematologic SMs, one was diagnosed with acute myeloid leukemia (AML), one with multiple myeloma (MM), one with myelodysplastic syndrome (MDS), one with B-cell acute lymphoblastic leukemia (B-ALL), and two with diffuse large B-cell lymphoma (DLBCL). The median age was 65.5 years (56–74 years). The median interval time between diagnosis of WM and hematologic SMs was 39.5 months (10–117 months). Among those with WM with hematologic SMs, five died and one survived. Overall survival (OS) was just 33 months (12–119 months) on median. A total of 32 patients died and 64 survived in the group of WM without hematologic SMs, and the median OS was 82 months (3–250 months). This is the first study in the Chinese population on hematologic SMs in WM. The purpose of this study was to investigate the prognosis of hematologic SMs in WM in the Chinese population, as well as to compare the population’s characteristics to those of other centers. We investigated the underlying causes further and presented a research strategy for our forthcoming investigation. We intend to investigate risk factors for SMs as well as more accessible screening methods.

Abstract Novel coronary Au@Bi nanospheres (NSs) are simply synthesized by sparkling gold nanoparticles (Au NPs) on the surface of bismuth (Bi) NSs and successfully used as highly impedance‐sensitive immunosensing platform to develop a new label‐free electrochemical immunosensor for the detection of carcinoembryonic antigen (CEA). Firstly, Bi NSs are prepared by one‐pot hydrothermal method, showing uniform sphere morphology with a dense oxide film formed outside Bi NSs due to the easy oxidation of Bi in the air. The oxide film significantly hinders the transmission of electrons and effectively improves the sensitivity of the proposed electrochemical impedance immunosensor. The surface functionalization of Bi NSs with Au NPs enhances the biocompatibility, stability, as well as active surface area of the produced Au@Bi NSs, preferable for the efficient loading of antibody molecules. The electrochemical impedance spectroscopy (EIS) is selected as the optical technique to measure CEA with the constructed immunosensor based on Au@Bi NSs. Because of the excellent impedance‐responsive performance, this new immunosensor displays highly sensitive detection toward CEA in a linear range of 50 fg mL−1–100 ng mL−1 with an extremely low detection limit of 9.83 fg mL−1 and could be potentially used in early clinical detection of cancer.

Fusarium oxysporum f. sp. vasinfectum (Fov) is a common soilborne fungal pathogen that causes Fusarium wilt (FW) disease in cotton. Although considerable progress has been made in cotton disease-resistance breeding against FW in China, and the R gene conferring resistance to Fov race 7 (FOV) in Upland cotton (Gossypium hirsutum) has been identified, knowledge regarding the evolution of fungal pathogenicity and virulence factors in Fov remains limited. In this study, we present a reference-scale genome assembly and annotation for FOV7, created through the integration of single-molecule real-time sequencing (PacBio) and high-throughput chromosome conformation capture (Hi-C) techniques. Comparative genomics analysis revealed the presence of six supernumerary scaffolds specific to FOV7. The genes or sequences within this region can potentially serve as reliable diagnostic markers for distinguishing Fov race 7. Furthermore, we conducted an analysis of the xylem sap proteome of FOV7-infected cotton plants, leading to the identification of 19 proteins that are secreted in xylem (FovSIX). Through a pathogenicity test involving knockout mutants, we demonstrated that FovSIX16 is crucial for the full virulence of FOV7. Overall, this study sheds light on the underlying mechanisms of Fov’s pathogenicity and provides valuable insights into potential management strategies for controlling FW.

Abstract Circular RNAs (circRNAs) are endogenous RNAs with a covalently closed single‐stranded transcript. They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets. Using the most powerful RNA sequencing and bioinformatics techniques, a large number of circRNAs have been identified and further functional studies have been performed. It is known that circRNAs act as potential biomarkers, sponges for microRNAs (miRNAs) and RNA‐binding proteins (RBPs), and regulators of mRNA transcription. They also participate in the translation of peptides or proteins. Many types of circRNAs are dysregulated in plasma or lung tissues, and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling in pulmonary hypertension (PH). One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge. However, other potential mechanisms of action of circRNAs are still being actively explored in PH. This paper presents a systematic review of the biogenesis, biological characterization, relevant underlying functions, and future perspectives for studies of circRNAs in the pathogenesis of PH.

WD-repeat protein 72WDR72;OMIM∗613214, a scaffolding protein lacking intrinsic enzymatic activity, produces numerous β-propeller blade formations, serves as a binding platform to assemble protein complexes and is critical for cell growth, differentiation, adhesion, and migration. Despite evidence supporting a basic role of WDR72 in the tumorigenesis of particular cancers, the value of WDR72 in non-small-cell lung cancer (NSCLC), the tumor with the highest mortality rate globally, is undocumented. We investigated the prognostic value of WDR72 in NSCLC and studied its potential immune function and its correlation with ferroptosis. According to The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype-Tissue Expression, and Gene Set Cancer Analysis, we used multiple bioinformatic strategies to investigate the possible oncogenic role of WDR72, analyze WDR72 and prognosis, and immune cell infiltration in different tumors correlation. WDR72 exhibited a high expression in NSCLC and a positive association with prognosis. WDR72 expression was related to immune cell infiltration and tumor immune microenvironment in NSCLC. Finally, we validated WDR72 in human NSCLC; it has a predictive value in NSCLC related to its function in tumor progression and immunity. The significance of our study is that WDR72 can be used as a potential indicator of lung cancer prognosis. Helping physicians more accurately predict patient survival and risk of disease progression.

Nodal Marginal Zone Lymphoma(NMZL) is an indolent lymphoma with a very low clinical incidence and is sometimes difficult to differentiate diagnostically from Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM). NMZL with elevated monoclonal immunoglobulin M (IgM) is even rarer. Nontraumatic chylothorax can be seen in aggressive lymphoma, which often happens with chest tightness and dyspnea as the primary clinical manifestation. We reported the first case of monoclonal IgM elevated NMZL complicated by atypical nontraumatic chylothorax. A 64-year-old male patient was first admitted to the Department of Respiratory Medicine with symptoms of chest tightness and shortness of breath. He was given several times thoracentesis to drain pleural effusion to improve pulmonary compression symptoms. The patient had a combination of elevated monoclonal IgM and atypical lymph node biopsy pathology. After two times lymph node biopsies and genetic testing, the patient was finally diagnosed with NMZL. Within a short time, he was admitted to the Department of Hematology due to the reappearance of massive pleural effusion, which indicated chylothorax. The patient repeatedly presented with left-sided pleural effusion, and the color went from red to yellow, and finally white. Only about half of the chylothorax cases present with typical clinical manifestations. We report this case intending to draw the attention of clinicians to hematologic malignancies with atypical nontraumatic chylothorax.

BackgroundWaldenstrom Macroglobulinemia (WM) is a rare and indolent lymphoma of B-cell origin characterized by elevated monoclonal IgM, with MYD88L265P mutation and CXCR4 mutation as common molecular alterations. B-cell Acute Lymphoblastic Leukemia (B-ALL) is clinically heterogeneous, characterized by abnormal proliferation and aggregation of immature lymphocytes in the bone marrow and lymphoid tissue. WM and ALL are hematologic malignancies of B-cell origin with completely different clinical manifestations and biological features. KMT2D and MECOM mutations are very rare in ALL and usually indicate poor disease prognosis. The coexistence of WM and ALL with KMT2D and MECOM mutations have not been reported.Case presentationA 74-year-old female patient was diagnosed with WM in July 2018 and received four cycles of chemotherapy of bortezomib and dexamethasone. In November 2018, she received immunomodulator thalidomide as maintenance therapy. In November 2020, Bruton’s Tyrosine Kinase inhibitors (BTKi) has been introduced into the Chinese market and she took zanubrutinib orally at a dose of 80 mg per day. The disease remained in remission. In December 2021, she presented with multiple enlarged lymph nodes throughout the body. Bone marrow and next-generation sequencing (NGS) suggested the coexistence of WM and B-ALL with KMT2D and MECOM mutations. The patient was treated with zanubrutinib in combination with vincristine and dexamethasone, after which she developed severe myelosuppression and septicemia. The patient finally got remission. Due to the patient’s age and poor status, she refused intravenous chemotherapy and is currently treated with zanubrutinib.ConclusionsThe coexistence of WM and B-ALL is very rare and has not been reported. The presence of both KMT2D and MECOM mutations predicts a poor prognosis and the possibility of insensitivity to conventional treatment options. BTKi achieves its anti-tumor effects by inhibiting BTK activation and blocking a series of malignant transformations in B-cell tumors. In addition, it also acts on T-cell immunity and tumor microenvironment. Combination therapy based on BTKi may improve the prognosis of this patient.

Abstract By hydrothermal reaction, the hydrangea‐like ZnS/ZnIn2S4 microspheres were prepared in the presence of thioacetamide. X‐ray photoelectron spectroscopy and high resolution transmission electron microscopy confirmed that the ultra‐long nanowires are composed of ZnS and ZnIn2S4. Scanning electron microscopy showed the morphology of ultra‐thin nanosheets with an average thickness of 8.5 nm cross from inside to outside, forming ZnS/ZnIn2S4 microspheres with a porous diameter of about 2.8 μm. Nitrogen adsorption desorption isotherm determined that the BET specific surface area of the microspheres was 109.19 m2/g which showed that they have a large specific surface area. The obtained ZnS/ZnIn2S4 microspheres showed broad absorbance ranging from UV (200 nm) to visible (520 nm) with low indirect band gaps of 2.08 eV. It leads to outstanding visible‐light‐driven photocatalysis for the degradation of xylenol orange (XO) and thymol blue (TB) in water, and the two dyes were almost completely degraded after 60 and 135 min, respectively. This provides new potential to explore nanomaterials for efficient photo‐driven degradation of organic dyes under visible light irradiation.

Abstract Thermal decomposition in solution is the most effective approach for achieving highly monodisperse iron oxide nanoparticles (IONPs). However, a simple, economical, and environment‐friendly iron precursor with high iron content remains in great demand. Although siderite (FeCO3) has been reported to produce iron oxide particles via calcination, it is difficult to control the shapes of the obtained particles compared to those obtained by solution methods. Herein, FeCO3 was employed as a precursor in solution thermal decomposition to prepare monodisperse IONPs and investigated the influence of reaction conditions on the particle size, including the concentration of oleic acid, concentration of the precursor, and the reaction temperature. The seed‐mediated growth method with FeCO3 as a precursor was also studied to extend the scope of particle size. The experimental results demonstrate that high‐quality IONPs can be synthesized in solution via FeCO3 thermal decomposition. The particle diameter was tuned between 3 and 20 nm by varying the reaction conditions, and by seed‐mediated growth. FeCO3 is thus a readily available, economical, environment‐friendly precursor with high iron content, which is a novel candidate for the synthesis of IONPs.

Zanubrutinib, a next-generation non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, shows great efficacy in the treatment of B cell malignancies. Some patients may experience a series of side effects after the treatment of zanubrutinib. Grade 4 dermatological toxicities are rare, which present as severe rash and skin infection. Herein, we retrospectively reported the grade 4 dermatological toxicities of zanubrutinib in three consecutive patients. They were treated with zanubrutinib 160 mg twice daily orally. One patient was diagnosed with Primary Breast Diffuse Large B-cell Lymphoma(PB-DLBCL) and two patients were diagnosed with Chronic Lymphocytic Leukemia(CLL). Within one month after zanubrutinib treatment, all three patients developed grade 4 dermatological toxicities, including bruising, maculopapular rash, petechiae, ecchymosis, hemorrhagic blister, acne-Like rash, papulopustular rash, and skin infections. Zanubrutinib was discontinued in two patients due to unacceptable dermatological toxicities. Safety data from pre-licensing clinical trials showed that zanubrutinib-related side effects were frequent but well tolerated. To date, no severe dermatological toxicities were reported. The majority of patients can be relieved with symptomatic treatment, but a very small percentage of patients may face discontinuation of the drug.

Polymerase chain reaction (PCR) has extensive bioanalytical applications in molecular diagnostics and genomic research studies for rapid detection and precise genomic amplification. Routine integrations for analytical workflow indicate certain limitations, including low specificity, efficiency, and sensitivity in conventional PCR, particularly towards amplifying high guanine–cytosine (GC) content. Further, there are many ways to enhance the reaction, for example, using different PCR strategies such as hot-start/touchdown PCR or adding some special modifications or additives such as organic solvents or compatible solutes, which can improve PCR yield. Due to the widespread use of bismuth-based materials in biomedicine, which have not yet been used for PCR optimization, this attracts our attention. In this study, two bismuth-based materials that are inexpensive and readily available were used to optimize GC-rich PCR. The results demonstrated that ammonium bismuth citrate and bismuth subcarbonate effectively enhanced PCR amplification of the GNAS1 promoter region (∼84% GC) and APOE (75.5% GC) gene of Homo sapiens mediated by Ex Taq DNA polymerase within the appropriate concentration range. Combining DMSO and glycerol additives was critical in obtaining the target amplicons. Thus, the solvents mixed with 3% DMSO and 5% glycerol were used in bismuth-based materials. That allowed for better dispersion of bismuth subcarbonate. As for the enhanced mechanisms, the surface interaction of PCR components, including Taq polymerase, primer, and products with bismuth-based materials, was maybe the main reason. The addition of materials can reduce the melting temperature (Tm), adsorb polymerase and modulate the amount of active polymerase in PCR, facilize the dissociation of DNA products, and enhance the specificity and efficiency of PCR. This work provided a class of candidate enhancers for PCR, deepened our understanding of the enhancement mechanisms of PCR, and also explored a new application field for bismuth-based materials.

Regulating redox homeostasis in tumor cells and exploiting oxidative stress to damage tumors is an efficacious strategy for cancer therapy. However, the strengths of organic nanomaterials within this strategy are often ignored. In this work, a light-triggered reactive oxygen species (ROS) damaging nanoamplifier (IrP-T) was developed for enhanced photodynamic therapy (PDT). The IrP-T was fabricated with an amphiphilic iridium complex and a MTH1 inhibitor (TH287). Under green light stimulation, IrP-T catalyzed the oxygen in cells to generate ROS for realizing oxidative damage; meanwhile, TH287 increased the accumulation of 8-oxo-dGTP, further strengthening oxidative stress and inducing cell death. IrP-T could maximize the use of a small amount of oxygen, thus further boosting the efficacy of PDT in hypoxic tumors. The construction of nanocapsules provided a valuable therapeutic strategy for oxidative damage and synergizing PDT.

In order to develop new anti-cancer drugs more efficiently and reduce side effects based on active drug targets, the virtual drug screening was carried out through the target of G-quadruplexes and 23 hit compounds were, thus, screened out as potential anticancer drugs. Six classical G-quadruplex complexes were introduced as query molecules, and the three-dimensional similarity of molecules was calculated by shape feature similarity (SHAFTS) method so as to reduce the range of potential compounds. Afterwards, the molecular docking technology was utilized to perform the final screening followed by the exploration of the binding between each compound and four different structures of G-quadruplex. In order to verify the anticancer activity of the selected compounds, compounds 1, 6 and 7 were chosen to treat A549 cells in vitro, the lung cancer epithelial cells, for further exploring their anticancer activity. These three compounds were found to be of good characteristics in the treatment of cancer, which revealed the great application prospect of the virtual screening method in developing new drugs.

To fabricate a highly biocompatible nanoplatform enabling synergistic therapy and real-time imaging, novel Au@Bi2S3 core shell nanobones (NBs) (Au@Bi2S3 NBs) with Au nanorods as cores were synthesized. The combination of Au nanorods with Bi2S3 film made the Au@Bi2S3 NBs exhibit ultrahigh photothermal (PT) conversion efficiency, remarkable photoacoustic (PA) imaging and high computed tomography (CT) performance; these Au@Bi2S3 NBs thus are a promising nanotheranostic agent for PT/PA/CT imaging. Subsequently, poly(N-vinylpyrrolidone)-modified Au@Bi2S3 NBs (Au@Bi2S3-PVP NBs) were successfully loaded with the anticancer drug doxorubicin (DOX), and a satisfactory pH sensitive release profile was achieved, thus revealing the great potential of Au@Bi2S3-PVP NBs in chemotherapy as a drug carrier to deliver DOX into cancer cells. Both in vitro and in vivo investigations demonstrated that the Au@Bi2S3-PVP NBs possessed multiple desired features for cancer therapy, including extremely low toxicity, good biocompatibility, high drug loading ability, precise tumor targeting and effective accumulation. Highly efficient ablation of the human liver cancer cell HepG2 was achieved through Au@Bi2S3-PVP NB-mediated photothermal therapy (PTT). As both a contrast enhancement probe and therapeutic agent, Au@Bi2S3-PVP NBs provided outstanding NIR-triggered multi-modal PT/PA/CT imaging-guided PTT and effectively inhibited the growth of HepG2 liver cancer cells via synergistic chemo/PT therapy.

The successful treatment of limb ischemia requires that promote angiogenesis along with microenvironment improvement. Zinc ions have been reported to stimulate angiogenesis, but application was limited to the toxicity concerns. We hypothesized that zinc based metal-EGCG capsule (EGCG/Zn Ps) can achieve sustained release Zn2+ resulting in reduced toxicity and improve angiogenesis as well as the improvement of microenvironment by ROS scavenging of EGCG. The surface morphology, zeta potential, infrared absorbance peaks and zinc ion release profile of the EGCG/Zn Ps were measured. In vitro, EGCG/Zn showed significantly antioxidant, anti-inflammatory and induced cell migration effect. In addition, EGCG/Zn Ps enabled the sustained release of zinc ions, which reduced cytotoxicity and enhanced the secretion of vascular endothelial growth factor (VEGF) in vitro and in vivo. In mouse models of limb ischemia, EGCG/Zn Ps promoted angiogenesis and cell proliferation in ischemic tissues. Moreover, EGCG/Zn Ps group exhibited the most significant recovery of limb ischemic score, limb temperature and blood flow than other groups. In conclusion, EGCG/Zn Ps is a safe and promising approach to combine the merit of Zn2+ and EGCG, thus enabling the direct application to limb ischemia.

Background:Varicose veins are found to be associated with increased risk of venous thromboembolism (VTE) in many observational studies, but whether varicose veins are causally associated with VTE remains unclear. Therefore, we used a series of Mendelian randomization (MR) methods to investigate that association.Methods23 independent single-nucleotide polymorphisms (SNPs) for varicose veins were obtained from the Pan UK Biobank analysis. The outcomes datasets for deep vein thrombosis (DVT), pulmonary embolism (PE) and venous thromboembolism (VTE) were obtained from the FinnGen study. Before analysis, body mass index (BMI) and height were included as confounders in our MR model. Basic MR [inverse-variance weighted (IVW), weight-median, penalized weighted-median and MR-Egger methods] and MR-PRESSO were performed against each outcome using the whole SNPs and SNPs after excluding those associated with confounders. If causal associations were suggested for any outcome, a basic MR validation analysis, a multivariable MR analysis with BMI and height, a Causal Analysis Using Summary Effect estimates (CAUSE), and a two-step MR analysis with BMI and height, would follow.ResultsUsing 21 qualified SNPs, the IVW method (OR: 1.173, 95% CI: 1.070–1.286, p < 0.001, FDR = 0.002), the weighted median method (OR: 1.255, 95% CI: 1.106–1.423, p < 0.001, FDR = 0.001), the penalized weighted median method (OR: 1.299, 95% CI: 1.128–1.495, p < 0.001, FDR = 0.001) and the MR-PRESSO (OR: 1.165, 95% CI: 1.067–1.273, p = 0.003, FDR = 0.009) suggested potential causal effect of varicose veins on DVT, but no cause effect was found for PE and VTE. Excluding SNPs associated with confounders yielded similar results. The causal association with DVT was validated using a self-reported DVT cohort (IVW, OR: 1.107, 95% CI: 1.041–1.178, p = 0.001). The causal association maintained after adjustment for height (OR = 1.105, 95% CI: 1.028–1.188, p = 0.007), BMI (OR = 1.148, 95% CI: 1.059–1.244, p < 0.001) and them both (OR = 1.104, 95% CI: 1.035–1.177, p = 0.003). The causal association also survived the strict CAUSE (p = 0.018). Finally, in two-step MR, height and BMI were found to have causal effects on both varicose veins and DVT.ConclusionGenetically predicted varicose veins may have a causal effect on DVT and may be one of the mediators of obesity and taller height that predispose to DVT.

Abstract Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative diseases (NDD) characterized by progressive degeneration of the central nervous system, and few medications are available to halt the progression of AD and PD. In the present study, an engineered strain MG136-pMG36e-GLP-1 was used to evaluate its neuroprotective effect on AD and PD mice, via the probiotics effects of Lactococcus lactis MG1363 and the constantly produced Glucagon-like peptide-1 (GLP-1) by the engineered strain. Our results indicated that oral administration of MG136-pMG36e-GLP-1 significantly reduced lipopolysaccharide (LPS)-induced memory impairment and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction through the toll-like receptor4 (TLR4)/nuclear factor-kappa B (NFκB) and protein kinase B (AKT)/Glycogen synthase kinase-3β (GSK3β) signaling pathway. High-throughput sequencing results showed that MG1363-pMG36e-GLP-1 reduced the abundance of the pathogens Enterococcus, Proteus, and increased the abundance of the probiotics Akkermansia muciniphila. These results suggest that the engineered strain may be a new intervention for treating AD and PD by reducing the occurrence of neuroinflammation.

Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc‐regulated transporter (ZRT)/iron‐regulated transporter (IRT) like protein transporters (ZIPs) encode membrane transport proteins, which are responsible for the absorption of zinc and play important roles in the pathogenesis of various human cancers. Tumor-associated macrophages (TAMs) are important participants in the regulation of tumor microenvironment and the development of HCC. Individual role of each ZIP involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of ZIPs in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of ZIPs between DSCs tissues and healthy controls. Notably, the transcription levels of ZIP2, ZIP5, ZIP8, ZIP9 and ZIP14 were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of Zips in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl4) inducing mouse model of HCC were established. Consistently, the mRNA levels of Zip2, Zip9, and Zip14 in liver tissues of HCC induced mice were also decreased compared with the healthy controls. In addition, mouse peritoneal elucidated macrophages (PEMs)-derived M1/M2 macrophages in vitro, as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of ZIPs. Our results showed that both Zip2 and Zip9 were up-regulated in M2-polarized macrophages. Zip2 transcript was also up-regulated M1-polarized macrophages, but Zip9 was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in ZIP9 transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that Zip9, but not Zip2, could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, Zip9 enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of IκBα/β to inhibit M1 macrophage polarization. Together, our results indicate that ZIP9 may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from the Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cutoff points of continuous variables; univariate and multivariate Cox analyses were used for variable selection, and the Kaplan–Meier curve was used to analyze the value of variables on prognosis. The C-index, Brier Score, and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio, and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in the derivation and validation cohorts by using a bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous non-Hodgkin lymphoma, and the prognosis of DLBCL patients is widely affected by multivariables. Clinical-factors-based prognostic systems stratify the prognosis of DLBCL with certain limitations, and the value of ferritin on the prognosis of DLBCL is unclear. In this study, 225 cases were retrieved from 4 centers of Huaihai Lymphoma Working Group (HHLWG) as the derivation cohort, and 66 cases were from the other 6 centers of HHLWG as external validation cohort. X-Tile program divided ferritin into three groups when applying 175.00 and 391.90 μg/L as the optimal cutoff points. Based on multivariable analysis, ferritin appeared to be a stronger predictor. A total of three variables (ferritin, age, and lactate dehydrogenase) were included for the development of the nomogram. The C-indexes were 0.73 and 0.70 in the derivation and validation cohort, and the calibration curve showed the consistency between the nomogram prediction and the actual observation. In conclusion, Ferritin-based nomogram enhanced the prognostic value of IPI in DLBCL.

With critical limb ischemia (CLI) being a multi-factorial disease, it is becoming evident that gene therapy with a multiple bio-functional growth factor could achieve better therapeutic outcomes. Cytochrome P450 epoxygenase-2J2 (CYP2J2) and its catalytic products epoxyeicosatrienoic acids (EETs) exhibit pleiotropic biological activities, including pro-angiogenic, anti-inflammatory and cardiovascular protective effects, which are considerably beneficial for reversing ischemia and restoring local blood flow in CLI. Here, we designed a nanoparticle-based pcDNA3.1-CYP2J2 plasmid DNA (pDNA) delivery system (nanoparticle/pDNA complex) composed of a novel three-arm star block copolymer (3S-PLGA-po-PEG), which was achieved by conjugating three-armed PLGA to PEG via the peroxalate ester bond. Considering the multiple bio-functions of CYP2J2-EETs and the sensitivity of the peroxalate ester bond to H2O2, this nanoparticle-based gene delivery system is expected to exhibit excellent pro-angiogenic effects while improving the high oxidative stress and inflammatory micro-environment in ischemic hindlimb. Our study reports the first application of CYP2J2 in the field of therapeutic angiogenesis for CLI treatment and our findings demonstrated good biocompatibility, stability and sustained release properties of the CYP2J2 nano-delivery system. In addition, this nanoparticle-based gene delivery system showed high transfection efficiency and efficient VEGF expression in vitro and in vivo. Intramuscular injection of nanoparticle/pDNA complexes into mice with hindlimb ischemia resulted in significant rapid blood flow recovery and improved muscle repair compared to mice treated with naked pDNA. In summary, 3S-PLGA-po-PEG/CYP2J2-pDNA complexes have tremendous potential and provide a practical strategy for the treatment of limb ischemia. Moreover, 3S-PLGA-po-PEG nanoparticles might be useful as a potential non-viral carrier for other gene delivery applications.

Rhenium (Re) is widely used in the diagnosis and treatment of cancer due to its unique physical and chemical properties. Re has more valence electrons in its outer shell, allowing it to exist in a variety of oxidation states and to form different geometric configurations with many different ligands. The luminescence properties, lipophilicity, and cytotoxicity of complexes can be adjusted by changing the ligand of Re. This article mainly reviews the development of radionuclide 188Re in radiotherapy and some innovative applications of Re as well as the different therapeutic approaches and imaging techniques used in cancer therapy. In addition, the current application and future challenges and opportunities of Re are also discussed.

Despite the significant improvement in the survival rate of cancer patients, the total cure of bone cancer is still a knotty clinical challenge. Traditional surgical resectionof bone tumors is less than satisfactory, which inevitably results in bone defects and the inevitable residual tumor cells. For the purpose of realizing minimal invasiveness and local curative effects, photothermal therapy (PTT) under the irradiation of near-infrared light has made extensive progress in ablating tumors, and various photothermal therapeutic agents (PTAs) for the treatment of bone tumors have thus been reported in the past few years, has and have tended to focus on osteogenic bio-scaffolds modified with PTAs in order to break through the limitation that PTT lacks, osteogenic capacity. These so-called bifunctional scaffolds simultaneously ablate bone tumors and generate new tissues at the bone defects. This review summarizes the recent application progress of various bifunctional scaffolds and puts forward some practical constraints and future perspectives on bifunctional scaffolds for tumor therapy and bone regeneration: two hawks with one arrow.

BackgroundCD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a rare subtype of DLBCL with invasive clinical features and poor prognosis. Current clinical variables based on prognostic systems for DLBCL are inadequate to accurately stratify the prognosis of CD5+ DLBCL.MethodsA total of 195 CD5+ DLBCL patients were retrospectively recruited from nine centers in Huaihai Lymphoma Working Group. MaxStat analysis was used to identify optimal cutoff points for continuous variables; univariable and multivariable Cox analyses were used for variable selection; Kaplan–Meier curve was used to analyze the value of variables on prognosis; and C-index, Brier score, and decision curve analysis were measured for predicting model performance.ResultsThe derivation and validation cohorts consisted of 131 and 64 patients. Of the whole cohort, median age at diagnosis was 61 years, of whom 100 (51.28%) were males and the 5‐year overall survival rate was 42.1%. MYC, BCL-2, and the coexpression of MYC/BCL-2 could distinguish the survival of CD5+ DLBCL. Multivariable analysis showed that age, IPI, red blood cell count, neutrophil count, MYC expression, and hepatosplenomegaly were independent predictors, and the prognostic nomogram was developed. The C‐index of the nomogram was 0.809 in the derivation and 0.770 in the validation cohort. Decision curve analysis proved that compared with IPI, the specific nomogram showed a better identification in CD5+ DLBCL.ConclusionThe proposed nomogram provided a valuable tool for prognosis prediction in patients with CD5+ DLBCL.

Polymerase Chain Reaction (PCR) is one of the most common technologies used to produce millions of copies of targeted nucleic acid in vitro and has become an indispensable technique in molecular biology. However, it suffers from low efficiency and specificity problems, false positive results, and so on. Although many conditions can be optimized to increase PCR yield, such as the magnesium ion concentration, the DNA polymerases, the number of cycles, and so on, they are not all-purpose and the optimization can be case dependent. Nano-sized materials offer a possible solution to improve both the quality and productivity of PCR. In the last two decades, nanoparticles (NPs) have attracted significant attention and gradually penetrated the field of life sciences because of their unique chemical and physical properties, such as their large surface area and small size effect, which have greatly promoted developments in life science and technology. Additionally, PCR technology assisted by NPs (NanoPCR) such as gold NPs (Au NPs), quantum dots (QDs), and carbon nanotubes (CNTs), etc., have been developed to significantly improve the specificity, efficiency, and sensitivity of PCR and to accelerate the PCR reaction process. This review discusses the roles of different types of NPs used to enhance PCR and summarizes their possible mechanisms.

Aspect-level sentiment classification aims to predict the sentiment polarities towards the target aspects given in sentences. To address the issues of insufficient semantic information extraction and high computational complexity of attention mechanisms in existing aspect-level sentiment classification models based on deep learning, a contextual graph attention network (CGAT) is proposed. The proposed model adopts two graph attention networks to aggregate syntactic structure information into target aspects and employs a contextual attention network to extract semantic information in sentence-aspect sequences, aiming to generate aspect-sensitive text features. In addition, a syntactic attention mechanism based on syntactic relative distance is proposed, and the Gaussian function is cleverly introduced as a syntactic weight function, which can reduce computational complexities and effectively highlight the words related to aspects in syntax. Experiments on three public sentiment datasets show that the proposed model can make better use of semantic information and syntactic structure information to improve the accuracy of sentiment classification.

Gallbladder cancer is a relatively rare malignancy that is generally diagnosed at an advanced stage. Palliative chemotherapy, radiotherapy, or immunotherapy may be appropriate options for advanced gallbladder cancer, instead of radical surgery. In the present report, we describe an extremely unusual case of a 59-year-old man diagnosed with advanced primary squamous cell carcinoma of the gallbladder, according to imagological and pathological examinations. The symptoms of the patient were atypical. Preliminary data indicated that not only the systemic inflammatory biomarkers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio but also jaundice might be correlated with the prognosis. Although the patient was treated with the best supportive care, overall survival time was only about 2 months. Advanced primary squamous cell carcinoma of gallbladder is incurable and highly lethal.

Virus infection is one of the threats to the health of organisms, and finding suitable antiviral agents is one of the main tasks of current researchers. Metal ions participate in multiple key reaction stages of organisms and maintain the important homeostasis of organisms. The application of synthetic metal-based nanomaterials as an antiviral therapy is a promising new research direction. Based on the application of synthetic metal-based nanomaterials in antiviral therapy, we summarize the research progress of metal-based nanomaterials in recent years. This review analyzes the three inhibition pathways of metal nanomaterials as antiviral therapeutic materials against viral infections, including direct inactivation, inhibition of virus adsorption and entry, and intracellular virus suppression; it further classifies and summarizes them according to their inhibition mechanisms. In addition, the use of metal nanomaterials as antiviral drug carriers and vaccine adjuvants is summarized. The analysis clarifies the antiviral mechanism of metal nanomaterials and broadens the application in the field of antiviral therapy.

The permafrost carbon–climate feedback is one of the major mechanisms in controlling the climate–ecosystem interactions in northern high latitudes. Of this feedback, methane (CH _4 ) emission from natural wetlands is critically important due to its high warming potential. The freeze–thaw transition has been confirmed to play an important role in annual CH _4 budget, yet the magnitude of this effect is uncertain. An intensive field campaign was carried out in the Sanjiang Plain, Northeast China to estimate the CH _4 emission in the spring freeze–thaw transition period. The observation concluded that a large CH _4 source was caused by spring thaw; the maximum hourly emission rate was 48.6 g C m ^−2 h ^−1 , more than three orders of the regularly observed CH _4 emission rate in the growing season. In some sporadically observed ‘hot spots’, the spring thawing effect contributed to a large CH _4 source of 31.3± 10.1 g C m ^−2 , which is approximately 80% of the previously calculated annual CH _4 emission in the same study area. If our results are typical for natural wetlands in the Northern Hemisphere permafrost region, we estimate a global CH _4 source strength of 0.5–1.0 Tg C (1 Tg =10 ^12 g) caused by spring thaw in the Northern Hemisphere permafrost region in the year 2011. Combining with available satellite and flask data, a regional extrapolation reaches a temporal pattern of CH _4 emission during 2003–2009 which is consistent with recently observed changes in atmospheric CH _4 concentration in the high latitudes. This suggests that the CH _4 emission upon spring thaw in the high latitudes might be enhanced by the projected climate warming. These findings indicate that the spring thawing effect is an important mechanism in the permafrost carbon–climate feedback and needs to be incorporated in Earth system models.