Bicyclo[2.2.0]hexene: A Multicyclic Mechanophore with Reactivity Diversified by External Forces.

Polymer mechanochemistry has been established as an enabling tool in accessing chemical reactivity and reaction pathways that are distinctive from their thermal counterparts. However, eliciting diversified reaction pathways by activating different constituent chemical bonds from the same mechanophore structure remains challenging. Here, we report the design of a bicyclo[2.2.0]hexene (BCH) mechanophore to leverage its structural simplicity and relatively low molecular symmetry to demonstrate this idea of multimodal activation. Upon changing the attachment points of pendant polymer chains, three different C-C bonds in bicyclo[2.2.0]hexene are specifically activated via externally applied force by sonication. Experimental characterization confirms that in different scenarios of polymer attachment, the regioisomers of BCH undergo different activation reactions, entailing retro-[2+2] cycloreversion, 1,3-allylic migration, and retro-4π ring-opening reactions, respectively. Control experiments with small-molecule analogues reveal that the observed diversified reactivity of BCH regioisomers is possible only with mechanical force. Theoretical studies further elucidate that the differences in the positions of substitution between regioisomers have a minimal impact on the potential energy surface of the parent BCH scaffold. The mechanochemical selectivity between different C-C bonds in each constitutional isomer is a result of selective and effective coupling of force to the aligned C-C bond in each case.

Malignant melanotic schwannoma of the cervical spinal cord: a case report.

Spinal cord malignant melanotic schwannoma (MMNST) is a rare central nervous system tumor that originates from the spinal cord or spinal myelin sheath cells and can produce melanin. This type of tumor is usually highly aggressive and malignant, with a poor prognosis. The clinical manifestations of spinal cord MMNST are mainly pain, paresthesia, muscle weakness, muscle atrophy, etc., and symptoms of spinal cord compression, such as intestinal and bladder dysfunction, paraplegia, etc. Early detection of tumor lesions can facilitate tumor removal, improve patients' quality of life, and prolong patients' survival. In this case report, a 27-year-old young woman was diagnosed with MMNST of the cervical spinal cord due to weakness of her limbs in our hospital, and underwent surgical resection. The patient's limbs returned to normal after surgery. It is worth mentioning that the patient visited our hospital 7 months ago for "right upper limb pain for 3 days" and was diagnosed with a cervical spine space-occupying lesion at the same position this time, but the pathology report was "hemosiderosis". The patient's limbs returned to normal after surgery. It is worth mentioning that the patient visited our hospital 7 months ago for "right upper limb pain for 3 days" and was diagnosed with a cervical spine space-occupying lesion at the same position this time, but the pathology report was "hemosiderosis". This case report aims to raise awareness of the problem of spinal cord MMNST and contribute to greater knowledge of this rare tumor. This case report aims to raise awareness of the problem of spinal cord MMNST and contribute to greater knowledge of this rare tumor.

LncRNA PVT1 promotes neuroinflammation after intracerebral hemorrhage by regulating the miR-128-3p/TXNIP axis.

OBJECTIVE: Intracerebral hemorrhage (ICH) has significant morbidity and mortality. TXNIP and the competing endogenous RNA (ceRNA) regulatory mechanism involved in long non-coding RNA (lncRNA) play roles in ICH. We probed the upstream microRNAs (miRNAs)/lncRNAs that regulated TXNIP expression in the ceRNA mechanism. METHODS: ICH mouse model was established, and ICH secondary injury was simulated in BV2 microglia by hemin treatment. TXNIP was silenced 48 h before ICH modeling. The ICH mouse brain water content (BWC) and brain lesion volume after ICH were recorded. Neuronal apoptosis and neurological deficits were evaluated by double staining of NeuN and TUNEL/modified Garcia/corner turn/forelimb placement tests. Iba1 + microglia number and tumor necrosis factor-α (TNF-α)/interleukin-1ß (IL-1ß)/IL-10/TXNIP/PVT1/miR-128-3p levels were assessed by immunohistochemistry, Western blot, ELISA, and RT-qPCR. Cell viability/death of BV2 cells conditioned medium-treated neuron HT22 cells were assessed by CCK-8/LDH assays. miRNA that had a targeted binding relationship with TXNIP was screened. The targeted bindings of miR-128-3p to TXNIP/PVT1 to miR-128-3p were verified by dual-luciferase reporter gene assay. RESULTS: TXNIP knockdown reduced post-ICH microglial activation/release of pro-inflammatory factors/brain edema/brain lesion volume/neurological deficits in mice and increased releases of anti-inflammatory factors. TXNIP/PVT1 knockdown inhibited hemin-induced inflammatory responses in BV2 cells and protected in vitro co-cultured HT22 cells. PVT1 was a sponge of miR-128-3p to repress TXNIP expression. miR-128-3p knockdown diminished PVT1 knockdown-inhibited hemin-induced BV2 cell inflammatory responses/neurotoxicity. CONCLUSIONS: PVT1 silencing reduced hemin-induced neuroinflammation and had a protective effect on neurons by increasing the targeted inhibition of TXNIP by miR-128-3p.

Vertical Differentiation of Microplastics Influenced by Thermal Stratification in a Deep Reservoir.

Microplastics (MPs) are an emerging environmental concern. However, vertical transport of MPs remains unclear, particularly in deep reservoirs with thermal stratification (TS). In this study, the vertical variation in MP organization, stability, migration, and the driving factors of the profile in a deep reservoir were comprehensively explored. This is the first observation that TS interfaces in a deep reservoir act as a buffer area to retard MP subsidence, especially at the interface between the epilimnion and the metalimnion. Interestingly, there was a size-selection phenomenon for MP sinking. In particular, the high accumulation of large-sized MPs (LMPs; >300 µm) indicated that LMPs were more susceptible to dramatic changes in water density at the TS interfaces. Furthermore, simultaneous analysis of water parameters and MP surface characteristics showed that the drivers of MP deposition were biological to abiotic transitions during different layers, which were influenced by algae and metals. Specifically, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy and microscopic Fourier transform infrared analyses implied that the occurrence of metals on the MP surface can promote MP deposition in the hypolimnion. Our findings demonstrated that TS significantly influenced the MP fate in deep reservoirs, and the hotspot of MP exposure risk for vulnerable benthic organisms on the reservoir floor deserves more attention.

Identifying tumor cell-released extracellular vesicles as biomarkers for breast cancer diagnosis by a three-dimensional hydrogel-based electrochemical immunosensor.

Tumor cell-released LC3+ extracellular vesicles (LC3+ EVs) participate in immunosuppression during autophagy and contribute to the occurrence and development of breast cancer. In view of the strong association between the LC3+ EVs and breast cancer, developing an effective strategy for the quantitative detection of LC3+ EVs levels with high sensitivity to identify LC3+ EVs as new biomarkers for accurate diagnosis of breast cancer is crucial, but yet not been reported. Herein, an ultrasensitive electrochemical immunosensor is presented for the quantitative determination of LC3+ EVs using a three-dimensional graphene oxide hydrogel-methylene blue composite as a redox probe, showing a low detection limit and a wide linear range. With this immunosensor, the expression levels of LC3+ EVs in various practical sample groups including different cancer cell lines, the peripheral blood of tumor-bearing mice before and after immunotherapy, and the peripheral blood from breast cancer patients with different subtypes and stages were clearly distinguished. This study demonstrated that LC3+ EVs were superior as biomarkers for the accurate diagnosis of breast cancer compared to traditional biomarkers, particularly for cancer subtype discrimination. This work would provide a new noninvasive detection tool for the early diagnosis and prognosis assessment of breast cancer in clinics.

Tumor cell-released LC3-positive EVs promote lung metastasis of breast cancer through enhancing premetastatic niche formation.

Most breast cancer-related deaths are caused by metastasis in vital organs including the lungs. Development of supportive metastatic microenvironments, referred to as premetastatic niches (PMNs), in certain distant organs before arrival of metastatic cells, is critical in metastasis. However, the mechanisms of PMN formation are not fully clear. Here, we demonstrated that chemoattractant C-C motif chemokine ligand 2 (CCL2) could be stimulated by heat shock protein 60 (HSP60) on the surface of murine 4 T1 breast cancer cell-released LC3+ extracellular vesicles (LC3+ EVs) via the TLR2-MyD88-NF-κB signal cascade in lung fibroblasts, which subsequently promoted lung PMN formation through recruiting monocytes and suppressing T cell function. Consistently, reduction of LC3+ EV release or HSP60 level or neutralization of CCL2 markedly attenuated PMN formation and lung metastasis. Furthermore, the number of circulating LC3+ EVs and HSP60 level on LC3+ EVs in the plasma of breast cancer patients were positively correlated with disease progression and lung metastasis, which might have potential value as biomarkers of lung metastasis in breast cancer patients (AUC = 0.898, 0.694, respectively). These findings illuminate a novel mechanism of PMN formation and might provide therapeutic targets for anti-metastasis therapy for patients with breast cancer.

The RNA-binding protein fragile-X mental retardation autosomal 1 (FXR1) modulates glioma cells sensitivity to temozolomide by regulating ferroptosis.

Temozolomide (TMZ) is a first-line chemotherapeutic agent for the treatment of glioma. However, at least 50% of glioma patients do not respond to TMZ, and the exact mechanism leading to TMZ resistance is still unclear. In the present study, we investigated molecular mechanisms underlying the resistance to TMZ in glioma cells. Glioma cell lines A172 and U251 were maintained in medium with increasing doses of TMZ for 12 months to induce the TMZ-resistance. Cells were then transduced with different adenoviral vectors to overexpress or inhibit RNA-binding protein fragile-X mental retardation autosomal 1 (FXR1) and glutathione peroxidase 4 (GPX4), which has been associated with the ferroptosis mechanism. Cell viability and cell death were analysed using cell counting Kit-8 (CCK-8) and Annexin V-FITC staining, respectively. RT-PCR, RNA-seq analysis, and RNA immunoprecipitation were used to analyse RNA expression; Western blot was used for protein expression. We discovered that RNA-binding protein fragile-X mental retardation autosomal 1 (FXR1) was upregulated in TMZ-resistance glioma. Knockdown of FXR1 could overcome TMZ-resistance by promoting ferroptosis. Mechanically, FXR1 could bind with GPX4 mRNA and positively regulate the expression of GPX4. Inhibition of GPX4 further increased the sensitivity to TMZ in glioma cells with upregulated FXR1. Our data suggest that targeting FXR1-GPX4 might be a potential strategy to overcome chemoresistance to TMZ in glioma cells.

Tumor cell-released autophagosomes (TRAPs) induce PD-L1-decorated NETs that suppress T-cell function to promote breast cancer pulmonary metastasis.

BACKGROUND: Lung metastasis is the primary cause of breast cancer-related mortality. Neutrophil extracellular traps (NETs) are involved in the progression of breast cancer. However, the mechanism of NET formation is not fully understood. This study posits that tumor cell-released autophagosomes (TRAPs) play a crucial role in this process. METHODS: TRAPs were isolated from breast cancer cell lines to analyze their impact on NET formation in both human and mouse neutrophils. The study used both in vitro and in vivo models, including Toll-like receptor 4 (TLR4-/-) mice and engineered breast cancer cell lines. Immunofluorescence, ELISA, Western blotting, RNA sequencing, and flow cytometry were employed to dissect the signaling pathways leading to NET production and to explore their immunosuppressive effects, particularly focusing on the impact of NETs on T-cell function. The therapeutic potential of targeting TRAP-induced NETs and their immunosuppressive functions was evaluated using DNase I and αPD-L1 antibodies. Clinical relevance was assessed by correlating circulating levels of TRAPs and NETs with lung metastasis in patients with breast cancer. RESULTS: This study showed that TRAPs induced the formation of NETs in both human and mouse neutrophils by using the high mobility group box 1 and activating the TLR4-Myd88-ERK/p38 signaling axis. More importantly, PD-L1 carried by TRAP-induced NETs inhibited T-cell function in vitro and in vivo, thereby contributing to the formation of lung premetastatic niche (PMN) immunosuppression. In contrast, Becn1 KD-4T1 breast tumors with decreased circulating TRAPs in vivo reduced the formation of NETs, which in turn attenuated the immunosuppressive effects in PMN and resulted in a reduction of breast cancer pulmonary metastasis in murine models. Moreover, treatment with αPD-L1 in combination with DNase I that degraded NETs restored T-cell function and significantly reduced tumor metastasis. TRAP levels in the peripheral blood positively correlated with NET levels and lung metastasis in patients with breast cancer. CONCLUSIONS: Our results demonstrate a novel role of TRAPs in the formation of PD-L1-decorated NETs, which may provide a new strategy for early detection and treatment of pulmonary metastasis in patients with breast cancer.

Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer.

PURPOSE: Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer. METHODS: Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice. RESULTS: HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice. CONCLUSIONS: These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody.

Fusion of various optimisation based feature smoothing methods for wearable and non-invasive blood glucose estimation.

The traditional blood glucose estimation method requires to take the invasive measurements several times a day. Therefore, it has a high infection risk and the users are suffered from the pain. Moreover, the long term consumable cost is high. Recently, the wearable and non-invasive blood glucose estimation approach has been proposed. However, due to the unreliability of the acquisition device, the presence of the noise and the variations of the acquisition environments, the obtained features and the reference blood glucose values are highly unreliable. Moreover, different subjects have different responses of the infrared light to the blood glucose. To address this issue, a polynomial fitting approach to smooth the obtained features or the reference blood glucose values has been proposed. In particular, the design of the coefficients in the polynomial is formulated as the various optimisation problems. First, the blood glucose values are estimated based on the individual optimisation approaches. Second, the absolute difference values between the estimated blood glucose values and the actual blood glucose values based on each optimisation approach are computed. Third, these absolute difference values for each optimisation approach are sorted in the ascending order. Fourth, for each sorted blood glucose value, the optimisation method corresponding to the minimum absolute difference value is selected. Fifth, the accumulate probability of each selected optimisation method is computed. If the accumulate probability of any selected optimisation method at a point is greater than a threshold value, then the accumulate probabilities of these three selected optimisation methods at that point are reset to zero. A range of the sorted blood glucose values are defined as that with the corresponding boundaries points being the previous reset point and this reset point. Hence, after performing the above procedures for all the sorted reference blood glucose values in the validation set, the regions of the sorted reference blood glucose values and the corresponding optimisation methods in these regions are determined. It is worth noting that the conventional lowpass denoising method was performed in the signal domain (either in the time domain or in the frequency domain), while the authors' proposed method is performed in the feature space or the reference blood glucose space. Hence, the authors' proposed method can further improve the reliability of the obtained feature values or the reference blood glucose values so as to improve the accuracy of the blood glucose estimation. Moreover, the individual modelling regression method has been employed here to suppress the effects of different users having different responses of the infrared light to the blood glucose values. The computer numerical simulation results show that the authors' proposed method yields the mean absolute relative deviation (MARD) at 0.0930 and the percentage of the test data falling in the zone A of the Clarke error grid at 94.1176%.

Thymosin α-1 in cancer therapy: Immunoregulation and potential applications.

Thymosin α-1 (Tα-1) is an immunomodulating polypeptide of 28 amino acids, which was the first peptide isolated from thymic tissue and has been widely used for the treatment of viral infections, immunodeficiencies, and especially malignancies. Tα-1 stimulates both innate and adaptive immune responses, and its regulation of innate immune cells and adaptive immune cells varies under different disease conditions. Pleiotropic regulation of immune cells by Tα-1 depends on activation of Toll-like receptors and its downstream signaling pathways in various immune microenvironments. For treatment of malignancies, the combination of Tα-1 and chemotherapy has a strong synergistic effect by enhancing the anti-tumor immune response. On the basis of the pleiotropic effect of Tα-1 on immune cells and the promising results of preclinical studies, Tα-1 may be a favorable immunomodulator to enhance the curative effect and decrease immune-related adverse events of immune checkpoint inhibitors to develop novel cancer therapies.

Scoparone induces both apoptosis and ferroptosis via multiple mechanisms in non-small-cell lung cancer cells.

The present study investigated the anti-tumour effects of scoparone, also known as 6,7-dimethoxycoumarin, in non-small-cell-lung cancer (NSCLC) cells. It was discovered that scoparone inhibited the proliferation and induced cell death of NSCLC cells. Scoparone induced both apoptosis and ferroptosis in NSCLC cells. Mechanically, scoparone treatment led to the FBW7-mediated ubiquitination and downregulation of Mcl-1. Moreover, scopaone induced Bax activation in a reactive oxygen species (ROS)-dependent manner. Interestingly, scoparone also triggered ferroptosis, a novel form of cell death, as evidenced by upregulation of lipid peroxidation, ROS, and iron levels. The mechanism investigation showed that scoparone activated the ROS/JNK/SP1/ACSL4 axis to trigger ferroptosis in NSCLC cells. Overall, our data suggest that scoparone is a promising agent for the treatment of NSCLC.

Experimental study of the bilateral asymmetric single-rivet occluder device for transcatheter patent foramen ovale closure with reserved interatrial septal puncture area.

Purpose: To evaluate a noval bilateral asymmetric single-rivet occluder with reserved interatrial septal puncture area for treating patent foramen ovale (PFO). Materials and methods: The study established a pig model of patent foramen ovale (PFO) by puncturing the oval fossa and then performing high-pressure balloon dilation. A specially designed bilateral asymmetric occluder for the reserved interatrial septal puncture area was then. used to close the PFO through catheter-based intervention. The pigs were kept for 3 months before undergoing a second catheter-based intervention, involving interatrial septal puncture using a newly developed occluder in the reserved interatrial septal puncture area. During 6 months, the experimental pigs underwent assessment using digital subtraction angiography (DSA), echocardiography, and histological evaluation. Results: A patent foramen ovale (PFO) model was successfully established in 6 pigs using the puncture atrial septum high-pressure balloon dilation method. The diameter of the unclosed PFO was measured (3.56 ± 0.25 mm). Using the newly developed occluder device, all 6 pigs with unclosed PFO underwent successful catheter-based closure surgeries, with intraoperative and postoperative transesophageal echocardiography showing excellent device positioning and complete closure without residual shunting. After 3 months of implantation, the catheter-based interatrial septal puncture was performed through the reserved interatrial septal puncture area, and all procedures were successful. Immediately following euthanasia, a histological examination revealed intact and undamaged occluder devices with visible puncture holes in the reserved interatrial septal puncture area. No fracture of the nitinol wire was observed, and the surface of the occluder device showed coverage of endothelial and connective tissues. Utilizing a bilateral asymmetric single-rivet occluder device implanted through the reserved interatrial septal puncture area has proven effective in closing PFO. After implantation, the occluder device allows subsequent interatrial septal puncture procedures through the reserved area. Conclusion: The novel occluder device demonstrated excellent closure performance, biocompatibility, and puncturability in the experiment. This indicates the feasibility of conducting further catheter-based interventions on the interatrial septum.

Microplastic reorganization in urban river before and after rainfall.

Microplastics (MPs) present in non-negligible amounts in urban environments, where urban rivers serve as important transport channels for MPs. However, the footprint of MPs in urban rivers under the influence of natural and anthropogenic factors is poorly understood. This study investigated the MPs organization, stability and pollution risk before and after rainfall in the Qing River, Beijing. Rainfall potentially diluted the MPs abundance, attributed to opening of barrages and increase of flow velocity. The proportion of small-sized MPs (SMPs, 48-300 µm) decreased slightly, whereas that of normal-sized MPs (NMPs, 300-1000 µm) and large-sized MPs (LMPs, > 1000 µm) increased. However, SMPs dominantly presented in the Qing River before and after rainfall. Polyethylene terephthalate (PET), polypropylene (PP), polyethylene (PE), and polystyrene (PS) were main polymers observed in the Qing River. The proportions of PET and PS decreased, while PP and PE increased after rainfall. The main types of MPs introduced by stormwater were PP and PE. The elevated MP diversity integrated index after rain suggested that rainfall enriched the local sources of MPs. Rainfall reduced the stability and fragmentation of MPs owing to the introduction of large debris. NMPs and LMPs were susceptible to further fragmentation and downsizing, implying that MPs abundance in the Qing River tended to rise and SMPs might enriched. In addition, alteration of MPs fragmentation and stability reflected that the likely input source was wastewater treatment plant and atmospheric deposition before rainfall, whereas soil and road dust were possible sources after rainfall. The pollution risk assessment defined the MPs pollution risk of Qing River as low level and decreased after rainfall. This study demonstrated that rainfall substantially influences MPs organization in urban river and provided empirical support for MPs environmental behavior under influence of natural and anthropogenic factors.

Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis.

The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5'-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer. SIGNIFICANCE: Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.

A narrative review of multiple mechanisms of progranulin in cancer: a potential target for anti-cancer therapy.

Progranulin (PGRN) is an autocrine growth factor and has important effects on regulation of cell growth, motility, tissue repair and embryonic development. Recent years, several researches found the expression of PGRN was at higher levels in a number of cancer cells and its high levels are associated with poor outcome of patients. More and more studies investigated the role of PGRN in cancer and found PGRN exerted various biological functions in cancer cells, such as promoting proliferation, inhibiting apoptosis, inducing migration and invasion of cells, accelerating angiogenesis and enhancing the effectiveness of chemoresistance and radiation. Now the effects of PGRN have been demonstrated in several cancers, including breast cancer, lung cancer, and bladder cancer. In addition, several signaling pathways and molecules are involved in the effects of PGRN on cancer cells, including Akt, mitogen-activated protein kinase (MAPK), vascular endothelial growth factor (VEGF) and cyclin D1. Therefore, PGRN is probably a significant diagnostic and prognostic biomarker for cancer and may be a potential target for anti-cancer therapy. Here, we reviewed the advancing field of PGRN in cancer as well as several signaling pathways activated by PGRN and confirmed PGRN is a key role in cancer. Moreover, future studies are still necessary to elucidate the biological functions and signaling pathways of PGRN in cancer.

Genome-Wide Analysis of SRNF Genes in Gossypium hirsutum Reveals the Role of GhSRNF18 in Primary Root Growth.

Root systems are instrumental for water and nutrient uptake and the anchorage of plants in the soil. Root regulating GL2-interacting repressors (GIRs) contain a Short RING-like Zinc-Finger (SRNF) domain, but there has been no comprehensive characterization about this gene family in any plant species. Here, we renamed the GIR-like proteins as SRNF proteins due to their conserved domain and identified 140 SRNF genes from 16 plant species including 24 GhSRNF genes in Gossypium hirsutum. Phylogenetic analysis of the SRNFs revealed both similarities and divergences between five subfamilies. Notably, synteny analysis revealed that polyploidization and whole-genome duplication contribute to the expansion of the GhSRNF gene family. Various cis-acting regulatory elements were shown to be pertinent to light, phytohormone, defense responsive, and meristem regulation. Furthermore, GhSRNF2/15 were predominantly expressed in root, whereas the expression of GhSRNF18 is positively correlated with the primary root (PR) length in G. hirsutum, quantified by quantitative real-time PCR (qRT-PCR). Over-expression of GhSRNF18 in Arabidopsis and virus-induced gene silencing (VIGS) of GhSRNF18 in G. hirsutum has revealed the role of GhSRNF18 in PR growth. The over-expression of GhSRNF18 in Arabidopsis resulted in an increase of meristematic activities and auxin accumulations in PRs, which were consistent with the transcriptomic data. Our results suggested that GhSRNF18 positively regulates PR growth. This study increased our understanding of the SRNF gene family in plants and provided a novel rationale for the further investigation of cotton root morphogenesis regulated by the GhSRNFs.

Effects of Combinatorial Ubiquitinated Protein-Based Nanovaccine and STING Agonist in Mice With Drug-Resistant and Metastatic Breast Cancer.

We previously reported that enriched ubiquitinated proteins (UPs) from tumor cells have the potential to be used as immunotherapy vaccine against cancer. Here we enriched UPs from epirubicin (EPB)-induced multi-drug-resistant cancer stem-like breast cancer cell line (4T1/EPB) and tested the efficacy of α-Al2O3-UPs-4T1/EPB (short for UPs-4T1/EPB) as therapeutic vaccine alone and in combination with the stimulator of interferon genes (STING) agonist in mice with drug-resistant and metastatic breast cancer. Vaccination with UPs-4T1/EPB exerted profound anti-tumor effects through augmented specific CD8+ T cell responses and amplified T cell receptor diversity of tumor-infiltrating lymphocytes (TILs). Importantly, the combination with STING agonist further facilitated the migration of mature CD8α+ dendritic cells to the lymph nodes and the infiltration of TILs within tumors, resulting in primary tumor regression and pulmonary metastasis eradication in mice. Moreover, the cured mice were completely resistant against a subsequent rechallenge with the same tumor. Our study indicates that this novel combinatorial immunotherapy with UPs-4T1/EPB vaccine and STING agonist is effective in mice with drug-resistant and metastatic breast cancer.

Distribution and trajectory of handgrip strength in Chinese non-institutionalized middle-aged and older adults: A longitudinal descriptive analysis.

Using a national sample, we explored the distribution of and longitudinal trajectory of handgrip strength (HGS) in Chinese non-institutionalized middle-aged and older adults. We included a total of 12292 participants in the cross-sectional distribution analysis and a total of 7193 in the longitudinal trajectory analysis. The mean HGS was significantly higher (P < 0.001) in males (38.88 kg) than in females (26.52 kg). The HGS centiles and mean HGS in both males and females decreased as age increased. HGS declined with time in a nonlinear manner. HGS declined faster in males than in females.

Anti-Tumor Efficacy of an Adjuvant Built-In Nanovaccine Based on Ubiquitinated Proteins from Tumor Cells.

BACKGROUND AND AIM: We have previously identified ubiquitinated proteins (UPs) from tumor cell lysates as a promising vaccine for cancer immunotherapy in different mouse tumor models. In this study, we aimed at developing a highly efficient therapeutic adjuvant built-in nanovaccine (α-Al2O3-UPs) by a simple method, in which UPs from tumor cells could be efficiently and conveniently enriched by α-Al2O3 nanoparticles covalently coupled with Vx3 proteins (α-Al2O3-CONH-Vx3). METHODS: The α-Al2O3 nanoparticles were modified with 4-hydroxybenzoic acid followed by coupling with ubiquitin-binding protein Vx3. It was then used to enrich UPs from 4T1 cell lysate. The stability and the efficiency for the UPs enrichment of α-Al2O3-CONH-Vx3 were examined. The ability of α-Al2O3-UPs to activate DCs was examined in vitro subsequently. The splenocytes from the vaccinated mice were re-stimulated with inactivated tumor cells, and the IFN-γ secretion was detected by ELISA and flow cytometry. Moreover, the therapeutic efficacy of α-Al2O3-UPs, alone and in combination with chemotherapy, was examined in 4T1 tumor-bearing mice. RESULTS: Our results showed that α-Al2O3-UPs were successfully synthesized and abundant UPs from tumor cell lysate were enriched by the new method. In vitro study showed that compared to the physical mixture of α-Al2O3 nanoparticles and UPs (α-Al2O3+UPs), α-Al2O3-UPs stimulation resulted in higher upregulations of CD80, CD86, MHC class I, and MHC class II on DCs, indicating the higher ability of DC activation. Moreover, α-Al2O3-UPs elicited a more effective immune response in mice, demonstrated by higher IFN-γ secretion than α-Al2O3+UPs. Furthermore, α-Al2O3-UPs also exhibited a more potent effect on tumor growth inhibition and survival prolongation in 4T1 tumor-bearing mice. Notably, when in combination with low dose chemotherapy, the anti-tumor effect was further enhanced, rather than using α-Al2O3-UPs alone. CONCLUSION: This study presents an adjuvant built-in nanovaccine generated by a new simple method that can be potentially applied to cancer immunotherapy and lays the experimental foundation for future clinical application.