A Novel Nano-Spherical Tip for Improving Precision in Elastic Modulus Measurements of Polymer Materials via Atomic Force Microscopy.

Micro-nano-scale mechanical properties are vital for engineering and biological materials. The elastic modulus is generally measured by processing the force-indentation curves obtained by atomic force microscopy (AFM). However, the measurement precision is largely affected by tip shape, tip wear, sample morphology, and the contact model. In such research, it has been found that the radius of the sharp tip increases due to wear during contact scanning, affecting elastic modulus calculations. For flat-ended tips, it is difficult to identify the contact condition, leading to inaccurate results. Our research team has invented a nano-spherical tip, obtained by implanting focused helium ions into a silicon microcantilever, causing it to expand into a silicon nanosphere. This nano-spherical tip has the advantages of sub-micro size and a smooth spherical surface. Comparative tests of the elastic modulus measurement were conducted on polytetrafluoroethylene (PTFE) and polypropylene (PP) using these three tips. Overall, the experimental results show that our nano-spherical tip with a consistent tip radius, symmetrical geometric shape, and resistance to wear and contamination can improve precision in elastic modulus measurements of polymer materials.

Partial remission with sintilimab monotherapy in a patient carrying a CD274 amplification in refractory diffuse large B­cell lymphoma: A case report.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with varying characteristics, in terms of genomic variation, cell morphology and clinical presentation. At present, only ~66% of patients are cured with initial treatment and those with refractory DLBCL exhibit a poor prognosis. Thus, further investigations into novel effective treatment options for DLBCL are required. The present study reports the case of a patient resistant to multiple therapies, including rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus enzastaurin (trial no. CTR20171560), GemOx plus lenalidomide and selinexor (trial no. ATG-010-DLBCL-001). The patient harbored a CD274 amplification, as identified via next-generation sequencing (NGS), and exhibited a high programmed death-ligand 1 Tumor Proportion Score of up to 95%. Consequently, the patient was treated with sintilimab monotherapy and the response lasted for 12 months of follow-up without major immune-related adverse events. This case highlights the role of NGS technology in selecting treatment options for refractory DLBCL. Furthermore, the results of the present study suggest that sintilimab may have potential in the treatment of patients with refractory DLBCL.

Nuclear translocation of PKM2 mediates keratinocyte metabolic reprogramming in psoriasis.

PKM2 mediates the Warburg effects and is crucial for tumorigenesis, but its role in hyperplastic skin disorders remains elusive. In this study, we investigated the function of PKM2 in psoriatic keratinocytes. We found that PKM2 expression and its nuclear translocation were induced in the epidermis of psoriasis patients, contributing to aerobic glycolysis and cell growth. Moreover, mass spectrometry combined with immunoprecipitation analysis revealed that PKM2 could interact with TRIM33, an E3 ubiquitin ligase in the nucleus, and this interaction is critical for the nuclear retention of PKM2. As a result of TRIM33-mediated ubiquitination, PKM2 nuclear protein kinase function is promoted, thus leading to the phosphorylation of STAT3. In addition, blocking PKM2 nuclear translocation abrogated TRIM33-triggered glycolysis and cell proliferation in keratinocytes. Taken together, our experiments demonstrate that ubiquitination regulates the nuclear retention of PKM2 in keratinocytes. Moreover, our results highlight a novel mechanism accounting for the metabolic reprogramming of keratinocytes in psoriasis patients.

Multi-omics immune regulatory mechanisms in lung adenocarcinoma metastasis and survival time.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Despite previous research on immune mechanisms and related molecules in LUAD, the specific regulatory mechanisms of these molecules in the immune microenvironment remain unclear. Furthermore, the impact of regulatory genes or RNA on LUAD metastasis and survival time is yet to be understood. To address these gaps, we collected a substantial amount of data, including 17,226 gene expression profiles from 1,018 samples, 370,640 methylation sites from 461 samples, and 248 miRNAs from 513 samples. Our aim was to explore the genes, miRNAs, and methylation sites associated with LUAD progression. Leveraging the regulatory functions of miRNAs and methylation sites, we identified target and regulated genes. Through the utilization of LASSO and survival analysis, we pinpointed 22 key genes that play pivotal roles in the immune regulatory mechanism of LUAD. Notably, the expression levels of these 22 genes demonstrated significant discriminatory power in predicting LUAD patient survival time. Additionally, our deep learning model accurately predicted distant metastasis in LUAD patients using the expression levels of these genes. Further pathway enrichment analysis revealed that these 22 genes are significantly enriched in pathways closely linked to LUAD progression. Through Immune Infiltration Assay, we observed that T cell CD4 memory resting, monocytes, and macrophages.M2 were the three most abundant cell types in the immune microenvironment of LUAD. These cells are known to play crucial roles in tumor growth, invasion, and metastasis. Single-cell data analysis further validated the functional significance of these genes, indicating their involvement not only in immune cells but also in epithelial cells, showcasing significant differential expression. Overall, this study sheds light on the regulatory mechanisms underlying the immune microenvironment of LUAD by identifying key genes associated with LUAD progression. The findings provide insights into potential prognostic markers and therapeutic targets.

Mechanism of breast cancer immune microenvironment in prognosis of heart failure.

The treatment of breast cancer can potentially impose a burden on the heart, leading to an increased risk of heart failure. Studies have shown that more than half of breast cancer patients die from non-tumor-related causes, with cardiovascular disease (CVD) being the leading cause of death. However, the underlying mechanism linking breast cancer prognosis and heart failure remains unclear. To investigate this, we conducted an analysis where we compared the differentially expressed genes (DEGs) in early and advanced breast cancer with genes associated with heart failure. This analysis revealed 18 genes that overlapped between the two conditions, with 15 of them being related to immune function. This suggests that immune pathways may play a role in the prognosis of breast cancer patients with heart failure. Using gene expression data from 1260 breast cancer patients, we further examined the impact of these 15 genes on survival time. Additionally, through enrichment analysis, we explored the functions and pathways associated with these genes in relation to breast cancer and heart failure. By constructing a transformer model, we discovered that the expression patterns of these 15 genes can accurately predict the occurrence of heart failure. The model achieved an AUC of 0.86 and an AUPR of 0.91. Moreover, through analysis of single-cell sequencing data from breast cancer patients undergoing PD-1 treatment and experiencing heart failure, we identified a significant number of cell-type-specific genes that were shared between both diseases. This suggests that changes in gene expression in immune cells following breast cancer treatment may be associated with the development of heart failure.

The emerging roles of Hedgehog signaling in tumor immune microenvironment.

The Hedgehog (Hh) signaling pathway is pervasively involved in human malignancies, making it an effective target for cancer treatment for decades. In addition to its direct role in regulating cancer cell attributes, recent work indicates that it has an immunoregulatory effect on tumor microenvironments. An integrated understanding of these actions of Hh signaling pathway in tumor cells and tumor microenvironments will pave the way for novel tumor treatments and further advances in anti-tumor immunotherapy. In this review, we discuss the most recent research about Hh signaling pathway transduction, with a particular emphasis on its role in modulating tumor immune/stroma cell phenotype and function, such as macrophage polarity, T cell response, and fibroblast activation, as well as their mutual interactions between tumor cells and nonneoplastic cells. We also summarize the recent advances in the development of Hh pathway inhibitors and nanoparticle formulation for Hh pathway modulation. We suggest that targeting Hh signaling effects on both tumor cells and tumor immune microenvironments could be more synergistic for cancer treatment.

Human bone marrow-derived mesenchymal stem overexpressing microRNA-124-3p inhibit DLBCL progression by downregulating the NFATc1/cMYC pathway.

BACKGROUND: Exosomes play important roles in intercellular communication by delivering microRNAs (miRNAs) that mediate tumor initiation and development, including those in diffuse large B cell lymphoma (DLBCL). To date, however, limited studies on the inhibitory effect of exosomes derived from human bone marrow mesenchymal stem cells (hBMSCs) on DLBCL progression have been reported. Therefore, this study aimed to investigate the role of hBMSC exosomes carrying microRNA-124-3p in the development of DLBCL. METHODS: Microarray-based expression analysis was adopted to identify differentially expressed genes and regulatory miRNAs, which revealed the candidate NFATc1. Next, the binding affinity between miR-124-3p and NFATc1 was detected by luciferase activity assays. The mechanism underlying NFATc1 regulation was investigated using lentiviral transfections. Subsequently, DLBCL cells were cocultured with exosomes derived from hBMSCs transfected with a miR-124-3p mimic or control. Proliferation and apoptosis were measured in vitro. Finally, the effects of hBMSC-miR-124-3p on tumor growth were investigated in vivo. RESULTS: MiR-124-3p was expressed at low levels, while NFATc1 was highly expressed in DLBCL cells. MiR-124-3p specifically targeted and negatively regulated the expression of NFATc1 in DLBCL cells, upregulated miR-124-3p-inhibited DLBCL cell proliferation and promoted apoptosis. The miR-124-3p derived from hBMSCs inhibits tumor growth both in vivo and in vitro via downregulation of the NFATc1/cMYC pathway. CONCLUSION: Human bone marrow-derived mesenchymal stem cell overexpressing microRNA-124-3p represses the development of DLBCL through the downregulation of NFATc1.

Advances in the treatment of Hodgkin's lymphoma (Review).

Hodgkin's lymphoma (HL) is a unique B­cell lymphoproliferative malignancy that has a critical pathogenesis characterized by a sparse population of Hodgkin and Reed­Sternberg cells surrounded by numerous dysfunctional immune cells. Although systemic chemotherapy with or without radiotherapy, has significantly improved the prognosis of the majority of patients with HL, a subset of patients remains refractory to first­line therapy or relapse after achieving an initial response. With the increased understanding of the biology and microenvironment of HL, novel strategies with notable efficacy and manageable toxicity, including targeted therapies, immunotherapy and cell therapy have emerged. The present review summarizes the progress made in developing novel therapies for HL and discusses future research directions in HL therapy.

Secondary hemophagocytic lymphohistiocytosis triggered by peripheral T-cell lymphoma: An unusual case report.

Hemophagocytic lymphohistiocytosis (HLH) is a severe syndrome of pathological immune activation caused by activated macrophages and cytotoxic T cells. We report a 65-year-old male Chinese patient with typical HLH features caused by peripheral T-cell lymphoma and then received chemotherapy. However, though the patient's symptoms and signs improved much, his liver function, especially bilirubin, worsened which could be caused by overwhelming cytokines production. Therefore, plasmapheresis was conducted two times and then his liver function significantly recovered. The patient got temporary remission and good quality of life for nearly 2 months but died because of disease progression. In conclusion, as HLH is associated with multiorgan failure, high rates of morbidity and mortality, there are three points to be mentioned. First, it is critical that HLH should be screened as early as possible and initiate effective therapies. Second, plasmapheresis could be a useful method to eliminate excess cytokines production and improve liver function. Third, organs support and nutrient supply are also necessary and important.

The regulation of skin homeostasis, repair and the pathogenesis of skin diseases by spatiotemporal activation of epidermal mTOR signaling.

The epidermis, the outmost layer of the skin, is a stratified squamous epithelium that protects the body from the external world. The epidermis and its appendages need constantly renew themselves and replace the damaged tissues caused by environmental assaults. The mechanistic target of rapamycin (mTOR) signaling is a central controller of cell growth and metabolism that plays a critical role in development, homeostasis and diseases. Recent findings suggest that mTOR signaling is activated in a spatiotemporal and context-dependent manner in the epidermis, coordinating diverse skin homeostatic processes. Dysregulation of mTOR signaling underlies the pathogenesis of skin diseases, including psoriasis and skin cancer. In this review, we discuss the role of epidermal mTOR signaling activity and function in skin, with a focus on skin barrier formation, hair regeneration, wound repair, as well as skin pathological disorders. We propose that fine-tuned control of mTOR signaling is essential for epidermal structural and functional integrity.

Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing.

Wound healing is a coordinated process that initially relies on pro-inflammatory macrophages, followed by a pro-resolution function of these cells. Changes in cellular metabolism likely dictate these distinct activities, but the nature of these changes has been unclear. Here, we profiled early- versus late-stage skin wound macrophages in mice at both the transcriptional and functional levels. We found that glycolytic metabolism in the early phase is not sufficient to ensure productive repair. Instead, by combining conditional disruption of the electron transport chain with deletion of mitochondrial aspartyl-tRNA synthetase, followed by single-cell sequencing analysis, we found that a subpopulation of early-stage wound macrophages are marked by mitochondrial ROS (mtROS) production and HIF1α stabilization, which ultimately drives a pro-angiogenic program essential for timely healing. In contrast, late-phase, pro-resolving wound macrophages are marked by IL-4Rα-mediated mitochondrial respiration and mitohormesis. Collectively, we identify changes in mitochondrial metabolism as a critical control mechanism for macrophage effector functions during wound healing.

A novel pine wood nematode effector, BxSCD1, suppresses plant immunity and interacts with an ethylene-forming enzyme in pine.

The plant-parasitic nematode Bursaphelenchus xylophilus, the causal agent of pine wilt disease (PWD), causes enormous economic loss every year. Currently, little is known about the pathogenic mechanisms of PWD. Several effectors have been identified in B. xylophilus, but their functions and host targets have yet to be elucidated. Here, we demonstrated that BxSCD1 suppresses cell death and inhibits B. xylophilus PAMP BxCDP1-triggered immunity in Nicotiana benthamiana and Pinus thunbergii. BxSCD1 was transcriptionally upregulated in the early stage of B. xylophilus infection. In situ hybridization experiments showed that BxSCD1 was specifically expressed in the dorsal glands and intestine. Cysteine residues are essential for the function of BxSCD1. Transient expression of BxSCD1 in N. benthamiana revealed that it was primarily targeted to the cytoplasm and nucleus. The morbidity was significantly reduced in P. thunbergii infected with B. xylophilus when BxSCD1 was silenced. We identified 1-aminocyclopropane-1-carboxylate oxidase 1, the actual ethylene-forming enzyme, as a host target of BxSCD1 by yeast two-hybrid and coimmunoprecipitation. Overall, this study illustrated that BxSCD1 played a critical role in the B. xylophilus-plant interaction.

Comparative transcriptomic analysis of candidate effectors to explore the infection and survival strategy of Bursaphelenchus xylophilus during different interaction stages with pine trees.

BACKGROUND: The pine wood nematode (PWN), Bursaphelenchus xylophilus, is a devastating pathogen of many Pinus species in China. The aim of this study was to understand the interactive molecular mechanism of PWN and its host by comparing differentially expressed genes and candidate effectors from three transcriptomes of B. xylophilus at different infection stages. RESULTS: In total, 62, 69 and 46 candidate effectors were identified in three transcriptomes (2.5 h postinfection, 6, 12 and 24 h postinoculation and 6 and 15 d postinfection, respectively). In addition to uncharacterized pioneers, other candidate effectors were involved in the degradation of host tissues, suppression of host defenses, targeting plant signaling pathways, feeding and detoxification, which helped B. xylophilus survive successfully in the host. Seven candidate effectors were identified in both our study and the B. xylophilus transcriptome at 2.5 h postinfection, and one candidate effector was identified in all three transcriptomes. These common candidate effectors were upregulated at infection stages, and one of them suppressed pathogen-associated molecular pattern (PAMP) PsXEG1-triggered cell death in Nicotiana benthamiana. CONCLUSIONS: The results indicated that B. xylophilus secreted various candidate effectors, and some of them continued to function throughout all infection stages. These various candidate effectors were important to B. xylophilus infection and survival, and they functioned in different ways (such as breaking down host cell walls, suppressing host defenses, promoting feeding efficiency, promoting detoxification and playing virulence functions). The present results provide valuable resources for in-depth research on the pathogenesis of B. xylophilus from the perspective of effectors.

Diabetes Impedes the Epigenetic Switch of Macrophages into Repair Mode.

In this issue of Immunity, Kimball et al. (2019) show that restoring expression of the chromatin modifying enzyme Setdb2 in macrophages rescues impaired wound healing associated with type 2 diabetes. Their findings reveal epigenetic regulation as central to the resolution of macrophage-mediated inflammation in tissue repair and have therapeutic implications for the treatment of diabetic wounds.

Effective remission of chidamide on treatment of advanced mycosis fungoides: An unusual case report.

Mycosis fungoides (MF) and Sézary syndrome are the most common types of primary cutaneous T cell lymphoma, which primarily involves skin without curative treatment. We report a case of a 29-year-old female Chinese patient, who developed multiple cutaneous lesions gradually for 5 years. However, the patient could not tolerate pruritus and ulceration of cutaneous lesions, so she was admitted to hospital and diagnosed with advanced MF based on clinical manifestation, laboratory, and image results. Then she received four cycles of COPE regimen (cyclophosphamide, vincristine, prednisolone, and etoposide). Although the skin lesions shrinked and sense of pruritus alleviated quickly after the chemotherapy, the effective remission duration was not satisfactory. Therefore, the patient received gemcitabine and thalidomide for three cycles subsequently. Still the remission duration was not long lasting. After that, she took chidamide orally two times a week. By the time of 7 weeks, the patches almost diminished and the patient did not feel itching for almost 6 months. And, she did not have any adverse effect and had a better quality of life than the period of chemotherapy.