The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression.

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor (TCR)-mediated signaling pathway, such as the lymphocyte-specific protein tyrosine kinase (Lck), Src family tyrosine kinases Fyn, and the phosphorylation levels of Zeta-chain-associated protein kinase-70 (ZAP70). For the first time, we have successfully produced PTPN22 CS transgenic mice in which the tyrosine phosphatase activity of PTPN22 is suppressed. Notably, the number of thymocytes in the PTPN22 CS mice was significantly reduced, and the expression of cytokines in the spleen and lymph nodes was changed significantly. Furthermore, PTPN22 CS facilitated the positive and negative selection of developing thymocytes, increased the expression of the TCRαß-CD3 complex on the thymus cell surface, and regulated their internalization and recycling. ZAP70, Lck, Phospholipase C gamma1(PLCγ1), and other proteins were observed to be reduced in PTPN22 CS mouse thymocytes. In summary, PTPN22 regulates TCR internalization and recycling via the modulation of the TCR signaling pathway and affects TCR expression on the T cell surface to regulate negative and positive selection. PTPN22 affected the development of the thymus, spleen, lymph nodes, and other peripheral immune organs in mice. Our study demonstrated that PTPN22 plays a crucial role in T cell development and provides a theoretical basis for immune system construction.

PTPN22 interacts with EB1 to regulate T-cell receptor signaling.

The PTPN22 gene encoding the Lyp/Pep protein tyrosine phosphatase is a negative regulator of T-cell receptor (TCR) signaling. Recent studies have shown that phosphorylation of end-binding protein 1 (EB1) is associated with the TCR activation. In this study, using 2-hybrid and mass spectrometry analyses, we identified EB1 as a protein associated with PTPN22. Furthermore, we discovered that EB1 specifically bound to the P1 domain of PTPN22 by competing with CSK, and the variant PTPN22-R620W does not affect the association with EB1, which is instrumental with respect to the regulation of TCR signaling. In addition, PTPN22 dephosphorylates EB1 at tyrosine-247 (Y247), which decreases the expression of the T-cell activation markers CD25 and CD69 and the phosphorylation levels of the TCR molecules ZAP-70, LAT, and Erk, leading to the eventual downregulation of the transcription factor NFAT and reduced the levels of secreted IL-2. The findings of this study provide new insights into the TCR signaling and the T-cell immune response, which are important for clarifying the mechanism of PTPN22-related autoimmune diseases.

Design of a Molecular Hybrid of Dual Peptide Inhibitors Coupled on AuNPs for Enhanced Inhibition of Amyloid ß-Protein Aggregation and Cytotoxicity.

Aggregation of amyloid-ß protein (Aß) is a pathological hallmark of Alzheimer's disease (AD), so the inhibition of Aß aggregation is an important strategy for the prevention and treatment of AD. Herein, we proposed to design molecular hybrids of peptide inhibitors by combining two peptide inhibitors, VVIA and LPFFD, into single sequences and examined their effects on Aß42 aggregation and cytotoxicity. The hybrid peptides exhibit increased but moderate inhibitory activity as compared to their two precursors. By conjugating the peptides onto gold nanoparticles (AuNPs), however, the inhibition activity of the corresponding peptide@AuNPs against Aß42 aggregation and cytotoxicity is greatly improved. Among them, VVIACLPFFD (VCD10)@AuNP is the most effective, which increases cell viability from 48% to 82% at a dosage as low as 0.1 nmol L-1 (NPs) or 40 nmol L-1 (peptide). The superior capacity of VCD10@AuNPs is considered due to its branched dual-inhibitor sequence, and its special surface orientation and conformation. These structural features promote its synergetic interactions with Aß on AuNP surface, leading to strong inhibitions of Aß oligomerization and fibrillation and the cytotoxicity caused by the aggregation species. The findings suggest that potent inhibitors can be derived by hybridization of multiple peptide inhibitors with the hybrid products coupled onto nanoparticles.

Tunable silicon-based all-dielectric metamaterials with strontium titanate thin film in terahertz range.

Silicon-based all-dielectric metamaterials (SAMs), with advantages like low loss and simple structure, are attracting more and more attention. However, SAMs usually suffer from narrow bandwidth and low tunability, and thereby their applications are seriously impeded. In this work, we propose and experimentally demonstrate a tunable SAMs in terahertz (THz) ranges by covering the SAMs with a layer of active medium, strontium titanate (STO). It shows that the THz responses of SAMs can be thermally tuned due to the temperature-dependent permittivity of STO. This work provides a convenient route to tunable SAMs from THz to optical ranges.

A case report of low-dose apatinib in the treatment of advanced triple-negative breast cancer.

Background: The current study shows that the incidence rate of triple-negative breast cancer accounts for 10-17% of invasive ductal carcinoma of the breast. There is no specific treatment target, the age of onset is relatively small, and the recurrence rate is relatively fast. The prognosis of breast cancer in different subtypes is the most unsatisfactory, with a 5-year survival rate of less than 15%. We report a typical case of metastatic advanced triple-negative breast cancer who responded well to apatinib mesylate after chemotherapy failure and achieved significant progression-free survival, which is relatively rare in triple-negative breast cancer with limited treatment means. Case Description: A 55-year-old female was surgically diagnosed as triple-negative breast cancer on April 17, 2015. After surgery, she had lung metastasis after standard adjuvant chemotherapy and radiotherapy. After receiving the NX regimen (vinorelbine, capecitabine) for 8 cycles, she progressed. Because the patient refused later, she was adjusted to apatinib mesylate, and serious adverse reactions occurred during the treatment process. By adjusting the drug dose, and low-dose apatinib treatment, the lung lesions were close to complete response (CR), reaching a progression-free survival period of 45 months. Conclusions: Low-dose apatinib may be a promising anti-tumor drug for triple-negative breast cancer patients, which needs more samples to verify. This case may provide a reference for the treatment selection of triple-negative metastatic breast cancer in the future.

Crucial role of hsa-mir-503, hsa-mir-1247, and their validation in prostate cancer.

BACKGROUND: Prostate cancer (PC) is a common urinary system malignancy, and advanced PC patients had a poor prognosis due to recurrence or distant metastasis. Therefore, it's imperative to reveal more details in tumorigenesis and prognosis of PC patients. METHODS: The miRNA and mRNA expression profile data of 485 PC patients were obtained from The Cancer Genome Atlas database. The univariate Cox regression was applied to screen miRNAs relating to prognosis of PC. Then miRTarBase was used to predict target mRNAs of miRNAs. The hsa-mir-503/hsa-mir-1247 knockdown in 22RV1 cells was established to evaluate the effect of these two miRNAs on tumor cell migration and invasion ability. Flow cytometry was used to detect the effect of hsa-mir-503/hsa-mir-1247 knockdown on 22RV1 apoptosis rate. RESULTS: Univariate Cox regression analysis identified hsa-mir-503 as a poor and hsa-mir-1247 as a favorable prognostic marker. Totally 649 target mRNAs were screened, among which DUSP19, FGF2, and SLC2A5 had a negative correlation with hsa-mir-503, while FGF2 and VSTM4 had a positive correlation with hsa-mir-1247. In 22RV1 cells, hsa-mir-503 was up-regulated, and hsa-mir-1247 was down-regulated. hsa-mir-503 knockdown attenuated the migration and invasion of 22RV1 cells, while hsa-mir-1247 knockdown exhibited the opposite effect. In addition, hsa-mir-503 knockdown promoted 22RV1 cell apoptosis. hsa-mir-1247 overexpression significantly inhibited the tumor growth of PC in vivo. CONCLUSIONS: Herein, we demonstrated that hsa-mir-503 and hsa-mir-1247 could serve as new prognostic markers of PC, and hsa-mir-1247 had great potential to inhibit PC progression by suppressing the migration and invasion ability in vitro and in vivo.

Preparation and Characterization of Calcium Carbonate Masterbatch-Alkali Soluble Polyester/Polyester Porous Fiber via Melt Spinning.

Porous fibers have gained significant attention for their lightweight and high porosity properties in applications such as insulation and filtration. However, the challenge remains in the development of cost-effective, high-performance, and industrially viable porous fibers. In this paper, porous fibers were fabricated through the melt spinning of an alkali soluble polyester (COPET)- CaCO3 masterbatch and PET slice. Controlled alkali and acid post-treatment techniques were employed to create porous structures within the fibers. The effects on the morphology, mechanical, thermodynamic, crystallinity, pore size, and thermal stability were investigated. The results indicate that the uniform dispersion of CaCO3 particles within the fiber matrix acts as nucleating agents during the granulation process, improving the thermal resistance and strength of the porous fiber. In addition, the porous fiber prepared by COPET/CaCO3 to PET with an 85/15 ratio and post-treated on 4% NaOH and 3% HCl exhibits a "spongy body" with uniformly small pores, favorable strength (2.71 cN/dtex), and elongation at break (47%).

PTPN18 Serves as a Potential Oncogene for Glioblastoma by Enhancing Immune Suppression.

Glioblastoma is characterized as one of the deadliest cancers in humans. The survival time is not improved by standard treatment. Although immunotherapy has revolutionized cancer treatment, the current therapy targets for glioblastoma patients are not satisfied. We systematically analyzed the expression patterns, predictive values, and immunological characteristics of PTPN18 in glioblastoma. The independent datasets and functional experiments were employed to validate our findings. Our data showed that PTPN18 is potentially cancerogenic in glioblastoma with advanced grades and poor prognosis. High expression of PTPN18 correlated with CD8+ T cell exhaustion and immune suppression in glioblastoma. In addition, PTPN18 facilitates glioblastoma progression by accelerating glioma cell prefiltration, colony formation, and tumor growth in mice. PTPN18 also promotes cell cycle progression and inhibits apoptosis. Our results illustrate the characterization of PTPN18 in glioblastoma and highlight the potential value as an immunotherapeutic target for glioblastoma treatment.

PTPN22 activates the PI3K pathway via 14-3-3τ in T cells.

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor-mediated signalling pathway, and its negative regulatory function protects organisms from autoimmune disease. 14-3-3τ is an adaptor protein that regulates target protein function through its intracellular localization. In the present study, we determined that PTPN22 binds to 14-3-3τ via the PTPN22-Ser640 phosphorylation side. PTPN22 binding to 14-3-3τ resulted in 14-3-3τ-Tyr179 dephosphorylation, and reduced the association between 14-3-3τ and Shc, which competitively increased 14-3-3ζ binding to Shc and activated phosphoinositide 3-kinase (PI3K) by bringing it to the membrane. In addition, PTPN22 decreased the tyrosine phosphorylation of p110 to activate PI3K. These two pathways cooperatively affect PI3K activity and the expression of PI3K downstream proteins, such as phosphorylated Akt, mammalian target of rapamycin and forkhead box O1, which inhibited the expression of some proinflammatory factors such as interleukin-1ß, interleukin-2, interleukin-6, interferon-γ and tumour necrosis factor-α. Our research provides a preliminary theory for PTPN22 regulating T cell activation, development and immune response via the PI3K/Akt/mammalian target of rapamycin pathway and brings new information for clarifying the functions of PTPN22 in autoimmune diseases.

Corrigendum: Immunogenomic landscape in breast cancer reveals immunotherapeutically relevant gene signatures.

[This corrects the article DOI: 10.3389/fimmu.2022.805184.].

Multilayer structured CNF/rGO aerogels and rGO film composites for efficient electromagnetic interference shielding.

The development of efficient electromagnetic interference (EMI) shielding materials with high electromagnetic waves (EMWs) absorption capacity is of great significance to alleviate secondary EMWs pollution. Herein, multilayered composites were prepared by stacking cellulose nanofibril (CNF)/reduced graphene oxide (rGO) aerogels and rGO film together. The porous aerogels and the dense film serve as the EMWs absorbing layer and reflecting layer, respectively. When the EMWs enter the multilayer composites, they go through the process of absorption-reflection-reabsorption, resulting in a high EMI shielding effectiveness (SE) of ~32 dB. Furthermore, both experimental and theoretical analyses were adopted to explore the effect of arrangement order of CNF/rGO aerogels on EMI shielding performance. The results indicate that composites with progressively higher graphene content exhibit a higher EMWs absorption capacity at the same total EMI SE. This work offers a feasible design for improving EMWs absorption without affecting the overall EMI shielding performance of the material.

Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer.

Protein tyrosine phosphatases function in dephosphorylating target proteins to regulate signaling pathways that control a broad spectrum of fundamental physiological and pathological processes. Detailed knowledge concerning the roles of classical PTPs in human cancer merits in-depth investigation. We comprehensively analyzed the regulatory mechanisms and clinical relevance of classical PTPs in more than 9000 tumor patients across 33 types of cancer. The independent datasets and functional experiments were employed to validate our findings. We exhibited the extensive dysregulation of classical PTPs and constructed the gene regulatory network in human cancer. Moreover, we characterized the correlation of classical PTPs with both drug-resistant and drug-sensitive responses to anti-cancer drugs. To evaluate the PTP activity in cancer prognosis, we generated a PTPscore based on the expression and hazard ratio of classical PTPs. Our study highlights the notable role of classical PTPs in cancer biology and provides novel intelligence to improve potential therapeutic strategies based on pTyr regulation.

Nuclear import of PTPN18 inhibits breast cancer metastasis mediated by MVP and importin ß2.

Distant metastasis is the primary cause of breast cancer-associated death. The existing information, such as the precise molecular mechanisms and effective therapeutic strategies targeting metastasis, is insufficient to combat breast cancer. This study demonstrates that the protein tyrosine phosphatase PTPN18 is downregulated in metastatic breast cancer tissues and is associated with better metastasis-free survival. Ectopic expression of PTPN18 inhibits breast cancer cell metastasis. PTPN18 is translocated from the cytoplasm to the nucleus by MVP and importin ß2 in breast cancer. Then, nuclear PTPN18 dephosphorylates ETS1 and promotes its degradation. Moreover, nuclear PTPN18 but not cytoplasmic PTPN18 suppresses transforming growth factor-ß signaling and epithelial-to-mesenchymal transition by targeting ETS1. Our data highlight PTPN18 as a suppressor of breast cancer metastasis and provide an effective antimetastatic therapeutic strategy.

Immunogenomic Landscape in Breast Cancer Reveals Immunotherapeutically Relevant Gene Signatures.

Breast cancer is characterized by some types of heterogeneity, high aggressive behaviour, and low immunotherapeutic efficiency. Detailed immune stratification is a prerequisite for interpreting resistance to treatment and escape from immune control. Hence, the immune landscape of breast cancer needs further understanding. We systematically clustered breast cancer into six immune subtypes based on the mRNA expression patterns of immune signatures and comprehensively depicted their characteristics. The immunotherapeutic benefit score (ITBscore) was validated to be a superior predictor of the response to immunotherapy in cohorts from various datasets. Six distinct immune subtypes related to divergences in biological functions, signatures of immune or stromal cells, extent of the adaptive immune response, genomic events, and clinical prognostication were identified. These six subtypes were characterized as immunologically quiet, chemokine dominant, lymphocyte depleted, wounding dominant, innate immune dominant, and IFN-γ dominant and exhibited features of the tumor microenvironment (TME). The high ITBscore subgroup, characterized by a high proportion of M1 macrophages:M2 macrophages, an activated inflammatory response, and increased mutational burden (such as mutations in TP53, CDH1 and CENPE), indicated better immunotherapeutic benefits. A low proportion of tumor-infiltrating lymphocytes (TILs) and an inadequate response to immune treatment were associated with the low ITBscore subgroup, which was also associated with poor survival. Analyses of four cohorts treated with immune checkpoint inhibitors (ICIs) suggested that patients with a high ITBscore received significant therapeutic advantages and clinical benefits. Our work may facilitate the understanding of immune phenotypes in shaping different TME landscapes and guide precision immuno-oncology and immunotherapy strategies.

Gene Expression-Based Immune Cell Infiltration Analyses of Prostate Cancer and Their Associations with Survival Outcome.

Prostate cancer is the second most common cancer and the fifth cause of cancer death in males. Currently, there are no effective therapies for prostate cancer yet, and the status of treatment remains severe. In this study, we analyzed the composition of tumor-infiltrating immune cells (TIICs) in prostate cancer and paracancerous samples based on the gene expression profiles using CIBERSORT. Calculation of the TIIC subset proportions in 52 paired prostate cancer and paracancerous samples showed that their proportions were similar in intergroup and varied in intragroup. Compared with the paracancerous samples, the proportion of M0 macrophages was significantly increased in prostate cancer samples. Cox regression analysis using the TIIC subpopulations as continuous variables revealed that high plasma cell proportion was associated with poor 3-year Disease-Free Survival (DFS) in prostate cancer (hazard ratios = 1.8e-76, p = 0.001). Moreover, three immune clusters, which presented distinct prognosis, were identified using hierarchical clustering analysis based on the proportions of TIIC subpopulations. Among them, cluster 1 had superior 3-year DFS, while cluster 3 showed inferior 3-year DFS (p = 0.025). In summary, our research provided a comprehensive analysis on the TIIC composition in prostate cancer and suggested that both plasma cells and different cluster patterns were associated with the prostate cancer prognosis, which should be helpful for the clinical surveillance and treatment of prostate cancer.

Efficient Delivery of Triptolide Plus a miR-30-5p Inhibitor Through the Use of Near Infrared Laser Responsive or CADY Modified MSNs for Efficacy in Rheumatoid Arthritis Therapeutics.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease for which treatment focuses on suppressing an overactive immune system and maintaining the physiological balance of synovial fibroblasts (SFs). We found that miR-30-5p was highly expressed in rheumatoid arthritis synovial fibroblasts (RASFs). Subsequently, we predicted that phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2) might be a putative target of miR-30-5p. Recent studies have reported that PIK3R2 can maintain the physiological homeostasis of RASFs. Therefore, miR-30-5p inhibitor has the potential to be used in the treatment of RA, but low levels of miR-30-5p inhibitor internalization affect its application. Triptolide (TP) is an effective drug in the treatment of RA but induces severe toxicity and has a narrow therapeutic window. In this study, the cell internalization performance of miR-30-5p inhibitor was improved by loading it into cell membrane penetrating peptide (CADY)-modified mesoporous silica nanoparticles (MSNs), and the toxicity of TP was decreased by loading it into a controlled drug release system based on MSNs. The nanodrug carrier was constructed by filling a phase-change material (PCM) of 1-tetradecanol and drugs into MSNs that could be triggered by an NIR laser with thermo-chemo combination RA therapy. Our results show that the miR-30-5p inhibitor-loaded MSNs@CADY significantly inhibited RASF proliferation and increased apoptosis. In addition, MSNs@PCM@TP under 808 nm laser irradiation were effective in downregulating immune system activation in an RA rat model. Finally, the results of a pharmacodynamics study showed that the combination of MSNs@CADY@miR-30-5p inhibitor and MSNs@PCM@TP under 808 nm laser significantly increased the effectiveness of RA treatment. These findings provide a novel understanding of RA pathogenesis and a theoretical basis for RA treatment.

Elevated Expression of LYPD3 Is Associated with Lung Adenocarcinoma Carcinogenesis and Poor Prognosis.

Aberrant expression of LYPD3 plays an oncogenic role in several types of cancer. However, the functions of LYPD3 in lung adenocarcinoma (LUAD) remain unclear. Here, we investigated the regulatory function, clinical value, and prognostic significance of LYPD3 in LUAD patients. The gene expression and DNA methylation data of LUAD tumor and paracancerous tissues were obtained from The Cancer Genome Atlas (TCGA) database. The association between LYPD3 expression and clinicopathological variables was analyzed. The results showed that LYPD3 was highly expressed in LUAD tumor compared with paracancerous tissues, which was positively correlated with the race (p = 0.0448), tumor stage (p = 0.0191), and survival status (p < 0.001). Furthermore, the expression of LYPD3 was able to be regulated by the methylation in LYPD3 promoter region, which was positively associated with the overall survival. Furthermore, we explored the related pathways through which LYPD3 affects the pathogenesis and prognosis of LUAD by gene set enrichment analysis, and found that LYPD3 might affect the clinical manifestations of LUAD by regulating the P53 signaling pathway. In the future, we would focus on exploring the molecular mechanism of LYPD3 in the regulation of the occurrence and development of LUAD to provide a research basis for the screening of methylation markers related to the treatment and prognosis.

Co-metabolic biodegradation of acetamiprid by Pseudoxanthomonas sp. AAP-7 isolated from a long-term acetamiprid-polluted soil.

An AAP-degrading bacterium, AAP-7, was isolated from AAP-polluted soil. AAP-7 was identified as Pseudoxanthomonas sp. on the basis of the comparative analysis of 16S rDNA sequences. The strain was able to transformate more than 80% AAP by means of co-metabolism and degraded AAP via hydrolysis or demethylation to form (E)-3-(((6-chloropyridin-3yl)methyl)(methyl)amino)acrylonitrile and N-((6-chloropyridin-3yl)methyl)-N-methylprop-1-en-2-amine, both of which transformed into ultimate product, which was 1-(6-chloropyridin-3yl)-N-methylmethanamine. A novel degradation pathway was proposed based on these metabolites. AAP could be transformed with a maximum specific degradation rate, half-saturation constant and inhibit constant of 1.775/36 h, 175.3 mg L(-1), and 396.5 mg L(-1), respectively, which proved that the degradation rate of AAP could be restrained at high AAP concentration. This paper highlights a significant potential use of co-metabolic cultures of microbial cells for the cleanup of AAP-contaminated soil.

[Role of Ang-2, Tie-2 and VEGFR-2 in angiogenesis in colorectal carcinoma and their prognostic value].

OBJECTIVE: To study the expression of angiotensin-2 (Ang-2), Tie-2 and vascular endothelial growth factor receptor-2 (VEGFR-2) in colorectal cancer and analyze their relationship with the occurrence, recurrence, metastasis, angiogenesis and prognosis of colorectal cancer. METHODS: Immunohistochemistry with SP method was used to detect the expressions of Ang-2, Tie-2 and VEGFR-2 in 118 colorectal cancer, 40 adjacent normal tissue and 40 benign colorectal lesion specimens. RESULTS: The positivity rates of Ang-2, Tie-2 and VEGFR-2 in colorectal cancer tissue were 74.58%, 69.49%, and 61.02%, respectively, significantly higher than those in the adjacent normal tissues (25.00%, 17.50%, and 17.50%, P<0.05) and benign colorectal lesion tissues (35.00%, 32.50%, and 32.50%, P<0.05). The rates of two or three coexpression were significantly higher than that of a single expression in the cancer tissues (61.02% vs 15.25%). The microvascular density (MVD) of colorectal cancer tissues was 31.43∓10.50, significantly higher than that of the adjacent normal tissues (10.61∓3.76) and benign colorectal lesions (16.89∓3.83) (P<0.05). The expressions of Ang-2, Tie-2, and VEGFR-2 were positively correlated with carcinoembryonic antigen (CEA) and MVD (P<0.05). The expression of Ang-2, but not Tie-2 and VEGFR-2, was positively correlated with CA199. Ang-2, Tie-2, and VEGFR-2 expressions showed significant differences between cases with tumor recurrence/metastasis and those without 5 years after radical mastectomy, and were all positively correlated with the 5-year survival rates (P<0.05). CONCLUSION: Ang-2, Tie-2 and VEGFR-2 are involved in the development, invasion, metastasis, and prognosis of colorectal cancer, and play important roles in the angiogenesis of the tumors.