Biology and Therapeutic Properties of Mesenchymal Stem Cells in Leukemia.

This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various cell types and modulate the immune system, are integral to the BM niche, influencing hematopoietic stem cell maintenance and functionality. This review extensively explores the intricate relationship between MSCs and leukemic cells in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. This review also addresses the potential clinical applications of MSCs in leukemia treatment. MSCs' role in hematopoietic stem cell transplantation, their antitumor effects, and strategies to disrupt chemo-resistance are discussed. Despite their therapeutic potential, the dual nature of MSCs in promoting and inhibiting tumor growth poses significant challenges. Further research is needed to understand MSCs' biological mechanisms in hematologic malignancies and develop targeted therapeutic strategies. This in-depth exploration of MSCs in leukemia provides crucial insights for advancing treatment modalities and improving patient outcomes in hematologic malignancies.

A common trajectory of gut microbiome development during the first month in healthy neonates with limited inter-individual environmental variations.

The early development of the gut microbiome is governed by multiple factors and has significantly long-term effects on later-in-life health. To minimize inter-individual variations in the environment, we determined developmental trajectories of the gut microbiome in 28 healthy neonates during their stay at a postpartum center. Stool samples were collected at three time points: the first-pass meconium within 24 h of life, and at 7 and 28 days of age. Illumina sequencing of the V3-V4 region of 16S rRNA was used to investigate microbiota profiles. We found that there was a distinct microbiota structure at each time point, with a significant shift during the first week. Proteobacteria was most abundant in the first-pass meconium; Firmicutes and Actinobacteria increased with age and were substituted as the major components. Except for a short-term influence of different delivery modes on the microbiota composition, early microbiome development was not remarkably affected by gravidity, maternal intrapartum antibiotic treatment, premature rupture of membranes, or postnatal phototherapy. Hence, our data showed a similar developmental trajectory of the gut microbiome during the first month in healthy neonates when limited in environmental variations. Environmental factors external to the host were crucial in the early microbiome development.

Immune cell profiles of idiopathic inflammatory myopathy patients expressed anti-aminoacyl tRNA synthetase or anti-melanoma differentiation-associated gene 5 autoantibodies.

BACKGROUND: Patients with idiopathic inflammatory myopathy (IIM) often express a different type of myositis-specific autoantibodies (MSAs), each associated with different clinical symptoms. Understanding the immunopathogenesis of various IIM subgroups can help improve the diagnosis and prognosis of IIM patients with different MSAs. However, the immune cell profiles of these IIM patients with anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies remain unclear. We focused on the immune cell profiles of IIM patients with anti-ARS or anti-MDA5 autoantibodies. RESULTS: The peripheral blood from IIM patients with anti-MDA5 autoantibody (MDA5 + group, n = 24) or one of the anti-ARS autoantibodies (ARS + group, n = 40) autoantibodies, and healthy controls (HC group, n = 60) were collected and examined. We found that IIM patients had a lower CD3 T cell population compared to the HC group. IIM patients showed a significantly lower TN cell population and a higher TEMRA cell population. Higher Th17 and Treg cell populations were found in these IIM patients than in the HC group. In these IIM patients, the MDA5 + group exhibited the higher percentages of Th17 and Treg cells than the ARS + group. It is noteworthy that the percentage of Th1 cells in the survival subgroup was higher than in the death subgroup in IIM patients with ARS + or MDA5 + . Furthermore, in the MDA5 + group, the percentage of Treg cells was higher in the survival subgroup compared to the death subgroup. CONCLUSIONS: Our study demonstrated that elevated Th1 may be a good prognostic indicator in IIM patients with ARS + or MDA5 + . Elevated Treg may also help predict a good prognosis in MDA5 + IIM patients. However, more large-scale studies and clinical samples are needed to verify the significance of Th1 and Treg cell subsets in clinical outcomes for these IIM patients with ARS + or MDA5 + . These data may help design a therapeutic approach that specifically targets the pathogenic immune molecular responsible for autoimmune attacks in IIM.

Ling Zhi-8, a fungal immunomodulatory protein in Ganoderma lucidum, alleviates CPT-11-induced intestinal injury via restoring claudin-1 expression.

CPT-11 (Irinotecan) remains an important chemotherapeutic agent against various solid tumors nowadays. Potential adverse effects, especially gastrointestinal toxicities, are the main limiting factor for its clinical utility. Ling Zhi-8 (LZ-8), a fungal immunomodulatory protein in Ganoderma lucidum mycelia, has potential for drug development due to its multiple bioactivities and functions. This study aimed to explore the influence of LZ-8 on CPT-11-treated IEC-6 cells in vitro and on mice with CPT-11-induced intestinal injury in vivo. The mechanism through which LZ-8 exerted its protective effects was also investigated. In the in vitro study, the viability and claudin-1 expression of IEC-6 cells decreased gradually with increasing concentrations of CPT-11, but LZ-8 treatment had no obvious influence on their viability, morphology, and claudin-1 expression. Pretreatment of LZ-8 significantly improved CPT-11-decreased cell viability and claudin-1 expression in IEC-6 cells. In mice with CPT-11-induced intestinal injury, LZ-8 treatment could ameliorate symptoms and mitigate intestinal damage. Meanwhile, LZ-8 restored claudin-1 expression in the intestinal membranes in CPT-11-treated mice. Collectively, our results demonstrated the protective effects of LZ-8 against CPT-11 damage in both IEC-6 cells and mice. LZ-8 can restore claudin-1 expression in intestinal cells following CPT-11 treatment, suggesting the role of claudin-1 in the scenario.

Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility.

Aplastic anemia (AA), a rare but potentially life-threatening disease, is a paradigm of bone marrow failure syndromes characterized by pancytopenia in the peripheral blood and hypocellularity in the bone marrow. The pathophysiology of acquired idiopathic AA is quite complex. Mesenchymal stem cells (MSCs), an important component of the bone marrow, are crucial in providing the specialized microenvironment for hematopoiesis. MSC dysfunction may result in an insufficient bone marrow and may be associated with the development of AA. In this comprehensive review, we summarized the current understanding about the involvement of MSCs in the pathogenesis of acquired idiopathic AA, along with the clinical application of MSCs for patients with the disease. The pathophysiology of AA, the major properties of MSCs, and results of MSC therapy in preclinical animal models of AA are also described. Several important issues regarding the clinical use of MSCs are discussed finally. With evolving knowledge from basic studies and clinical applications, we anticipate that more patients with the disease can benefit from the therapeutic effects of MSCs in the near future.

Alterations of mesenchymal stem cells on regulating Th17 and Treg differentiation in severe aplastic anemia.

Immune-mediated hematopoietic destruction is a key factor in idiopathic severe aplastic anemia (SAA). With great immunomodulatory functions, mesenchymal stem cells (MSCs) are important for bone marrow niche. While the underlying etiology of immunologic changes in SAA bone marrow remains unknown, dysfunctional MSCs are implicated as a major cause. To provide evidence for their defects in immunomodulation, alterations of SAA MSCs in regulating T cell differentiation were determined. During differentiation from CD4+ T cells into T helper 17 (Th17) cells under polarization conditions, impaired inhibition on IL-17 and IL-1ß production was noted when cocultured with SAA MSCs compared to control MSCs (P < 0.05). After stimulation of Th17 activation, the percentage of IL-17-secreting cells was significantly increased in the SAA group (9.1 ± 1.5% vs 6.6 ± 0.4%, P < 0.01). Under regulatory T (Treg) polarization, a higher percentage of CD4+CD25+FoxP3+ Treg cells was detected when cocultured with SAA MSCs compared to control MSCs (8.1 ± 0.5% vs 5.8 ± 0.8%, P < 0.01). Inconsistently, transforming growth factor-ß (TGF-ß) concentrations in the culture supernatant were decreased and IL-1ß concentrations were elevated in the SAA group. Our data indicated impaired inhibition of SAA MSCs on Th17 activation and aberrant regulation of SAA MSCs on Treg differentiation. Increased IL-17 and IL-1ß levels with decreased TGF-ß levels in the supernatant suggested the potential of SAA MSCs for triggering a hyperinflammatory environment. Dysfunctional MSCs could contribute to the lack of immunoprotection in the bone marrow, which may be associated with SAA.

Assessing the Immune Cell Subset and Genetic Mutations in Patients With Palindromic Rheumatism Seronegative for Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide.

OBJECTIVE: The etiology underlying cases of palindromic rheumatism (PR) not associated with other rheumatic diseases in patients who are seronegative for rheumatoid factor and anti-cyclic citrullinated peptide (seronegative PR) is unclear. We aimed to investigate the immune cells and genes involved. METHODS: This was a single-center comparative study of 48 patients with seronegative PR and 48 healthy controls. Mass cytometry and RNA sequencing were used to identify distinct immune cell subsets in blood. Among the 48 seronegative PR patients, plasma samples from 40 patients were evaluated by enzyme-linked immunosorbent assay for cytokine levels, and peripheral blood samples from 25 patients were evaluated by flow cytometry for mononuclear cell subsets. Plasma samples from 21 patients were evaluated by real-time polymerase chain reaction for differential gene and protein expression, and samples from 3 patients were analyzed with whole-exome sequencing for gene mutations. RESULTS: Immunophenotyping revealed a markedly increased frequency of CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells in seronegative PR patients with active flares compared with healthy controls (P < 0.0001 for both cell subset comparisons). Gene enrichment analyses of RNA-sequencing data from sorted CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells showed involvement of the inflammatory/stress response, phagocytosis, and regulation of apoptosis functional pathways. Up-regulated expression of CXCL16 and IL10RA was observed in monocytes from PR patients. Up-regulation of PFKFB3, DDIT4, and TGFB1, and down-regulation of PDIA6 were found in monocytes and lymphocytes from PR patients with active flares and PR patients in intercritical periods. Plasma levels of S100A8/A9 and interleukin-1ß were elevated in PR patients. Whole-exome sequencing revealed novel polygenic mutations in HACL1, KDM5A, RASAL1, HAVCR2, PRDM9, MBOAT4, and JRKL. CONCLUSION: In seronegative PR patients, we identified a distinct CD14+CD11b+CD36+ cell subset that can induce an inflammatory response under stress and exert antiinflammatory effects after phagocytosis of apoptotic cells, and a CD4+CD25-CD69+ T cell subset with pro- and antiinflammatory properties. Individuals with genetic mutations involving epigenetic modification, potentiation and resolution of stress-induced inflammation/apoptosis, and a dysregulated endoplasmic reticulum stress response could be predisposed to seronegative PR.

Lipocalin 2 Reduces MET Levels by Inhibiting MEK/ERK Signaling to Inhibit Nasopharyngeal Carcinoma Cell Migration.

Nasopharyngeal carcinoma (NPC) is the most common cancer that occurs in the nasopharynx, and it is difficult to detect early. The main cause of death of NPC patients is cancer metastasis. Lipocalin 2 (LCN2) has been shown to be involved in a variety of carcinogenesis processes. Here, we aimed to study the role of LCN2 in NPC cells and determine its underlying mechanism. We found that LCN2 was expressed differently in NPC cell lines, namely HONE-1, NPC-39, and NPC-BM. The down-regulation of LCN2 levels by siRNA targeting LCN2 (siLCN2) increased cell migration and invasion in HONE-1 cells, while the up-regulation of LCN2 levels by transfection with the LCN2 expression plasmid decreased cell migration and invasion in NPC-BM cells. Furthermore, LCN2 levels negatively regulated the phosphorylation of MEK/ERK pathways. The treatment of the specific MEK/ERK inhibitor, U0126, reduced cell migration in HONE-1 cells, whereas the treatment of tBHQ, an ERK activator, enhanced cell migration in NPC-BM cells. Based on the bioinformatics data, there was a moderately negative correlation between LCN2 and MET in metastatic NPC tissues (r = -0.5946, p = 0.0022). Indeed, the manipulation of LCN2 levels negatively regulated MET levels in these NPC cells. The treatment of U0126 reduced siLCN2-increased MET levels, while the treatment of tBHQ enhanced LCN2-enhanced MET levels. Interestingly, the down-regulation of MET levels by siMET further decreased siLCN2-enhanced MET levels and cell migration. Therefore, LCN2 inhibits NPC cell migration by reducing MET levels through MEK/ERK signaling.

Antithymocyte Globulin Plus Post-Transplant Cyclophosphamide Combination as an Effective Strategy for Graft-versus-Host Disease Prevention in Haploidentical Peripheral Blood Stem Cell Transplantation for Children with High-Risk Malignancies.

Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this setting. The addition of antithymocyte globulin (ATG) in PTCy-based regimens for GVHD reduction in haploidentical hematopoietic stem cell transplantation is rational and was reported in adult series. However, its feasibility is unknown in pediatric patients. Here, we firstly describe our experience of 15 consecutive children with high-risk malignancies receiving haploidentical peripheral blood stem cell transplantation using ATG plus PTCy for GVHD prophylaxis. Only three patients developed grade 1-2 acute GVHD, limited to skin. No grade 3-4 acute GVHD and chronic GVHD were observed. Viral reactivations were frequently seen but manageable. Six patients relapsed, as the main cause of death in our series. None died from events related to GVHD. Our data suggest that ATG plus PTCy is an effective strategy for GVHD prevention in haploidentical peripheral blood stem cell transplantation and is feasible in children with high-risk malignancies.

Clinical Consideration for Mesenchymal Stem Cells in Treatment of COVID-19.

COVID-19, which has strongly affected the 21st century, is caused by severe acute respiratory syndrome (SARS)-CoV-2. The emergence of viral variants has rendered even vaccinated people prone to infection; thus, completely eradicating COVID-19 may be impossible. COVID-19 causes hyperinflammation, leading to organ damage and even death. SARS-CoV-2 infects not only the lungs, causing acute respiratory distress syndrome, but also the extrapulmonary organs. Not all patients with COVID-19 respond adequately to treatments with antiviral and anti-inflammatory drugs. Therefore, new treatments are urgently needed. Mesenchymal stem cells (MSCs) exhibit immunomodulatory activity and are used to safely and effectively treat various immune disorders. Evidence has indicated the efficacy of MSCs against COVID-19. However, the safety and efficacy of MSCs must be probed further. For this reason, we explored key clinical challenges associated with MSC therapy for COVID-19, such as sources, administration routes, cell dosage, treatment timepoint, and virus reactivation. We identified several challenges that must be addressed before MSCs can be clinically applied.

Immunomodulation of Mesenchymal Stem Cells in Acute Lung Injury: From Preclinical Animal Models to Treatment of Severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health challenge worldwide. Owing to the emergence of novel viral variants, the risks of reinfections and vaccine breakthrough infections has increased considerably despite a mass of vaccination. The formation of cytokine storm, which subsequently leads to acute respiratory distress syndrome, is the major cause of mortality in patients with COVID-19. Based on results of preclinical animal models and clinical trials of acute lung injury and acute respiratory distress syndrome, the immunomodulatory, tissue repair, and antiviral properties of MSCs highlight their potential to treat COVID-19. This review article summarizes the potential mechanisms and outcomes of MSC therapy in COVID-19, along with the pathogenesis of the SARS-CoV-2 infection. The properties of MSCs and lessons from preclinical animal models of acute lung injury are mentioned ahead. Important issues related to the use of MSCs in COVID-19 are discussed finally.

Immunomodulation via MyD88-NFκB Signaling Pathway from Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury.

Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88−NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1ß, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88−NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.

Effect of WW Domain-Containing Oxidoreductase Gene Polymorphism on Clinicopathological Characteristics of Patients with EGFR Mutant Lung Adenocarcinoma in Taiwan.

Lung adenocarcinoma is the most common histological type of non-small cell lung cancer, which accounts for the majority of lung cancers. Previous studies have showed that dysregulation of WW domain-containing oxidoreductase (WWOX) participates in the generation of several cancer types, including lung cancer. However, whether these WWOX polymorphisms are related to the clinical risk of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is worthy of investigation. The present study examined the relationship between the WWOX single-nucleotide polymorphisms (SNPs; rs11545028, rs12918952, rs3764340, rs73569323, and rs383362) and the clinicopathological factors in lung adenocarcinoma patients with or without EGFR mutations. We found that there was no significant difference in the genotype distribution of WWOX polymorphism between EGFR wild-type and EGFR mutant in patients with lung adenocarcinoma. Our results demonstrated that the presence of at least one G genotype (CG and GG) allele on WWOX rs3764340 was associated with a significantly higher risk of nearby lymph node involvement in those patients harboring EGFR mutations (odds ratio (OR) = 3.881, p = 0.010) compared with the CC genotype. Furthermore, in the subgroup of lung adenocarcinoma patients with the EGFR-L858R mutation, both WWOX rs3764340 C/G (OR = 5.209, p = 0.023) and rs73569323 C/T polymorphisms (OR = 3.886, p = 0.039) exhibited significant associations with the size of primary tumors and the invasion of adjacent tissues. In conclusion, these data indicate that WWOX SNPs may help predict tumor growth and invasion in patients with EGFR mutant lung adenocarcinoma, especially those with the EGFR-L858R mutant in Taiwan.

The Enhancing Effect of Fungal Immunomodulatory Protein-Volvariella Volvacea (FIP-vvo) on Maturation and Function of Mouse Dendritic Cells.

Volvariella volvacea, also known as straw mushroom, is a common edible mushroom in Chinese cuisine. It contains many nutrients for human health. A fungal immunomodulatory protein (FIP) has been isolated from V. volvacea and named FIP-vvo. Although the regulatory effects of many FIPs on immunity have been identified, the impact of FIP-vvo in modulating dendritic cells (DCs), which play a key role to connect the innate and the adaptive immunity, is not known. In this study, we aim to study the effect of FIP-vvo on the DC maturation and function. We found that FIP-vvo slightly increased the generation of CD11c+ bone marrow-derived DC (BMDC). In addition, the surface expression of MHCII was promoted in BMDCs after the treatment of FIP-vvo, suggesting that FIP-vvo induces DC maturation. Furthermore, FIP-vvo enhanced the ability of BMDCs to activate antigen-specific T cell responses in vitro. In the in vivo study, the FIP-vvo treatment facilitated T cell response in lymph nodes. Therefore, for the first time, our data demonstrated that FIP-vvo promoted DC maturation and function and suggested that FIP-vvo could have benefits for human health by enhancing immunity.

Chinese Herbal Medicine Usage Reduces Overall Mortality in HIV-Infected Patients With Osteoporosis or Fractures.

The survival of patients with HIV has greatly improved, due to Anti-Retroviral Therapy (ART). However, long-term HIV survivors often develop serious bone abnormalities, possibly due to the interplay of osteoblasts, osteoclasts, HIV ad ART. We evaluated in a nation-wide study in Taiwan the effect of Chinese herbal medicine (CHM) on overall mortality in HIV patients with osteoporosis or fractures. Enrollment period was between 1998 and 2011. Patients with osteoporosis or fractures before the HIV infection, and those with less than 14 days CHM use, were excluded. This left 498 patients, 160 CHM users, 338 without CHM. Univariate Kaplan-Meier and multivariate Cox regression analysis were used to compare the overall mortality in these 2 groups. Due to the nature of Chinese medicine, CHMs inevitably varied. We therefore also used rule mining and network analysis to determine which major CHM clusters were prescribed to the patients. CHM users had a much Lower mortality (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.24-0.77, p < 0.005) and higher survival (p = 0.004, log-rank test). Although the CHMs greatly varied, network analysis identified one main cluster of strongly related CHM combinations (Chuan-Xiong-Cha-Tiao-San (CXCTS), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Liu-He-Tang (LHT), Huang-Qin-Tang (HQT), Jia-Wei-Ping-Wei-San (JWPWS), and Dang-Gui-Long-Hui-Wan (DGLHuiW)). CHM as an additional treatment strongly improves overall survival in HIV-infected patients with osteoporosis and fractures.

Timing, Dosage, and Adherence of Antiretroviral Therapy and Risk of Osteoporosis in Patients With Human Immunodeficiency Virus Infection in Taiwan: A Nested Case-Control Study.

The progression of acquired immunodeficiency syndrome is delayed in patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART). However, long-term ART is associated with adverse effects. Osteoporosis is one of the adverse effects and is a multifactorial systemic skeletal disease associated with bone fragility and an increased risk of fracture. We performed a longitudinal, comprehensive, nested case-control study to explore the effect of ART on the risk of osteoporosis in 104 osteoporotic and 416 non-osteoporotic patients with HIV infection at their average age about 29 years old in Taiwan. Patients with history of ART, current exposure to ART, higher cumulative defined daily doses (DDDs), or higher ART adherence were at a higher risk of osteoporosis (p < 0.05). Patients receiving nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine-lamivudine combination, lamivudine-abacavir combination, and abacavir alone) and protease inhibitor (PI)-containing regimen (lopinavir-ritonavir combination, ritonavir, and atazanavir) had a higher risk of osteoporosis (p < 0.05). Especially, patients receiving high doses of the PIs lopinavir-ritonavir combination had an increased risk of osteoporosis (p < 0.05). In conclusion, history of ART, current exposure to ART, higher cumulative DDDs, and higher ART adherence were associated with an increased risk of osteoporosis. Furthermore, NRTI- and PI-containing regimens and high doses of PIs lopinavir-ritonavir combination may be associated with an increased risk of osteoporosis in patients with HIV infection in Taiwan.

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-ß Pathways.

Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that mediates the elongation of chondroitin sulfate (CS), is a critical elicitor of the malignant characteristics of HCC as it modifies the potent tumor suppressor, decorin (DCN). CHPF expression is frequently downregulated in HCC tumors, which is associated with the poor overall survival of HCC patients. We observed that restoring CHPF expression suppressed HCC cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that TGF-ß signaling is associated with CHPF-induced phenotype changes. We found that DCN, as a TGF-ß regulator, is modified by CHPF, and that it affects the distribution of DCN on the surface of HCC cells. Importantly, our results confirm that CHPF and DCN expression levels are positively correlated in primary HCC tissues. Taken together, our results suggest that CHPF dysregulation contributes to the malignancy of HCC cells, and our study provides novel insights into the significance of CS, which affects DCN expression in the TME.

Redox sensor NPGPx restrains ZAP70 activity and modulates T cell homeostasis.

Emerging evidences implicate the contribution of ROS to T cell activation and signaling. The tyrosine kinase, ζ-chain-associated protein of 70 kDa (ZAP70), is essential for T cell development and activation. However, it remains elusive whether a direct redox regulation affects ZAP70 activity upon TCR stimulation. Here, we show that deficiency of non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), a redox sensor, results in T cell hyperproliferation and elevated cytokine productions. T cell-specific NPGPx-knockout mice reveal enhanced T-dependent humoral responses and are susceptible to experimental autoimmune encephalomyelitis (EAE). Through proteomic approaches, ZAP70 is identified as the key interacting protein of NPGPx through disulfide bonding. NPGPx is activated by ROS generated from TCR stimulation, and modulates ZAP70 activity through redox switching to reduce ZAP70 recruitment to TCR/CD3 complex in membrane lipid raft, therefore subduing TCR responses. These results reveal a delicate redox mechanism that NPGPx serves as a modulator to curb ZAP70 functions in maintaining T cell homeostasis.

Migraine as a Risk Factor for Peripheral Artery Occlusive Disease: A Population-Based Cohort Study.

We aim to evaluate the development of peripheral occlusive artery disease (PAOD) in patients with migraine by using the National Health Insurance Research Database in Taiwan. A retrospective cohort study was conducted and individuals with diagnostic codes of migraine were enrolled in the study group after excluding those diagnosed with PAOD before the index date. Each subject with migraine was propensity-score matched to another non-migraine patient and the latter served as the control group. A total of 37,288 patients were finally enrolled in the groups. The primary outcome was set as the development of PAOD between the two groups while multiple possible risk factors, including demographic data and comorbidities, were analyzed via the Cox proportional hazards regression. There were 885 and 530 PAOD events in the study and control groups, and the study group had a significantly higher adjusted hazard ratio (1.65, 95% confidential interval: 1.48-1.84, p < 0.001), and the cumulative incidence also revealed a correlation between migraine and PAOD. Other potential risk factors related to the existence of PAOD include age, hypertension, chronic kidney disease, diabetes mellitus, coronary artery disease, stroke, and asthma. For individuals without certain systemic diseases including hypertension, chronic liver disease, chronic kidney disease, coronary artery disease, stroke, asthma, or heart failure, the hazard ratio of subsequent PAOD was significantly higher in the migraine patients than that in the non-migraine individuals (all p < 0.001). In conclusion, the presence of migraine is a significant risk factor for the development of subsequent PAOD.

FGFR4 Gene Polymorphism Reduces the Risk of Distant Metastasis in Lung Adenocarcinoma in Taiwan.

Fibroblast growth factor receptor 4 (FGFR4) is involved in multiple physiological and pathological processes. Several genetic variants of FGFR4 have been shown to be associated with tumor progression in many cancers. However, its association, such as genetic variants and expression levels, with lung cancer is controversial. The present study examined the relationship between four single-nucleotide polymorphisms (SNPs; rs2011077 T/C, rs351855 G/A, rs7708357 G/A, and rs1966265 A/G) of FGFR4 and the risk of lung adenocarcinoma with the epidermal growth factor receptor (EGFR) mutation status in a Taiwanese cohort. The results demonstrated that FGFR4 rs2011077 (odds ratio (OR) = 0.348, 95% confidence interval (CI) = 0.136-0.891, p = 0.024), and rs351855 (OR = 0.296, 95% CI = 0.116-0.751, p = 0.008) showed an inverse association with distant metastasis in wild-type EGFR lung adenocarcinoma. Furthermore, a database analysis using The Cancer Genome Atlas revealed that the higher FGFR4 expression level was correlated with poor survival rates in wild-type EGFR lung adenocarcinoma. In conclusion, the data suggest that FGFR4 SNPs may help in identifying patient subgroups at low-risk for tumor metastasis, among carriers of lung adenocarcinoma bearing wild-type EGFR.