Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.     

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

Skin injury can trigger formation of new lesions in psoriasis (Koebner phenomenon). The mechanisms through which injury exacerbates psoriasis are unclear. During wound repair, epidermal keratinocytes are activated and produce abundant IL‐36γ, further promoting the skin inflammation. IL‐17A is the cornerstone cytokine in the pathogenesis of psoriasis. We sought to investigate the effects of IL‐17A on injury‐induced keratinocyte activation and IL‐36γ production. Here, we demonstrated that dsRNA released from necrotic keratinocytes induced the expression of IL‐36γ. Silencing of TLR3 by siRNA decreased the IL‐36γ induction by necrotic keratinocyte supernatant. Co‐stimulation with dsRNA and IL‐17A synergistically increased the expression of IL‐36γ and other proinflammatory mediators (CCL20, CXCL8, DEFB4 and LCN2) in keratinocytes. The synergistic effects were not dependent on TLR3 upregulation, TNF receptor signalling and mRNA stabilization. Co‐stimulation with dsRNA and IL‐17A resulted in an accumulation of IκBζ. The synergistic upregulation of IL‐36γ and proinflammatory mediators were inhibited by IκBζ siRNA. Co‐stimulation with IL‐17A and poly(I:C) markedly activated the p38 MAPK and NF‐κB pathway, compared with poly(I:C). Blockade of p38 MAPK and NF‐κB suppressed dsRNA/IL‐17A–mediated IκBζ and IL‐36γ induction. These findings demonstrated that IL‐17A synergistically enhanced the dsRNA‐mediated IL‐36γ production through a p38 MAPK‐, NF‐κB–, and IκBζ‐dependent mechanism.     

Does CETP rs5882, rs708272, SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, VEGFA rs833068, IL6 rs1800795 polymorphisms play a role in optic neuritis development?

Objectives: Optic neuritis (ON) is defined as inflammation of the optic nerve, which is mostly idiopathic. However, it can be associated with various causes (demyelinating lesions, autoimmune disorders, infectious and inflammatory conditions). Inflammatory demyelinating disorder of the optic nerve can be associated with multiple sclerosis. It is thought that CETP, SIRT1, FGFR2, STAT3, VEGFA and IL6 genes play a key role in this autoimmune inflammatory disease. The aim of our study was to determine if the frequency of the CETP, SIRT1, FGFR2, STAT3, VEGFA and IL6 gene polymorphisms have an influence on the development of acute ON.

Methods: The study enrolled patients with ON and a random sample of healthy population. The genotyping test of the CETPrs5882,rs708272, SIRT1rs12778366, FGFR2rs2981582, STAT3rs744166, VEGFArs833068, IL6rs1800795 polymorphisms was carried out using the RT-PCR method.

Results: Our study determined that the G/A genotype of CETPrs708272 was associated with two-fold-decreased odds of ON development under the codominant (OR = 0.495;95%CI:0.256–0.959) and overdominant (OR = 0.501;95%CI:0.280–0.895) models. Also, each allele C at VEGFArs833068 was associated with 1.7-fold increased odds of ON development under the additive model (OR = 1.733;95%CI:1.148–2.615). Furthermore, IL6 rs1800795 G/G genotype was associated with increased odds of ON development under the codominant (OR = 2.869;95%CI:1.280–6.434) and recessive (OR = 2.315;95%CI:1.251–4.285) models.

Conclusions: We revealed that the genotypes of CETPrs708272 G/A, IL6rs1800795 G/G, and each allele C at VEGFArs833068 were associated with ON. CETPrs708272 G/G genotype was associated with decreased by 62% odds of ON with MS development under the recessive (OR = 0.379;95%CI:0.155–0.929; p = .034) model.     

Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS): A proof-of-concept study

Objective

To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs.

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Generalized pustular psoriasis (GPP) is now known to be caused by biallelic variants in IL36RN and monoallelic variants in CARD14 and AP1S3. The presence of a modifier locus or oligogenic inheritance have been hypothesized. We report on a patient with a unique coinheritance of pathogenic variants in IL36RN (c.115+6T>C) and TNFAIP3 (c.547C>T, p.R183 * ) causing the genetic entities GPP and familial Behçet‐like autoinflammatory syndrome (AISBL). The heterozygous variant in IL36RN identified by Sanger sequencing was inherited from his unaffected father, while the heterozygous variant in TNFAIP3 was detected by whole‐exome sequencing and was also identified in the patient's AISBL‐affected maternal relatives. Further functional studies are required to research whether the variant of TNFAIP3 plays a part in the development of GPP or simply causes the Behçet's disease phenotype. However, our data suggest that whole‐exome sequencing for the heterozygous carrier of the IL36RN gene in GPP be used to find the potential second genetic locus.     

MOB1A regulates glucose deprivation-induced autophagy via IL6-STAT3 pathway in gallbladder carcinoma

MOB kinase activator 1A (MOB1A) plays an important role in many diseases and cancers. Here, we observed that MOB1A was substantially overexpressed in gallbladder carcinoma (GBC) tissues compared with nontumor tissues. The high expression of MOB1A was closely associated with poor survival in patients with GBC at advanced TNM stages. Furthermore, our study indicated that MOB1A promoted autophagy by activating the IL6/STAT3 signaling pathway and regulating the chemosensitivity to gemcitabine under glucose deprivation conditions both in vitro and in vivo. In conclusion, these findings suggested that MOB1A is critical for the development of GBC via the MOB1A-IL6/STAT3-autophagy axis.     

Association study between vitiligo and autoimmune-related genes CYP27B1, REL,TNFAIP3, IL2 and IL21

The aetiology of vitiligo has not been fully elucidated, and several hypotheses have been investigated; among them, the most explored assumes an autoimmune basis for the disease. Supporting this hypothesis is the frequent co-occurrence of autoimmune diseases with vitiligo. In addition, various genetic loci associated with vitiligo harbour key immune response genes. Our general hypothesis is that autoimmunity-associated genes participate in the control of vitiligo susceptibility. To investigate this hypothesis, we tested for association between vitiligo and genes CYP27B1, REL, TNFAIP3 and IL2/IL21, all previously related to autoimmune diseases associated with vitiligo. The study was performed using two independent population samples: a family-based discovery set (211 trios) and a replication set (131 cases/119 controls). Statistically significant association with vitiligo was detected between markers of the REL and IL2 gene in the family-based sample. Both association signals were concentrated among patients displaying autoimmune comorbidity and non-segmental vitiligo. Evidence for validation was detected for IL2 marker. Our findings suggest REL and IL2 as new vitiligo susceptibility genes and reinforce the hypothesis of a shared genetic mechanism controlling vitiligo and other autoimmune diseases.     

Interleukin 17A genetic variations and susceptibility to non‐small cell lung cancer

Lung cancer is the leading cause of cancer‐related death, in which non‐small cell lung cancer (NSCLC) is the most common type. Evidence have shown that interleukin 17 (IL‐17) greatly involves in human immune responses. In this study, we investigated the effect of IL‐17 on NSCLC by examining the association between IL‐17A genetic polymorphisms and the susceptibility to NSCLC. IL‐17A ‐420A/G and IL‐17A ‐73G/A polymorphisms were detected in 330 NSCLC patients and 382 healthy controls. We found that subjects carrying ?73GA genotype or AA genotype had 2.09‐fold or 2.52‐fold increased risk of NSCLC than those with ?73GG genotype [odds ratio (OR) = 2.09, 95% confidence interval (CI), 1.46 – 2.98, p < 0.001; OR = 2.52, 95% CI, 1.30–4.88, p = 0.005, respectively). However, the IL‐17A ‐420A/G did not reveal any correlation with the cancer. Further investigation showed that prevalence of IL‐17A ?73GA genotype and A allele were significantly increased in adenocarcinoma patients (OR = 1.75, 95% CI, 1.08–2.86, p = 0.024, OR = 1.57, 95% CI, 1.09–2.28, p = 0.016, respectively). We also evaluated the effect of the polymorphisms on gene expression, and identified that peripheral blood mononuclear cells with IL‐17A ‐73GA and AA genotypes produced significantly higher level of IL‐17 than the cells with IL‐17A ‐73GG genotype. Our results suggest that IL‐17A ‐73G/A genetic variations may upregulate IL‐17 expression and are associated with increased susceptibility to NSCLC.     

Interleukin-6 serum levels predict surgical intervention in infants with necrotizing enterocolitis

Background

Symptoms at suspicion of necrotizing enterocolitis (NEC) are often nonspecific and several biomarkers have been evaluated for their discriminative power to both diagnose and predict the course from NEC suspicion to complicated disease requiring surgical intervention. Thus, we aimed to assess the utility of interleukin-6 (IL-6) to predict surgical intervention in infants suffering from NEC and, furthermore, to discriminate infants with starting NEC or late-onset sepsis (LOS).