Experimental and molecular pathology最新文献

Pruritus, also known as itching, is a complex sensation that involves the activation of specific physiological and cellular receptors. The skin is innervated with sensory nerves as well as some receptors for various sensations, and its immune system has prominent neurological connections. Sensory neurons have a considerable impact on the sensation of itching. However, immune cells also play a role in this process, as they release pruritogens. Disruption of the dermal barrier activates an immune response, initiating a series of chemical, physical, and cellular reactions. These reactions involve various cell types, including keratinocytes, as well as immune cells involved in innate and adaptive immunity. Collective activation of these immune responses confers protection against potential pathogens. Thus, understanding the molecular and cellular mechanisms that contribute to pruritus in host skin is crucial for the advancement of effective treatment approaches. This review provides a comprehensive analysis of the present knowledge concerning the molecular and cellular mechanisms underlying itching signaling in the skin. Additionally, this review explored the integration of these mechanisms with the broader context of itch mediators and the expression of their receptors in the skin.

Familial Mediterranean Fever (FMF) is a recurrent polyserositis characterized by self-limiting episodes or attacks of fever along with serosal inflammation. It mainly impacts people of the Mediterranean and Middle Eastern basin. FMF is a recessive autoinflammatory condition caused by mutation in the MEFV gene located on chromosome 16p13. MEFV mutations lead to the activation of the pyrin inflammasome resulting in an uncontrolled release of IL-1β. Various in vitro, in vivo and ex vivo experimental models have been developed to further comprehend the etiology and pathogenesis of FMF. These models have been proven to be clinically relevant to human FMF and can provide significant information about biological systems with respect to this condition. Additionally, these models have provided pertinent contributions to the development of potent therapeutic strategies against FMF. In this review, we describe the different experimental models utilized in FMF and we focus primarily on the most widely used models that have produced prominent insights into the pathophysiology of the disease.

Background

Neoadjuvant chemotherapy (NCT) can induce a pathological complete response (pCR) in breast cancer patients, leading to improved outcomes. However, predicting which patients will achieve pCR remains a challenge. CD10, a myoepithelial marker, has shown diagnostic and prognostic value in metastatic tumors. Its potential as a predictor of chemosensitivity to anthracycline-based NCT in breast cancer is unknown.

Aim

This retrospective study aimed to investigate the potential of CD10 cancer cell expression as a predictive marker of chemosensitivity in breast cancers treated with anthracycline-based neoadjuvant chemotherapy.

Methods

We analyzed 130 patients with invasive ductal carcinoma who received anthracycline-based NCT. CD10 expression was assessed by immunohistochemistry on pre-treatment biopsies. Statistical analysis evaluated the association between CD10 expression and pCR rates.

Results

Univariate analysis revealed that ER-positive and CD10-negative tumors had lower pCR rates [OR 7.4830 (95% CI 2.7762–20.1699); p = 0.0001]. Multivariate analysis confirmed ER status as a strong predictor of poor response [OR 0.085 (95% CI 0.024–0.30); p < 0.001] and CD10 expression as a predictor of a favourable response [OR 0.11 (0.8–0.19); p = 0.049]. CD10 expression significantly predicted pCR in ER-negative cases [OR 0.1098 (0.0268–0.4503); p = 0.0022] and triple-negative breast cancer [OR 0.0966 (95% CI 0.0270–0.3462); p = 0.0003]. Concordance was observed between core biopsies and excised samples.

Conclusion

Positive CD10 cancer cell expression may predict increased response to anthracycline-based neoadjuvant chemotherapy in ER-negative and triple-negative breast cancer cases. Further research is needed to validate these findings in larger cohorts and determine the clinical utility of CD10 as a predictive marker.

Background and aims

Interleukin-6 (IL-6) is an acute-phase protein that plays an important role in the inflammatory response, vascular inflammation, and atherosclerosis process. The study aimed to establish whether IL-6 gene polymorphisms and IL-6 concentrations are associated with premature coronary artery disease (pCAD) and cardiovascular risk factors.

Methods

The IL-6 concentrations and the rs2069827, rs1800796, and rs1800795 IL-6 polymorphisms were determined in 1150 pCAD patients and 1083 healthy controls (coronary artery calcium equal to zero determined by tomography).

Results

The IL-6 polymorphisms studied were not associated with pCAD, but they were associated with cardiovascular risk factors in patients and controls. In controls, under the dominant model, the rs1800795 C allele and the rs2069827 T allele were associated with a low risk of central obesity (OR = 0.401, p = 0.017 and OR = 0.577, p = 0.031, respectively), hypoalphalipoproteinemia (OR = 0.581, p = 0.027 and OR = 0.700, p = 0.014, respectively) and hypertriglyceridemia (OR = 0.575, p = 0.030 and OR = 0.728, p = 0.033, respectively). In pCAD, the rs1800795 C allele was associated with an increased risk of hypoalphalipoproteinemia (OR = 1.370, p_additive = 0.025) and increased C-reactive protein (CRP) concentrations (OR = 1.491, p_additive = 0.007). pCAD patients had significantly higher serum IL-6 concentrations compared to controls (p = 0.002). In the total population, individuals carrying the rs1800795 GC + CC genotypes had higher levels of IL-6 than carriers of the GG genotype (p = 0.025). In control individuals carrying the C allele (CG + CC), an inverse correlation was observed between IL-6 and HDL-cholesterol levels (p = 0.003).

Conclusions

In summary, the IL-6 polymorphisms were not associated with pCAD, however, they were associated with cardiovascular risk factors in pCAD patients and healthy controls. Individuals carrying the rs1800795 GC + CC genotypes had higher levels of IL-6 than carriers of the GG genotype.

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease without early diagnostic and specific therapeutic approaches. Podocyte apoptosis and loss play important roles in the pathological process of DKD. This study aimed to explore whether urinary exosomes from type 2 diabetes patients with DKD could induce podocyte apoptosis and the underlying pathological mechanisms. The exosomes were isolated from the urine samples of patients with DKD (DKD-Exo). Later, they were taken up and internalized by MPC5 cells. MPC5 cells were co-cultured with DKD-Exo (45 μg/ml) for 24 h in the presence or absence of microRNA-145-5p (miR-145-5p) inhibitor, fasudil and pcDNA-Srgap2 transfection. MiR-145-5p and Srgap2 expression was evaluated using real-time quantitative PCR. The protein levels of Srgap2, Bcl-2, Bax, and cleaved caspase-3, as well as ROCK activity were determined using Western blotting. Cell apoptosis was measured using flow cytometry and the TUNEL assay. miR-145-5p expression in MPC5 cells exposed to DKD-Exo was markedly upregulated. miR-145-5p negatively regulated Srgap2 levels. Exposure of MPC5 cells to DKD-Exo reduced Srgap2 expression and activated ROCK, which was partly reversed by the presence of the miR-145-5p inhibitor or Srgap2 overexpression. The apoptosis of MPC5 cells exposed to DKD-Exo increased significantly, which was counteracted by the addition of the miR-145-5p inhibitor and fasudil. The results showed that urinary exosomal miR-145-5p from patients with DKD induced podocyte apoptosis by inhibiting Srgap2 and activating the RhoA/ROCK pathway, suggesting that urinary exosomal miR-145-5p is involved in the pathological process of DKD and could become a noninvasive diagnostic biomarker for DKD.