Pathology, research and practice最新文献

Background: Little is known about the protein expression of the transient receptor potential canonical (TRPC) channels 1, 3, and 6 in the thyroid. Research in human tissue is insufficient. Our aim was to investigate the distribution of TRPC1, 3, and 6 in the healthy human thyroid.

Methods: Healthy samples were collected from seven nitrite pickling salt-ethanol-polyethylene glycol-fixed cadavers and from one patient who had undergone neck surgery (5 males, 3 females; median = 81.0, interquartile range = 6.5 years). The protein expression profiles of TRPC1, 3, and 6 were assessed using immunohistochemistry with knockout-validated antibodies. A monoclonal calcitonin antibody was used to detect calcitonin-producing C-cells.

Results: All samples were labeled as healthy, displaying age-appropriate signs of degeneration. TRPC1, 3, and 6 immunolabeling in thyrocytes showed irregular staining patterns leaving selected cells with intense staining, some without. The comparison of calcitonin- and TRPC1-, 3-, and 6-immunolabeled slides strongly suggested TRPC1, 3, and 6 expression in C-cells. Connective tissue showed no immunoreactivity.

Conclusions: This is, to the authors' knowledge, the first detailed description of the distribution of these channels in the human thyroid. We conclude that TRPC1, 3, and 6 are expressed in thyrocytes and C-cells of the human thyroid. Further studies are necessary to confirm these small-case-number results and to explore the relevance of these versatile channels in thyroidal health and disease.

As an indispensable trace metal element in the organism, copper acts as a key catalytic cofactor in a wide range of biological processes. Copper homeostasis disorders can be caused by either copper excess or deficiency, and copper homeostasis disorders will affect the normal physiological functions of cells and induce cell death through a variety of mechanisms, such as the emerging cuproptosis model. The imbalance of copper homeostasis will lead to the occurrence of cancer, and copper is a key factor in cell signalling, so copper is involved in the development of cancer by promoting cell proliferation, angiogenesis and metastasis, etc. The therapeutic role of Cuproptosis as a hotspot of research in cancer has also attracted much attention. Therefore, this paper comprehensively searches the literature to review the roles and mechanisms of Cuproptosis in the treatment of malignant tumours, aiming to provide new insights into the role and mechanism of Cuproptosis in anti-malignant tumour therapy and present novel ideas and methods.

Humans have more than 270,000 lncRNAs. Among these, lncRNA HOXA-AS2 is considered a transformative gene involved in various cellular processes, including cell proliferation, apoptosis, migration, and invasion. Thus, it can be regarded as a potential tumor marker for both diagnosis and prognosis. Aberrant expression of lncRNAs is associated with many cancers, including hepatocellular carcinoma (HCC), gallbladder carcinoma (GBC), acute promyelocytic leukemia (APL), lung cancer (LC), prostate cancer (PC), osteosarcoma (OS), colorectal cancer (CRC), cervical cancer (CC), and acute myeloid leukemia (AML). Targeting lncRNAs could be a promising strategy to complement or replace current cancer treatments. As a non-coding oncogene, lncRNA HOXA-AS2 is implicated in multiple cancers and could serve as a potential biomarker for various malignancies. The tumor size and disease stage of several cancers are correlated with HOXA-AS2 expression. Silencing HOXA-AS2 effectively suppresses tumor cell proliferation and promotes apoptosis, thereby inhibiting the progression of multiple cancer types. The regulatory mechanisms of HOXA-AS2 include inducing epithelial-mesenchymal transition (EMT), overexpressing B-cell lymphoma-2 (Bcl-2) and MYC proto-oncogene (c-Myc), gene silencing, activating AKT-MMP signaling pathways, EZH2 and LSD1, and functioning within a competing endogenous RNA (ceRNA) regulatory network by competitively binding miRNAs. This review surveys recent research on the structure, biological functions, abnormal expression, regulatory mechanisms, and diagnostic and therapeutic potential of HOXA-AS2 in various cancers.

Nanofibers are among the promising platforms for efficient delivery of drugs (both hydrophilic and hydrophobic) through harnessing polymers with different natures as their base. Hydrophobic low-solubility agents such as curcumin could be incorporated in various types of electrospun nanofibers for different aims in drug delivery, such as enhancing its solubility, making this agent sustained release with improved pharmacological efficacy. Through using this nanoplatform, curcumin may become more bioavailable and more efficcious in the field of cancer therapy as well as tissue engineering and wound healing for local delivery of this anti-inflammatory and antioxidant agent. In this review, the characteristics of curcumin-loaded nanofibers, their targeting potential or stimuli-responsiveness accompanied with therapeutic anti-cancerous applications of them (mostly in local application) are securitized. These nanofibers follow the aim of enhancing curcumin's therapeutic effectiveness and release profile. We laso elaborate on the mechanisms of action through which curcumin exerts its effect on various cancerous cells after its incorporation in various types of nanofibers which have been prepared by exploiting different polymers.

Background: Tertiary lymphoid structures (TLSs) associate with prognosis of many malignancies. However, the clinical significance of TLSs is not well-elucidated in nasopharyngeal carcinoma (NPC) patients.

Material and methods: In this whole population-based multicenter study, a total of 115 patients treated for NPC were included. The patients were treated at the five Finnish university hospitals. TLSs were assessed in routine hematoxylin and eosin (HE)-stained sections.

Results: Presence of TLSs associates significantly with improved survival in NPC. Absence of TLSs had a significant association with a poor disease-specific survival of NPC with a hazard ratio (HR) of 1.96 (95 % CI 1.09-3.53, P = 0.025) in the multivariable analysis. Similarly, absence of TLSs associated with worse overall survival with a HR of 1.68 (95 % CI 1.02-2.75, P = 0.040).

Conclusion: TLSs seem to be associated with prognosis of NPC patients. Having TLSs in NPC tumors correlates with good survival. The assessment of TLSs could aid in understanding the clinical behavior and in planning the treatment of NPC.

Pseudomyxoma peritonei (PMP) is a rare disease caused by mucin-producing tumors that develop most frequently from the appendix. The disease is characterized by the accumulation of mucin in the abdominal cavity. Although frequent mutations in the KRAS and GNAS genes have been reported in PMP, gene expression profiles of the tumors remain to be fully clarified because of its rarity and the difficulties in collecting pure cancerous cells scattered within the mucin. To disclose the molecular features of PMP cells, we performed RNA-seq analysis of ten PMPs and their matched non-tumorous colonic epithelium in combination with laser-microdissection. As a result, we identified a total of 32 differently expressed genes (DEGs) between the tumors and non-tumorous colonic epithelium. A cell-of-origin subtype analysis with the nearest template prediction algorithm corroborated that PMP tumor cells belonged to the goblet cell subtype, and tumorous cells of PMP appear to arise from goblet cells. Interestingly, over representation analysis (ORA) uncovered that the tumors were significantly associated with three ontology terms, namely epithelial mesenchymal transition (EMT), angiogenesis, and inflammatory response. Comparison of gene expression profiles between disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous adenocarcinomas (PMCA) identified a total of 687 DEGs. Additional gene set enrichment analysis (GSEA) revealed that ontology terms "G2M checkpoint" and "E2F targets" were significantly enriched in PMCA supporting the view that PMCA has more aggressive properties than DPAM. These data may be useful to further understand the molecular characteristics of PMP.

Background: RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported.

Materials and methods: A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAF^mut), MMRd/BRAF^mut, and MMRd/BRAF wild type (BRAF^wt). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit.

Results: The MMRd/BRAF^mut group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAF^wt and the MMRp/BRAF^mut groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAF^mut group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAF^wt group presented 50.0 % of CIMP-H adenocarcinomas.

Conclusions: Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAF^mut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.

Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript1 (MALAT1) has emerged as a crucial biomarker and therapeutic target for kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and renal cell carcinoma (RCC). LncRNAs are non-coding RNAs that have more than 200 nucleotides that play a crucial role in gene regulation at the post-translational stage, transcriptional, and epigenetic levels. LncRNA MALAT1 regulates gene expression and modulates cellular functions such as proliferation, inflammation, apoptosis, and fibrosis, which are key pathophysiology of kidney diseases. Overexpression of lncRNA MALAT1 has been consistently observed in kidney tissue, correlating with the severity and progression of kidney disease. In AKI, lncRNA MALAT1 exacerbates inflammation and tissue damage, contributing to disease progression. In CKD and DKD, lncRNA MALAT1 is implicated in the regulation of fibrosis by modulating key pathways, including focal adhesion kinase (FAK), toll-like receptor 4 (TLR4), NOD-like receptor protein3 (NLRP3), and nuclear factor kappa B (NF-κB), play pivotal roles in promoting disease progression. In LN, lncRNA MALAT1 has been linked to immune regulation and kidney damage, while in RCC, its role in promoting tumor growth and metastasis has been well documented. Preclinical research has demonstrated that therapeutic strategies targeting lncRNA MALAT1, such as knockdown and knockout, can reduce inflammation and fibrosis while improving kidney function. The fundamental role of lncRNA MALAT1 in kidney disease progression is yet to be fully understood. However, lncRNA MALAT1 has shown promise as a biomarker and therapeutic target to mitigate kidney disease development. This review highlights the potential of lncRNAs MALAT1 as diagnostic biomarkers and therapeutic targets, offering insights into a comprehensive approach to managing kidney diseases in the future.

Background: Patients with high-grade serous carcinoma (HGSC) are commonly diagnosed at late disease stages and after primary tumors have disseminated in the peritoneum. The overexpression of tight junction proteins has been associated with poor prognosis in this setting, potentially reflecting the tumor´s adaptive changes in the disease cascade.

Methods: By performing immunohistochemistry in a large single-center cohort of a total of 705 HGSC, we test the hypothesis that the protein expression of PReferentially expressed Antigen of MElanoma (PRAME) contains prognostic, predictive or clinically translatable information. We further examine its co-expression with tight junction proteins.

Results: We confirmed the nuclear expression of PRAME in 442 (63 %) of specimens with comparable expression levels in peritoneal and pleural effusions (p = 0.72), and in effusions versus surgical specimens (p = 0.339). In effusions, any degree of expression of PRAME was significantly associated with suboptimal debulking surgery during primary treatment (p = 0.034). In surgical specimens, higher expression of PRAME was significantly linked to more advanced FIGO stage (p = 0.021). PRAME expression was not associated with other clinico-pathologic factors as age, CA125 levels, chemoresistance or survival, but correlated with PRAME mRNA levels. Significant correlation was found between expression levels of PRAME and the tight junction protein Occludin (p = 0.002).

Conclusion: Taken together, our study confirms PRAME to be expressed in the majority of HGSC effusions and surgical samples. The association of high levels of PRAME expression with incomplete surgical resection status and advanced stage disease may suggest PRAME expression as adaptative mechanism during disease dissemination. This finding warrants confirmation in independent series.

Biomarkers that identify tumors with better/worse prognosis can help reduce treatment costs and contribute to patient survival. In urothelial bladder cancer (UBC), accurate prediction of recurrence and progression is essential to inform therapeutic management. Herein, we explore the role of genetic variants of xenobiotic metabolic pathways in UBC susceptibility and prognosis. In total, 295 participants with UBC and 295 controls were genotyped using TaqMan® probes. CYP1A1 (rs1048943), CYP3A4 (rs4646437), CYP3A5 (rs4646450), UGT2B7 (rs7438135), and UGT2B15 (rs3100) allele frequencies were compared between UBC patients and controls and were analyzed concerning tumor grade, invasion, and recurrence. CYP3A4 (AA) increased susceptibility to UBC 3-fold when interacting with CYP3A5 (AA+AA). The susceptibility was higher in CYP3A4 (AA) males (OR=3.189) and individuals exposed to pesticides (OR=5.492). When interacting with hypertension, the allele C of CYP1A1 also increased UBC susceptibility by 2-fold. The UGT2B15 mutant allele was associated with high-grade tumors (OR=2.196) and recurrences (OR=2.561), as well as tumor grade when associated with mutated alleles of CYP3A4 (OR=6.171) and CYP3A5 (OR=3.492). Genes-encoding proteins were further analyzed using the STRING program, demonstrating that the proteins had known interactions in databases and were co-expressed. This study is a pioneer in evaluating these variants in a Latin American population from Brazil and confirms occupational pesticide exposure as a risk factor for UBC, mainly in genetically susceptible individuals. Furthermore, these variants may have additional clinical value for predicting susceptibility and prognostic stratification in patients with exposure-related cancers such as UBC.