J. Mol. Pathol., Volume 5, Issue 4 (December 2024) – 10 articles

Calcium ions (Ca²⁺) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of excitotoxicity, the excessive release of glutamate in the synapses can trigger the activation of postsynaptic receptors. Upon activation, Ca²⁺ influx into the cell from the extracellular space via their associated ion channels, most notably L-type Ca²⁺ channels. Previous studies have indicated that α-synuclein (α-syn), a typical cytosolic protein, plays a significant role in the pathogenesis of Parkinson’s disease (PD). It is also worth noting that the aggregated form of α-syn has the capacity to affect Ca²⁺ homeostasis by altering the function of Ca²⁺ regulation. The upregulation of leucine-rich repeat kinase 2 (LRRK2) is closely associated with PD pathogenesis. LRRK2 mutants exhibit a dysregulation of calcium signaling, resulting in dopaminergic neuronal degeneration. It could therefore be proposed that α-syn and LRRK2 play important roles in the mechanisms underlying Ca²⁺ dyshomeostasis and excitotoxicity in PD. Full article

Introduction: Colorectal cancer screening programs are effective in reducing incidence and mortality. In Europe, every FIT+ patient is referred to colonoscopy. The available data show that ~75.0% of these patients are negative. It is desirable to select patients at a greater risk of having a positive colonoscopy. Materials and Methods: 711 subjects, aged 50–74, attending the screening program of ASL-NA-3-SUD (Naples, Italy), were enrolled in a cross-sectional study to evaluate the performance of the QuantiDNA™ test and the non-inferiority of an alternative approach (AAP). This evaluation is based on FIT+ and QuantiDNA™+ patients referred to colonoscopy, compared to Standard of Care (SOC) colonoscopy following a FIT+ test alone. A non-inferiority margin (NIM) for colorectal neoplasia (CN) and advanced adenomas (AA) was set at −10% and at −3.8% for CRC. Results: The odds ratio was 1.76 (p-value = 0.009). The detection rate of AAP was 15.9% for colorectal neoplasia, 13.0% for advanced adenoma, and 3.0% for CRC. The risk difference between AAP and SOC was −5.07% (95% C.I. −9.23, −0.90) for colorectal neoplasia, −4.02% (95% C.I. −7.89, −0.16) for advanced adenomas, and −1.04% (95% C.I. −3.16, 1.07) for CRC. This data suggests that AAP is non-inferior to SOC for detecting CN, AA, and CRC. The expected decrease in colonoscopies is 33.4%. Conclusions: The QuantiDNA™ test is straightforward, non-invasive, and well-tolerated. Data from this study indicate that it is effective in the reduction of the need for colonoscopy examinations (−33.4%) and is non-inferior to SOC in the detection of significant colorectal lesions. Full article

Glioblastoma is a highly aggressive malignancy affecting the brain and central nervous system. It is the most common malignant primary brain tumor, yet its prognosis remains poor. Median survival typically ranges from around 13 months with standard treatment to up to 19.9 months in some recent clinical trials. Despite advances in treatment, the aggressive nature of glioblastoma continues to present significant challenges for improving patient outcomes. This study aimed to analyze various biological, radiological, and molecular factors associated with glioblastoma recurrence and to estimate survival outcomes. A total of 104 glioblastoma patients diagnosed between January 2017 and September 2022 were included. Patient demographics, treatment received, and molecular characteristics were obtained from the Electronic Patient Record (EPR). Tumor molecular characteristics were analyzed using the OnkoSight Advanced CNS NGS panel. Statistical analyses were performed to develop a prognostic model for glioblastoma recurrence and estimate survival rates. Among the patients, 65.4% had no recurrence, with a mean age of 63 years. No gender or BMI differences were observed, but ages <60 years were associated with recurrence. Radiological findings showed no significant differences in tumor size, necrosis, site, or focality. In multivariate analysis, the female gender, obesity, old age (>60 years), or bifocal tumors were associated with decreased glioblastoma recurrence. However, factors like tumor site, size, necrosis, MGMT promoter methylation, and EGFR alteration showed no significant association with recurrence. Median survival was 12 months, with older age significantly associated with shorter survival. Tumor sizes >4 cm showed shorter survival trends but not statistically significantly. Patients who lived longer experienced more tumor recurrence incidents. Standard or non-standard treatments were associated with longer median survival compared to no treatment. Our findings provide insights into factors influencing glioblastoma recurrence and survival. Age, gender, and tumor characteristics play pivotal roles in recurrence. Understanding these factors could aid in optimizing treatment strategies and improving patient outcomes. However, further multicentric investigations are needed to validate these findings. This study emphasizes the importance of considering biological and radiological factors in clinical decision-making for glioblastoma cases. Full article

Background/Objectives: Colorectal cancer (CRC) is the third leading cause of cancer death globally, with rising incidence. The immunohistochemistry (IHC) for mismatch repair (MMR) proteins is the first technique used in routine practice to evaluate an MMR status. Microsatellite instability (MSI) may be tested in case of doubt during IHC staining. This study introduces a novel high-resolution melt (HRM) protocol for MSI detection and compares it with traditional fragment length analysis (FLA) via capillary electrophoresis. Methods: A total of 100 formalin-fixed and paraffin-embedded CRC specimens were analyzed using two distinct protocols: one based on FLA (TrueMark MSI Assay kit) and another one based on HRM (AmoyDx^® Microsatellite Instability Detection Kit). Results: Overall, 68 (68.0%) of the cases were MSS, and 32 (32.0%) were MSI-H. HRM analysis was first successfully carried out in all the cases. A perfect concordance in MSI evaluation between HRM and FLA was observed. HRM showed slightly shorter hands-on time and turnaround time. Conclusions: We provided evidence of the validity of this new HRM approach in determining the MSI status of colorectal carcinomas. Full article

Periodontal disease remains a significant global health concern, characterized by complex host–pathogen interactions leading to tissue destruction. This review explored the role of pattern recognition receptors (PRRs) in the pathogenesis of periodontal disease, synthesizing current knowledge on their molecular mechanisms and potential as therapeutic targets. We examined the diverse family of PRRs, focusing on toll-like receptors (TLRs) and NOD-like receptors (NLRs), elucidating their activation by periodontal pathogens and subsequent downstream signaling cascades. This review highlights the intricate interplay between PRR-mediated pathways, including NF-κB and MAPK signaling, and their impact on inflammatory responses and bone metabolism in periodontal tissues. We discussed the emerging concept of PRR crosstalk and its implications for periodontal homeostasis and disease progression. Furthermore, this review addressed the potential of PRR-targeted therapies, exploring both challenges and opportunities in translating molecular insights into clinical applications. By providing an overview of PRRs in periodontal health and disease, this review aims to stimulate future research directions and inform the development of novel diagnostic and therapeutic strategies in periodontology. Full article

Birt–Hogg–Dubé syndrome (BHDS) is an autosomal dominant disease characterized by skin, lung, and renal manifestations. This syndrome is caused by a germline mutation in the FLCN gene, which leads to disruption in multiple downstream pathways. Renal cell carcinomas are one of the serious clinical manifestations of the disease, which usually presents as bilateral and multiple tumors. Morphologically, most of these tumors are classified as hybrid oncocytic tumors. Recent advances in molecular techniques have shed light on the pathogenesis of these renal tumors. In this review, we evaluate and summarize the current knowledge of BHDS, pathologic changes, and its molecular basis with the focus on the renal hybrid oncocytic tumor (HOT), their pathogenesis, and molecular underpinning. Full article

The rising global incidence of uterine cancer has been linked to the escalating prevalence of obesity. Obesity results in insulin resistance which alters the IGF system, thereby driving cancer progression via increased cell proliferation and the inhibition of apoptosis, although the precise mechanisms remain unclear. In a previous study, we compared the levels of IGF1 and IGF2 between fifty endometrial cancer patients (study group) and fifty age-matched non-cancer patients with benign gynaecological conditions (control group), identifying a correlation with menopause. Building on these data, we now report that IGF levels in pre-menopausal women were significantly lower in the study group compared to the control group, a pattern not observed in post-menopausal women. We undertook the receiver operating characteristic (ROC) curve analysis for calculating the potential of IGF1 and IGF2 to effectively distinguish pre-menopausal women with endometrial cancer from those without it. For pre-menopausal women, the area under ROC curve values were 0.966 for IGF1 and 0.955 for IGF2, both with significant p-values, indicating that IGF1 and IGF2 levels have the potential to be diagnostic biomarkers for distinguishing pre-menopausal women with endometrial cancer from those without it. In summary, our findings emphasise the importance of considering menopausal status in the context of IGF level assessments and suggest that IGF1 and IGF2 could play a crucial role in the early diagnosis of endometrial cancer in pre-menopausal women. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by symmetrical joint inflammation, cartilage degradation, and bone erosion. This review explores the multifaceted aspects of RA pathogenesis, focusing on the dynamic interplay between innate and adaptive immune responses, genetic predisposition, and environmental triggers. The development of RA involves genetic susceptibility and trigger events such as infections, trauma, smoking, obesity, and microbiome alterations, fostering autoimmune reactions and tissue/organ destruction. The innate immune response, including toll-like receptor activation and synovial fibroblasts’ roles, contributes to the acceleration of inflammatory processes in joint tissues. Monocytes and macrophages organize and sustain chronic joint inflammation, leading to tissue damage and bone resorption, while highlighting the significance of CD14 and CD16 subsets in RA pathogenesis. In the adaptive immune response, aberrant activation and proliferation of CD4+ T cells and the role of regulatory T cells in maintaining immune tolerance are discussed. Target cytokines like TNF-α, IL-6, IL-1, IL-17, and BAFF, as well as chemokines such as CCL2, CXCL10, CCL5, and CXCL12, have emerged as critical components in managing chronic inflammation and joint damage in RA. This comprehensive overview provides insights into the pathophysiology of RA and potential therapeutic avenues, emphasizing the importance of understanding these complex immunological and genetic mechanisms for developing more effective treatment strategies. Full article

The extracellular matrix is an organized three-dimensional network of protein-based molecules and other macromolecules that provide structural and biochemical support to tissues. Depending on its biochemical and structural properties, the extracellular matrix influences cell adhesion and signal transduction and, in general, can influence cell differentiation and proliferation through specific mechanisms of chemical and mechanical sensing. The development of body tissues during ontogenesis is accompanied by changes not only in cells but also in the composition and properties of the extracellular matrix. Similarly, tumor development in carcinogenesis is accompanied by a continuous change in the properties of the extracellular matrix of tumor cells, called ‘oncomatrix’, as the tumor matures, from the development of the primary focus to the stage of metastasis. In this paper, the characteristics of the composition and properties of the extracellular matrix of tumor tissues are considered, as well as changes to the composition and properties of the matrix during the evolution of the tumor and metastasis. The extracellular matrix patterns of tumor tissues can be used as biomarkers of oncological diseases as well as potential targets for promising anti-tumor therapies. Full article

Aggressive B-cell lymphoma encompasses Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and, as per the 2016 WHO classification, high-grade B-cell lymphoma (HGBL) not otherwise specified (NOS) and HGBL double/triple hit (DH/TH). However, the diagnostic distinction of HGBL from BL and DLBCL is difficult by means of histology/immunostaining in a substantial number of patients. This study aimed to improve subtyping by the identification of molecular features of aggressive B-cell lymphomas, with a specific focus on HGBL. To this end, we performed a comprehensive gene expression and mutational pattern analysis as well as the detection of B-cell clonality of 34 cases diagnosed with BL (n = 4), DLBCL (n = 16), HGBL DH (n = 8), and HGBL NOS (n = 6). Three distinct molecular subgroups were identified based on gene expression, primarily influenced by MYC expression/translocation and cell proliferation. In HGBL, compared to BL, there was an upregulation of PRKAR2B and TERT. HGBL DH exhibited elevated expression of GAMT and SMIM14, while HGBL NOS showed increased expression of MIR155HG and LZTS1. Our gene mutation analysis revealed MYC, ARID1A, BCL2, KMT2D, and PIM1 as the most affected genes in B-cell lymphoma, with BCL2 and CREBBP predominant in HGBL DH, and MYC and PIM1 in HGBL NOS. Clonality analysis of immunoglobulin heavy and light chain rearrangements did not show distinguishable V- or J-usage between the diagnostic subgroups. Full article