Pathophysiology, Volume 32, Issue 4 (December 2025) – 7 articles

Objectives: To evaluate the diagnostic and prognostic value of histophenotyping of the extracellular matrix of the cervical stroma at cervical intraepithelial neoplasia (CIN). Methods: Retrospective analysis of 160 biopsies and surgical preparations of the cervix in women of reproductive age included cases of CIN 1–3 and the group with confirmed persistence or lesion progression (CIN P) at repeated biopsy. The control group (n = 40) consisted of morphologically intact cervical tissue. Histophenotypes were evaluated by staining with hematoxylin, eosin, and Masson trichrome, and classified as follows: normal (dense parallel bundles of type I collagen), intermediate (disorganized and fragmented type I collagen fibers), and myxoid (amorphous weakly fibrillar matrix). The clinical, viral, and inflammatory characteristics between histophenotypes were statistically compared. Results: The distribution of histophenotypes of the extracellular matrix of the cervix varied significantly depending on the CIN degree (p < 0.001). In the control group, the normal pattern was detected in 97.5% of cases; its frequency decreased from CIN 1 (27.5%) to CIN 2 (12.5%) and was absent at CIN 3. The frequency of the myxoid pattern increased significantly in severe and persistent forms: 55% at CIN 3 and 62.5% at CIN P. Human papillomavirus 16/18 was most frequently detected in groups with intermediate (69.1%) and myxoid (27.2%) patterns. Inflammatory changes were more often accompanied by disorganized extracellular matrix; however, intermediate and myxoid types also occurred in the absence of inflammation. Conclusions: The myxoid histophenotype of the extracellular matrix is significantly associated with the high degree of dysplasia and CIN persistence. It can reflect the morphological equivalent of tumor-associated stroma remodeling. Histophenotyping of the extracellular matrix of the cervix appears to be a promising method of risk stratification and may complement existing diagnostic algorithms for CIN. Full article

Background/Objectives: Testicular germ cell tumours (GCT) have high cure rates, especially in early stages. MicroRNA-371a-3p (M371) has recently emerged as a highly sensitive biomarker for malignant GCTs, except teratoma. This study aimed to evaluate the diagnostic performance of M371-test in a real-life clinical setting, compared to conventional markers alpha-fetoprotein (AFP), lactate-dehydrogenase (LDH), and beta-human chorionic gonadotropin (β-HCG) in patients with suspected GCT. Methods: The study, approved by the Ethic-Committee of the Provincial Hospital of Bolzano (N.97-2021), included 91 M371-tests, performed from March 2021 to May 2025. A total of 75 patients had suspected GCT; 19 healthy males served as control. Serum levels of M371, AFP, LDH, and β-HCG were compared with final histopathological diagnosis. M371 was also assessed in controls to evaluate test performance. Secondary analyses investigated correlations between preoperative M371 levels and tumour size in non-metastatic patients, and between M371-levels and clinical stage in the entire GCT cohort. A cut-off of RQ > 5 (relative quantification) was used to calculate sensitivity, specificity, and predictive values. Results: M371 showed a sensitivity of 90.9% and specificity of 89.3%, outperforming in terms of sensitivity AFP (20.4%/96.4%), LDH (40.9%/96.4%), and β-HCG (43.1%/100%). Positive predictive value (PPV) and negative predictive value (NPV) were 93.0% and 86.2%, respectively. Sensitivity was 95% for non-seminomas and 87.5% for seminomas. In non-metastatic patients, M371 levels correlated with tumour size and were significantly higher in advanced stages (median RQ 1128.35 vs. 98.36; p = 0.015). Conclusions: M371 showed excellent diagnostic performance, even for small tumours, supporting its clinical use. Further studies are needed to define its role in treatment planning and follow-up. Full article

Current standard treatments for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a urological disorder with anxiety as a major comorbidity, are limited in success rates. Recent findings revealed the anti-inflammatory and neuroprotective effects of CO-releasing molecules (CO-RMs), but there is a gap in the knowledge on its effects in CP/CPPS. Therefore, the objective of our study was to investigate the potential therapeutic effects of CORM-A1 on the scrotal pain threshold and anxiety-related behaviors in experimental model of CP/CPPS. Adult Wistar albino male rats were randomized to Sham (intraprostatic saline) or CP/CPPS (intraprostatic λ-carrageenan) groups (n = 12). Half received CORM-A1 (2 mg/kg/day, i.p., days 1–7), others PBS, forming four subgroups (n = 6). The pain threshold (by an electronic von Frey esthesiometer) and anxiety-like behavior (by an open field, elevated plus maze and light/dark test) were assessed; prostates were histologically examined. Carrageenan-induced CP/CPPS caused significant mechanical pain hypersensitivity (p < 0.001), anxiety-like behaviors (p < 0.001–0.05), and histological prostate damage when compared to corresponding Sham groups. CORM-A1 treatment increased pain thresholds (p < 0.001) and improved behavioral outcomes (p < 0.001–0.01) in all ethological tests. These findings indicate that CORM-A1 exerts analgesic and anxiolytic effects in an experimental model of CP/CPPS in rats. Full article

The morphogenesis of the primordial gut relies on signaling pathways such as Wnt, FGF, Notch, Hedgehog, and Hippo. Reciprocal crosstalk between the endoderm and mesoderm is integrated into the signaling pathways, resulting in craniocaudal patterning. These pathways are also involved in adult intestinal homeostasis including cell proliferation and specification of cell fate. Perturbations in this process can cause growth disturbances manifesting as adenomas, serrated lesions, and cancer. Significant differences have been observed between right and left colon cancers in the hindgut, and between the jejunoileum, appendix, and right colon in the midgut. The question is to what extent the embryology of the mid- and hindgut contributes to differences in the underlying tumor biology. This review examines the precursor lesions and consensus molecular subtypes (CMS) of colorectal cancer (CRC) to highlight the significance of embryology and tumor microenvironment (TME) in CRC. The three main precursor lesions, i.e., adenomas, serrated lesions, and inflammatory bowel disease-associated dysplasia, are linked to the CMS classification, which is based on transcriptomic profiling and clinical features. Both embryologic and micro-environmental underpinnings of the mid- and hindgut contribute to the differences in the tumors arising from them, and they may do so by recapitulating embryonic signaling cascades. This manifests in the range of CRC CMS and histologic cancer subtypes and in tumors that show multidirectional differentiation, the so-called stem cell carcinomas. Emerging evidence shows the limitations of CMS particularly in patients on systemic therapy who develop drug resistance. The focus is thus transitioning from CMS to specific components of the TME. Full article

Background/Objectives: Lichen Planus Pemphigoides (LPP) represents a rare variant of Oral Lichen Planus in which the typical pemphigoid-associated antibodies, BP180 and BP230, are present. The objectives of this Systematic Review are to analyze the data currently available in the literature on this rare condition, with the aim of laying the groundwork for future investigations and research. Methods: This Systematic Review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD420251133018. Subsequently, a search was conducted on PubMed/Medline, Scopus, and Ovid using specific keywords combined with Boolean operators. Articles published up to 2025 were included. The following types of studies were considered eligible: case reports, clinical conferences, clinical studies, clinical trials, controlled clinical trials, letters, multicenter studies, observational studies, randomized controlled trials, and human-based studies. Book chapters, systematic reviews, narrative reviews, in vitro studies, and animal models were excluded. Results: A total of 67 articles were initially identified; following thorough review and exclusion, 20 articles were retained. The patient data extracted from these selected studies were used to construct a table in which patients were categorized according to both qualitative and quantitative variables. The results highlight that LPP is a condition requiring a complex diagnostic process involving both histological examination and serological testing (Immunofluorescence and Enzyme-Linked Immunosorbent Assay—ELISA). Conclusions: Furthermore, with the advent of immunotherapy, an increasingly well-documented new category of drug-induced LPP has emerged, associated with PD-1 and PD-L1 inhibitors. Full article

Background: Obstructive Sleep Apnea Syndrome (OSAS) is a prevalent and underdiagnosed condition with significant systemic and quality-of-life impacts. While polysomnography remains the gold standard for diagnosis, cone-beam computed tomography (CBCT) presents a potential adjunctive imaging tool for anatomical airway evaluation. Objective: We aimed to assess the effectiveness of three-dimensional airway evaluation via CBCT as a complementary diagnostic tool for OSAS. Methods: A diagnostic test study (experimental pilot study) was conducted using CBCT scans of 30 patients, divided into two groups: 15 scans from patients with a confirmed OSAS diagnosis through polysomnography and 15 scans from healthy controls. Five tomographic variables were analyzed: anteroposterior distance, lateral distance, minimum cross-sectional area, airway volume, and airway shape. Statistical analysis was performed comparing both groups. Results: The minimum cross-sectional area and airway volume showed statistically significant differences between the OSAS and control groups (p = 0.038 and p = 0.0055, respectively). Anteroposterior and lateral distances showed trends toward significance but were not statistically significant. Conclusions: CBCT-based airway analysis, particularly focusing on volumetric and cross-sectional area parameters, demonstrates strong potential as a complementary tool in the diagnosis of peripheral-type OSAS. However, it cannot replace polysomnography, especially for central OSAS diagnosis. Full article

Background and objectives: Hypertension is a worldwide burden, for which fetal malnutrition is a risk factor. Another societal challenge is environmental waste. Our research focusses on cocoa shell extract (CSE), a cocoa by-product with antioxidant bioactive components. Male rats exposed to fetal malnutrition develop hypertension and endothelial dysfunction, which are improved by CSE supplementation. We hypothesized that effects of CSE are related to an antioxidant action. Methods: Adult male and female offspring of dams exposed to 50% food restriction during gestation (MUN) and controls were supplemented for 3 weeks with CSE (250 mg/kg/day) or a vehicle. We assessed plasma SOD activity, GSH and carbonyls (via spectrophotometry) and aortic expression of enzymes related to ROS degradation or production (via Western blotting). Results: MUN males showed lower Nrf2 expression and increased carbonyls, SOD activity and mitochondrial SOD2 expression, without alterations in GSH or the related enzyme CGLM. No changes in xanthine oxidase or NADPH subunits (p22phox and p47phox) were detected, suggesting a different origin of superoxide anion. Phosphorylated-eNOS/eNOS and 3-nitrotyrosine expression were increased without changes in plasma nitrates. MUN females only showed plasma SOD and aortic 3-nitrotyrosine elevation. CSE supplementation reduced SOD2 and p-eNOS/eNOS expression and SOD activity and increased Nrf2 expression. Conclusions: MUN arteries exhibit oxidative damage, with a higher impact on males. SOD2 and p-eNOS/e-NOS overexpression may be a counteracting mechanism that compensates for superoxide anion overproduction, likely involving mitochondria. The reversal of these alterations by CSE supplementation is probably related to a reduction in vascular superoxide anion through a direct scavenging action of its bioactive components. A longer supplementation period may be needed to increase endogenous antioxidants through Nrf2 and to reduce oxidative–nitrosative damage. Full article