Sex Differences in Glomerular Lesions, in Atherosclerosis Progression, and in the Response to Angiotensin-Converting Enzyme Inhibitors in the ApoE-/- Mice Model.

This study analyzes sex-based differences in renal structure and the response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Eight weeks old ApoE-/- mice received enalapril (5 mg/kg/day, subcutaneous) or PBS (control) for an additional 14 weeks. Each group consisted of six males and six females. Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells, and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in the female group), and hypertrophy of the PECs in males. This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

Biomarkers of tumor-reactive CD4+ and CD8+ TILs associate with improved prognosis in endometrial cancer.

BACKGROUND: Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear. METHODS: To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+ and CD4+ EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+ and CD4+ TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+ and CD4+ tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival. RESULTS: We found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1- and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+ and PD-1hiCD39+ T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+ T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hi compared with PD-1- or PD-1dim T cells, and in fact, it was the CD4+PD-1hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+ TILs and PD-1hi and CXCL13 by CD4+ Tconv TILs, correlated with prolonged survival of patients with EC. CONCLUSIONS: Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hi and CD39 or PD-1hi can be used to select and expand CD8+ and CD4+ tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+ and CD4+ lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity.

Radio-Histological Correlation of Lung Features in Severe COVID-19 Through CT-Scan and Lung Ultrasound Evaluation.

Background: Patients with coronavirus disease 2019 (COVID-19) can develop severe bilateral pneumonia leading to respiratory failure. Lung histological samples were scarce due to the high risk of contamination during autopsies. We aimed to correlate histological COVID-19 features with radiological findings through lung ultrasound (LU)-guided postmortem core needle biopsies (CNBs) and computerized tomography (CT) scans. Methodology: We performed an observational prospective study, including 30 consecutive patients with severe COVID-19. The thorax was divided into 12 explorations regions to correlate LU and CT-scan features. Histological findings were also related to radiological features through CNBs. Results: Mean age was 62.56 ± 13.27 years old, with 96.7% male patients. Postmortem LU-guided CNBs were performed in 13 patients. Thirty patients were evaluated with both thoracic LU and chest CT scan, representing a total of 279 thoracic regions explored. The most frequent LU finding was B2-lines (49.1%). The most CT-scan finding was ground-glass opacity (GGO, 29%). Pathological CT-scan findings were commonly observed when B2-lines or C-lines were identified through LU (positive predictive value, PPV, 87.1%). Twenty-five postmortem echo-guided histological samples were obtained from 12 patients. Histological samples showed diffuse alveolar damage (DAD) (75%) and chronic interstitial inflammation (25%). The observed DAD was heterogeneous, showing multiple evolving patterns of damage, including exudative (33.3%), fibrotic (33.3%), and organizing (8.3%) phases. In those patients with acute or exudative pattern, two lesions were distinguished: classic hyaline membrane; fibrin "plug" in alveolar space (acute fibrinous organizing pneumonia, AFOP). C-profile was described in 33.3% and presented histological signs of DAD and lung fibrosis. The predominant findings were collagen deposition (50%) and AFOP (50%). B2-lines were identified in 66.7%; the presence of hyaline membrane was the predominant finding (37.5%), then organizing pneumonia (12.5%) and fibrosis (37.5%). No A-lines or B1-lines were observed in these patients. Conclusion: LU B2-lines and C-profile are predominantly identified in patients with severe COVID-19 with respiratory worsening, which correspond to different CT patterns and histological findings of DAD and lung fibrosis.