High HbA1c levels affect motility parameters and overexpress oxidative stress of human mature spermatozoa

The aim of this study is to investigate, by a validated in vitro model, the effect of diabetic plasma on ejaculated human spermatozoa. Plasma of 51 male diabetic patients (mean age 62.28 ± 9.28 years) was selected according to their HbA_1c level: low HBA_1c ≤ 5% (31 mmol/mol), moderate HBA_1c 6%–8% (42–64 mmol/mol) and high HBA_1c ≥ 10% (86 mmol/mol). The plasma was tested on eighteen normal semen samples by analysing gametes motility using a computer Sperm Class Analyzer® and their corresponding oxidative stress (OS) status using thiobarbituric acid-reactive substances assay. The results indicated that diabetic plasma affected all sperm motility parameters with high HbA_1c showing the most important deleterious effects. Low gametes' straight-line velocity was observed in high HbA_1c level, mainly after 20 min of co-incubation (8.78 ± 0.47 µm/s). Also, the highest lipid peroxidation (nmoles MDA/10⁸ SPZ) was observed in high HbA_1c values (0.92 ± 0.09), higher than those in spermatozoa treated with H₂O₂ (0.85 ± 0.04). Conclusively, a direct impact of diabetic plasma on spermatozoa is revealed with overexpression of OS as the underlying mechanism. These findings suggested that it is strongly recommended to control clinically the glycaemic level and OS in diabetic patients for the maintenance of male fertility.     

SPARC in cancer-associated fibroblasts is an independent poor prognostic factor in non-metastatic triple-negative breast cancer and exhibits pro-tumor activity

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and lacks specific targeted therapeutic agents. The current mechanistic evidence from cell-based studies suggests that the matricellular protein SPARC has a tumor-promoting role in TNBC; however, data on the clinical relevance of SPARC expression/secretion by tumor and stromal cells in TNBC are limited. Here, we analyzed by immunohistochemistry the prognostic value of tumor and stromal cell SPARC expression in 148 patients with non-metastatic TNBC and long follow-up (median: 5.4 years). We also quantified PD-L1 and PD-1 expression. We detected SPARC expression in tumor cells (42.4%), cancer-associated fibroblasts (CAFs; 88.1%), tumor-associated macrophages (77.1%), endothelial cells (75.2%) and tumor-infiltrating lymphocytes (9.8%). Recurrence-free survival was significantly lower in patients with SPARC-expressing CAFs. Multivariate analysis showed that SPARC expression in CAFs was an independent prognostic factor. We also detected tumor and stromal cell SPARC expression in TNBC cytosols, and in patient-derived xenografts and cell lines. Furthermore, we analyzed publicly available single-cell mRNA sequencing data and found that in TNBC, SPARC is expressed by different CAF subpopulations, including myofibroblasts and inflammatory fibroblasts that are involved in tumor-related processes. We then showed that fibroblast-secreted SPARC had a tumor-promoting role by inhibiting TNBC cell adhesion and stimulating their motility and invasiveness. Overall, our study demonstrates that SPARC expression in CAFs is an independent prognostic marker of poor outcome in TNBC. Patients with SPARC-expressing CAFs could be eligible for anti-SPARC targeted therapy.     

New cytotoxic aristolactams from Pararistolochia flos-avis

Two new aristolactams, aristolactam-FI [1] and -FII [2], were isolated from active extracts of Pararistolochia flos-avis. Their structures were elucidated on the basis of nmr, ms, uv, and ir spectral data. Aristolactam-I [3] and -AII [4] were also isolated from this plant. Aristolactam-AII showed cytotoxicity against PS and KB cells in culture.     

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

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Are HLA antigens implicated in the pathogenesis of non-haemorrhagic deterioration following aneurysmal subarachnoid haemorrhage.

Aneursymal subarachnoid haemorrhage is frequently complicated by non-haemorrhagic deterioration. HLA typing was studied in a group of 40 patients who had sustained an aneurysmal subarachnoid haemorrhage in order to assess its ability to identify those who are likely to experience non-haemorrhagic deterioration. The antigen HLA-B7 appeared to be associated with an increased likelihood of this event supervening. Conversely, the antigen HLA-DR3, seemed to exert a "protective" influence.     

The combination of GM-CSF and IL-2 as local adjuvant shows synergy in enhancing peptide vaccines and provides long term tumor protection

Many strategies have been used to enhance the peptide vaccine immune response and to establish therapeutic benefits. This includes the utilization of cytokines to improve antigen presentation or enhance T cell response. Here, we have tested the combination of GM-CSF and IL-2 as locally administered adjuvant to enhance the immune response to the HPV16 E7 peptide. Female C57BL/6 mice were immunized intradermally with a 9-mer HPV16 E7 peptide (aa: 49-57) alone, or in combination with GM-CSF, IL-2, or both cytokines. Specific immune responses were measured by ELISA and Chromium-Release Assays. Furthermore, therapeutic effects of these vaccines and long term tumor protection were assessed in mice bearing established tumors. We showed that GM-CSF and IL-2, when co-administered locally in an emulsion with peptide, exert a synergistic effect in enhancing the immune response to the antigen. This combination induced higher CTL and cytokine release responses and did not increase the T(reg) population. Therapeutic intervention with this synergistic combination led to a complete response of established tumors. Furthermore, this combination induced a memory response which protected mice against subsequent additional tumor challenge. We identified a new vaccine adjuvant, a local combination of GM-CSF and IL-2, which is synergistic in enhancing peptide specific immune response through local effect without increasing T(reg) cells. This immune response was found to be long lasting and protective in tumor bearing mice.