Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep

Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial‐ and muscular‐dependent pathways. This was associated with an enhanced nitric oxide‐dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN.     

Spontaneous generation of functional osteoclasts from synovial fluid mononuclear cells as a model of inflammatory osteoclastogenesis

In osteoimmunology, osteoclastogenesis is understood in the context of the immune system. Today, the in vitro model for osteoclastogenesis necessitates the addition of recombinant human receptor activator of nuclear factor kappa‐B ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF). The peripheral joints of patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) are characterized by an immune‐mediated inflammation that can lead to bone destruction. Here, we evaluate spontaneous in vitro osteoclastogenesis in cultures of synovial fluid mononuclear cells (SFMCs) activated only in vivo. SFMCs were isolated and cultured for 21 days at 0.5–1.0 × 10⁶ cells/mL in culture medium. SFMCs and healthy control peripheral blood monocytes were cultured with RANKL and M‐CSF as controls. Tartrate‐resistant acid phosphatase (TRAP) positive multinucleated cells were found in the SFMC cultures after 21 days. These cells expressed the osteoclast genes calcitonin receptor, cathepsin K, and integrin β3, formed lacunae on dentin plates and secreted matrix metalloproteinase 9 (MMP9) and TRAP. Adding RANKL and M‐CSF potentiated this secretion. In conclusion, we show that SFMCs from inflamed peripheral joints can spontaneously develop into functionally active osteoclasts ex vivo. Our study provides a simple in vitro model for studying inflammatory osteoclastogenesis.     

Kaposi sarcoma following postmastectomy lymphedema

Classical Kaposi sarcoma (KS) usually appears on lower extremities accompanied or preceded by local lymphedema. However, the development in areas of chronic lymphedema of the arms following mastectomy, mimicking a Stewart–Treves syndrome, has rarely been described. We report an 81‐year‐old woman who developed multiple, erythematous to purple tumors, located on areas of post mastectomy lymphedema. Histopathological examination evidenced several dermal nodules formed by spindle‐shaped cells that delimitated slit‐like vascular spaces with some red cell extravasation. Immunohistochemically, the human herpesvirus type 8 (HHV‐8) latent nuclear antigen‐1 was detected in the nuclei of most tumoral cells confirming the diagnosis of KS. Lymphedema could promote the development of certain tumors by altering immunocompetence. Although angiosarcoma (AS) is the most frequent neoplasia arising in the setting of chronic lymphedema, other tumors such as benign lymphangiomatous papules (BLAP) or KS can also develop in lymphedematous limbs. It is important to establish the difference between AS and KS because their prognosis and treatment are very different. Identification by immunohistochemistry of HHV‐8 is useful for the distinction between KS and AS or BLAP.     

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.