Azelaic acid reduced senescence‐like phenotype in photo‐irradiated human dermal fibroblasts: possible implication of PPARγ

Azelaic acid (AzA) has been used for the treatment for inflammatory skin diseases, such as acne and rosacea. Interestingly, an improvement in skin texture has been observed after long‐time treatment with AzA. We previously unrevealed that anti‐inflammatory activity of AzA involves a specific activation of PPARγ, a nuclear receptor that plays a relevant role in inflammation and even in ageing processes. As rosacea has been considered as a photo‐aggravated disease, we investigated the ability of AzA to counteract stress‐induced premature cell senescence (SIPS). We employed a SIPS model based on single exposure of human dermal fibroblasts (HDFs) to UVA and 8‐methoxypsoralen (PUVA), previously reported to activate a senescence‐like phenotype, including long‐term growth arrest, flattened morphology and increased synthesis of matrix metalloproteinases (MMPs) and senescence‐associated β‐galactosidase (SA‐β‐gal). We found that PUVA‐treated HDFs grown in the presence of AzA maintained their morphology and reduced MMP‐1 release and SA‐β‐galactosidase‐positive cells. Moreover, AzA induced a reduction in ROS generation, an up‐modulation of antioxidant enzymes and a decrease in cell membrane lipid damages in PUVA‐treated HDFs. Further evidences of AzA anti‐senescence effect were repression of p53 and p21, increase in type I pro‐collagen and abrogation of the enhanced expression of growth factors, such as HGF and SCF. Interestingly, PUVA‐SIPS showed a decreased activation of PPARγ and AzA counteracted this effect, suggesting that AzA effect involves PPARγ modulation. All together these data showed that AzA interferes with PUVA‐induced senescence‐like phenotype and its ability to activate PPAR‐γ provides relevant insights into the anti‐senescence mechanism.     

Expression profiles of PRKG1, SDF2L1 and PPP1R12A are predictive and prognostic factors for therapy response and survival in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGS-EOCs) is generally sensitive to front-line platinum (Pt)-based chemotherapy although most patients at an advanced stage relapse with progressive resistant disease. Clinical or molecular data to identify primary resistant cases at diagnosis are not yet available. HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients were retrospectively selected from two independent tumor tissue collections. Pathway analysis was done integrating miRNA and mRNA expression profiles. Signatures were further validated in silico on a cohort of 838 HGS-EOC cases from a published dataset. In all, 131 mRNAs and 5 miRNAs belonging to different functionally related molecular pathways distinguish Pt-s from Pt-r cases. Then, 17 out of 23 selected elements were validated by orthogonal approaches (SI signature). As resistance to Pt is associated with a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was assessed, and 14 genes associated with PFS and OS, in multivariate analyses (SII signature). The prognostic value of the SII signature was validated in a third extensive cohort. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) served as independent prognostic biomarkers of Pt-response and survival. The study identified a prognostic molecular signature based on the combined expression profile of three genes which had never been associated with the clinical outcome of HGS-EOC. This may lead to early identification, at the time of diagnosis, of patients who would not greatly benefit from standard chemotherapy and are thus eligible for novel investigational approaches.     

Targeting A3 and A2A adenosine receptors in the fight against cancer

Introduction: There is a vicious cycle of tumor hypoxia, high adenosine levels, immune suppression and cancer growth that involves the use of adenosine receptor ligands in tumors. After several years of research, the candidates emerging as promising new anticancer drugs are A₃ adenosine receptor agonists and A_2A receptor antagonists.

Areas covered: The authors give an updated overview of the field related to A₃ receptor agonists and A_2A receptor antagonists in cancer and propose their perspectives on the status of these compounds in oncology. The rationale for the modulation of adenosine receptors in cancer is addressed, starting from the first in vitro evidence of their efficacy up to the animal and clinical studies.

Expert opinion: A₃ and A_2A receptors are attractive targets in oncologic therapy due to their involvement in cancer progression and immune-resistance. Of relevance, the A₃ subtype is also a tumor marker to be used in a personalized drug treatment program while the A_2A receptor, playing a non-redundant role in immunomodulation, may be blocked in combination with checkpoint inhibitors to improve their efficacy. The future will reveal how successful this approach is in the fight against cancer.     

Serum osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand levels in patients with a history of differentiated thyroid carcinoma: a case-controlled cohort study

Overt hyperthyroidism is associated with changes in bone metabolism, whereas the effect of levothyroxine (L-T4) load in patients with differentiated thyroid carcinoma (DTC) is controversial. The aim of our study was to evaluate osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (RANK-L) in patients with DTC with suppressed endogenous thyrotropin due to L-T4 regimen. A cohort of 80 subjects with DTC (68 women and 12 men; age range, 27-81 years) was studied. A cohort of 55 subjects with a history of partial or total surgery for nonmalignant thyroid pathology served as a control group. Groups were matched for sex, age, and body mass index. Per-week dosage of L-T4 was significantly higher in patients with DTC than in controls (P < .001). More elevated free T(4) concentrations (P < .001) and more suppressed thyrotropin and thyroglobulin levels (P < .001) were found in subjects with DTC than in controls. No difference in serum or urinary parameters related to bone metabolism or dual-energy x-ray absorptiometry was noted between the groups. Overall, OPG levels were similar in both groups but were significantly (P = .03) lower in postmenopausal women with DTC than in postmenopausal control women. Only control women showed lower OPG levels in premenopausal than in postmenopausal (P = .002) conditions. Overall, RANK-L levels were significantly higher (P = .03) in subjects with DTC than in controls. In both groups, OPG and RANK-L levels were unrelated to each other. A significant positive correlation was seen between OPG levels and age in both subjects with DTC (P < .001) and controls (P < .001). Serum RANK-L correlated negatively with age in subjects with DTC (P = .05). Although there were several differences in L-T4 dosages, OPG and RANK-L levels were similar in patients with a history of DTC and those with a history of nonmalignant thyroid diseases. The correlation between circulating OPG and RANK-L levels was not significant. The increase in OPG with age indicates its protective role in bone loss. The cause of bone loss after long-term L-T4 load will be more extensively studied.     

Effects of vestibular and neck proprioceptive stimulation on posture as a function of hypnotizability

Previous studies on the role of hypnotizability in postural control indicate that the body sway of subjects with high or low hypnotizability to hypnosis is differentially modulated by eye closure. The aim of this study was to investigate whether hypnotizability also modulates the postural response to electrical vestibular stimulation and to head rotation in nonhypnotized individuals. The center of pressure (CoP) displacements were monitored in highs and lows standing on a stabilometric platform with closed eyes during basal conditions and electrical vestibular stimulation in 3 different positions of the head. Results showed that the CoP stimulus-locked displacements as well as the CoP mean position, area, and mean velocity were similar in highs and lows, but only in lows did the head position modulate the mean velocity. This finding might reflect a difference in sensory-motor integration between the 2 groups.