A Practical Overview of the Role of Capillaroscopy in Rheumatic Diseases

Nailfold capillaroscopy is currently the best method to investigate microvascular abnormalities in systemic sclerosis and related conditions, and in other rheumatic conditions in which there is a clinical suspicion of microangiopathy. Although easy to perform, it is essential that the operators have been properly trained about correct method of images acquisition and interpretation. There are some parameters to indicate a normal/healthy capillaroscopic picture, but it is important to consider that there is a great variability in the capillary structure both interindividual and intraindividual. The early differential diagnosis between primary and secondary RP is the best advantage that the technique may offer.Remarkable capillaroscopic alterations are found in the majority of cases of systemic sclerosis and the so-called “scleroderma spectrum disorders†(dermatomyositis, mixed connective tissue disease, undifferentiated connective tissue disease). Nevertheless, some capillaroscopic changes have been observed in systemic lupus erythematosus, Sjogren’s syndrome, psoriatic and rheumatoid arthritis.Discussion about controversies on this topic should be encouraged, leading to a progressive development of capillaroscopy as a routine investigation in rheumatology

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

Cyclin-Dependent Kinases (CDKs) are well-known reliable targets for cancer treatment being often deregulated. Among them, since the transcription-associated CDK9 represents the sentry of cell transcriptional homeostasis, it can be a valuable target for managing cancers in which the transcriptional machinery is dysregulated by tumor-driver oncogenes. Here we give an overview of some natural compounds identified as CDK inhibitors with reported activity also against CDK9, that were taken as a model for the development of highly active synthetic anti-CDK9 agents. After, we summarize the data on CDK9 inhibition in a group of rare pediatric solid tumors such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and malignant rhabdoid tumors (soft tissue sarcomas), highlighting the more recent results in this field. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer

Germline TP53 pathogenic variants and breast cancer: A narrative review

Breast cancer; Prognosis; TreatmentCáncer de mama; Pronóstico; TratamientoCàncer de mama; Pronòstic; TractamentApproximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80–90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.The project was partially funded by a Gilead Sciences Medical Grant (Fellowship Program 2022) (no grant number)

Cubic or Not Cubic? Combined Experimental and Computational Investigation of the Short-Range Order of Tin Halide Perovskites

Tin-based metal halide perovskites with a composition of ASnX3 (where A= MA or FA and X = I or Br) have been investigated by means of X-ray total scattering techniques coupled to pair distribution function (PDF) analysis. These studies revealed that that none of the four perovskites has a cubic symmetry at the local scale and that a degree of increasing distortion is always present, in particular when the cation size is increased, i.e., from MA to FA, and the hardness of the anion is increased, i.e., from Br- to I-. Electronic structure calculations provided good agreement with experimental band gaps for the four perovskites when local dynamical distortions were included in the calculations. The averaged structure obtained from molecular dynamics simulations was consistent with experimental local structures determined via X-ray PDF, thus highlighting the robustness of computational modeling and strengthening the correlation between experimental and computational results

MicroRNs and cardiovascular diseas es: from bench to beside

MicroRNAs (microRNAs or miRs) are small, noncoding RNAs that control gene expression by binding to and repressing specific mRNA target and have emered as powerful regulators of many biological processes. Understanding miRNAs-biology and functions may be pivotal to get a better insight into pathophysiological mechanisms responsible for a large number of morbid conditions and may lay the foundations for the development of novel therapeutic interventions. Moreover, besides their intracellular functions, miRs are present in the human circulation in a remarkably stable cell-free form, and their plasmatic levels have been proposed as biomarkers for several pathological conditions. The present review aims to summarize the current evidences with regard to biological role of miRNAs in cardiovascular system and their involvement in the pathogenesis of cardiovascular diseases including atherosclerosis, heart failure and pathological heart and vascular remodelling and to highlight their potential use as novel biomarkers and as therapeutic targets in cardiac and vascular diseases

Metabolic and anthropometric changes in early breast cancer patients receiving adjuvant therapy

Weight gain and metabolic changes have been related to survival of early breast cancer patients (EBC). ''However, factors influencing metabolism post-diagnosis are not fully understood. We measured anthropometric [body mass index (BMI), body weight, waist and hip circumferences, and waist-to-hip ratio] and metabolic (levels of insulin, glucose, H1Ac, total, HDL, and LDL cholesterol, triglycerides, and the homeostasis model assessment score [HOMA]) parameters in 433 pre- and post-menopausal women with EBC at diagnosis and 3, 6, 9, 12, and 24 months thereafter. At diagnosis, compared with post-menopausal women, pre-menopausal patients were more likely to be leaner and to have a lower BMI, smaller waist and hip circumferences, and waist-to-hip ratio. They had also lower glucose, HbA1c, and triglyceride levels and a lower HOMA score. Furthermore, they were more likely to have an estrogen- and/or progesterone-positive tumor and a higher proliferating breast cancer. During the first two post-diagnosis years, all women showed a significant increase of weight (+0.72 kg/year, P < 0.001), waist circumference (+1.53 cm/year, P < 0.001), and plasma levels of LDL cholesterol (+5.4 mg/dl per year, P = 0.045) and triglycerides (+10.73 mg/dl per year, P = 0.017). In patients receiving chemotherapy only, there was a significant increase in hip circumference (+3.16 cm/year, P < 0.001) and plasma cholesterol levels (+21.26 mg/dl per year, P < 0.001). We showed that weight, body fat distribution, and lipid profile changed in EBC patients receiving adjuvant therapy. These changes occurred during the first 2 years after diagnosis and were not specifically related to chemotherapy, menopausal status, or initial body weight

Combined effect of obesity and diabetes on early breast cancer outcome: A prospective observational study

Background: Previous studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients. Materials and Methods: Overall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi-square test and survival data by the log-rank test. Results: At diagnosis, obese and diabetic patients were more likely to be older (p < 0.0001) and post-menopausal (p < 0.0001) and to have a tumor larger than 2 cm (p < 0.0001) than patients in groups 1–3. At univariate analyses, obese and diabetic patients had a worse disease-free survival (p = 0.01) and overall survival (p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for diseasefree survival (hazard ratio=2.62, 95% CI 1.23–5.60) but not for overall survival. Conclusions: At diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cance

Study of the effects of different biomaterials on osteogenic differentiation of oral-periosteal cells

Bone regeneration is currently one of the most important challenges for regenerative medicine and it is considered an ideal clinical strategy in the maxillo-facial area [1]. Bone resorption of alveolar crest occurring after tooth extraction leads to several risks for future treatments, including dental implants. For this reason, alveolar ridge preservation (ARP) has become a key component of contemporary clinical dentistry. Several clinical techniques and bone substitute materials can be used to fill the socket after tooth extraction. For all of them, the principle aim is to keep the shape and the size of the bone socket of the extracted tooth allowing inserting the dental implants [2]. The goal of our study was to compare different biocompatible scaffolds based on PLGA (Fisiograft®), Bioglass (Activioss®) and collagen (Sombrero®) in an in vitro model of tissue engineering for dental applications. The cells used in our study derived from Periosteum obtained from four different patients that underwent socket preservation selected by the School of Dentistry of the University of Pavia, previous informed consent. We created bio-complexes constituted by mesenchymal-periosteal cells seeded on different types of biomaterials and we performed adhesion, morphological, proliferative and bone differentiation analyses at different time points (7, 14 and 28 days of culture) in proliferative and osteogenic conditions. Bone differentiation was evaluated by qRT-PCR on genes involved in osteoblast development, like BMP-2, Osteocalcin and Periostin. Our results demonstrated that Sombrero® enhanced adhesion and proliferation of periosteal cells, as highlighted by Haematoxylin-Eosin staining and XTT test (3 and 7 days). Long-term studies (14 and 28 days) demonstrated that periosteal differentiation is about the same among the different materials tested. From these preliminary studies we can conclude that it could be advantageous the clinical use of both collagenic and PLGA scaffolds in order to ameliorate initial colonization and subsequent mechanical support in maxillo-bone regeneration. This work was supported by grant from NATO 2016 (“RAWINTS” (G-984961): RApid Skin Wound healing by INtegrated Tissue engineering and Sensing)

MET inhibition sensitizes rhabdomyosarcoma cells to NOTCH signaling suppression

Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through gamma-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition