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Background: Accurate estimation of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) incidence is crucial for assessing breast-implant-associated risk. However, the size of the implanted population worldwide is unknown, making it challenging to appropriately estimate this figure. This study aims to provide a new reliable and reproducible method to estimate the breast-implanted-population (BIP), reporting a reliable annual BIA-ALCL incidence estimate. Moreover, we discuss all activities performed over the past decade in collecting complete histories, managing, and monitoring outcomes of each Italian case., Methods: Data from the National Breast Implant Registry and from manufacturers have been used to define a new formula to estimate the BIP at risk of developing a breast-implant-related event. From the BIA-ALCL registry, complete information on Italian cases has been collected and analysed. Overall survival is estimated by the Kaplan-Meier curve., Results: From 2010 to June 2024, 111 BIA-ALCL cases were recorded in Italy. The estimated incidence rate showed an upward trend, ranging from 2.68 to 6.35 cases per 100,000 patient-years. Thanks to newly promoted disease awareness, most patients had a complete response to treatment, resulting in a three-year overall survival rate estimate of 98.2%., Conclusions: The BIP formula showed to be an innovative, effective and reproducible tool to make a reliable estimation of the implanted population, confirming that BIA-ALCL is a rare disease with an incidence rate estimate varying from 2.7 to 6.3 cases/100.000 patient-years in the last five years. Eleven-year experience in this field also confirmed that this disease has a favorable prognosis if properly treated., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: From 2013 onwards, a large outbreak of Mycobacterium chimaera (MC) invasive infection, which was correlated with the use of contaminated heater-cooler units (HCUs) during open chest surgery, was reported from all over the world. Here, we report the results of the epidemiological and molecular investigations conducted in Italy after the alarm raised about this epidemic event., Methods: MC strains isolated from patients or from HCU devices were characterized by genomic sequencing and molecular epidemiological analysis., Results: Through retrospective epidemiological analysis conducted between January 2010 and December 2022, 40 possible cases of patients infected with MC were identified. Thirty-six strains isolated from these patients were analysed by whole genome sequencing (WGS) and were found to belong to the genotypes 1.1 or 1.8, which are the genotypes correlated with the outbreak. Most of the cases presented with prosthetic valve endocarditis, vascular graft infection or disseminated infection. Among the cases found, there were 21 deaths. The same analysis was carried out on HCU devices. A total of 251 HCUs were found to be contaminated by MC; genotypes 1.1 or 1.8 were identified in 28 of those HCUs., Conclusions: To ensure patients' safety and adequate follow-up, clinicians and general practitioners were made aware of the results and public health measures, and recommendations were issued to prevent further cases in the healthcare settings. The Italian Society of Cardiac Surgery performed a national survey to assess the incidence of HCU-related MC prosthetic infections in cardiac surgery. No cases were reported after HCU replacement or structural modification and disinfection and possibly safe allocation outside surgical rooms.

Background: Breast implant-associated anaplastic large-cell lymphoma is a rare disease with a favourable prognosis if adequately treated. Same staged patients have usually a similar prognosis and outcomes, but in our experience, IIA-staged patients have a wider prognosis with outcomes that vary from complete disease response to death. This study aimed to understand and identify all the factors that could influence the prognosis of this group of patients and verify if their prognosis matches the stage they belong to., Material and Methods: Patients in stage IIA have been divided into two subgroups: IIAb with lymphoma extension towards the glandular tissue and IIAcw with tumour extension towards the chest-wall. The overall survival (OS) and event-free survival (EFS) of 64 BIA-ALCL cases were evaluated for each staged group., Results: Significant differences of OS and EFS between IIAb and IIAcw patients (log-rank p = 0.046 and log-rank p = 0.018, respectively) were observed and poor prognosis joined IIAcw- and IV-staged patients., Conclusion: Chest-wall infiltration is a critical prognostic factor in BIA-ALCL patients as it influences the possibility of performing a surgical radical tumour extirpation. Our results could represent valid assistance for the physicians in choosing the most appropriate BIA-ALCL prognostic category and treatment and could promote further wider studies to provide stronger evidence on a possible revision of the MDA TNM classification., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Copy number variations (CNVs) can contribute to genetic variation among individuals and/or have a significant influence in causing diseases. Many studies consider new CNVs' effects on protein family evolution giving rise to gene duplicates or losses. "Unsuccessful" duplicates that remain in the genome as pseudogenes often exhibit functional roles. So, changes in gene and pseudogene number may contribute to development or act as susceptibility alleles of diseases., Case Presentation: We report a de novo heterozygous 271 Kb microdeletion at 8q21.2 region which includes the family of REXO1L genes and pseudogenes in a young man affected by global development delay, progeroid signs, and gastrointestinal anomalies. Molecular and cellular analysis showed that the REXO1L1 gene hemizygosity in a patient's fibroblasts induces genetic instability and increased apoptosis after treatment with different DNA damage-induced agents., Conclusions: The present results support the hypothesis that low copy gene number within REXO1L1 cluster could play a significant role in this complex clinical and cellular phenotype.

We tried to identify molecular markers in peripheral blood to predict high risk of aneurysm rupture. Extraction of the total population of peripheral blood mononuclear cell (PBMC) from total blood volume, total RNA extraction from PBMC and Agilent One Color Gene-expression Oligo-Microarray were performed on peripheral venous blood samples from 45 patients with ruptured, unruptured cerebral aneurysms and control group (15). Mean foreground/ background signal intensities and A (log2(R*G)/2) values were calculated for each spot. Genes with absolute fold change (FC) greater than or equal to plus or minus 1.5 and p-value less than 0.05 were considered differentially expressed in the 3 groups (Student T-test). Genes coding for MMPs were strongly underexpressed in ruptured aneurysms group, suggesting a possible role in aneurysms development more than their rupture. Genes coding for adhesine proteins of the extracellular matrix (ICAM1) and cytoskeleton (WIPF1,TUBA4A) were underexpressed in ruptured aneurysms. Genes coding proteins involved in the regulation of apoptotic processes may be important in aneurysm development and rupture, resulting into an increased rate of remodeling processes in the arterial wall. Fas coding gene, SUMO1, ZFAT, BCL2, CCR5 genes were all over-represented in unruptured aneurysms. The coexisting over-representation of pro-apoptotic genes and the underexpression of cytoskeleton and extracellular matrix genes confirms that aneurysms development and evolution are part of a degenerative process of the arterial wall not involved in aneurysms rupture. MMPs may be involved in repairing chronic damages to the arterial walls and preventing SAH. Unexpectedly, Heat Shock Proteins (HSP90AA1, HSPA1A, HSPB1), G and RAS proteins, generally activated by stress situations were under-represented in aneurysmal walls. Further PCR and Western Blotting studies are needed to confirm such findings and to identify diagnostic and prognostic markers in order to define screening protocols for intracranial aneurysms.

Hirsutism is the development of androgen-dependent terminal body hair in women in places in which terminal hair are normally not found. It is often associated with hyperandrogenemia and/or polycystic ovary syndrome (PCOS), but the existence of uncommom hirsutism forms that are not related to altered androgen plasma levels lead also to the definition of - idiopathic hirsutism. Although the pathophysiology of hirsutism has been linked to increasing 5-alpha reductase (SRD5A) activity and to an alteration of the androgen receptor (AR) transcriptional machinery, many aspects remain unclear. In particular, the relationships between androgens and local factors are poorly understood. In the present paper, we selected for a genital skin biopsy, 8 women affected with severe hirsutism (Ferriman-Gallway score greater than 25) but with normal plasma androgen levels, with the exception of slightly higher serum 3alpha-diol-glucuronide levels, and 6 healthy controls and analyzed their androgen- and insulin-specific transcriptional profile using a specific custom low density microarray (AndroChip 2, GPL9164). We identified the over-expression of the Son of Sevenless-1 (SOS1) gene in all of the hirsute skin fibroblast primary cell cultures compared to control healthy women. Since SOS1 is a guanine nucleotide exchange factor that couples receptor tyrosine kinases to the RAS signaling pathway that controls cell proliferation and differentiation, we further analyzed SOS1 expression, protein level and RAS signaling activation pathway in an in vitro model (NHDF, normal human dermal fibroblast cell line). NHDF treated for 24 h with different concentrations of DHT and T showed an increase in SOS1 levels (both mRNA and protein) and also an activation of the RAS pathway. Our in vivo and in vitro data represent a novel preliminary observation that factors activating SOS1 could act as local proliferative modulators linked to the androgen pathway in the pilosebaceous unit. SOS1 over-expression may play a role in the regulation of the RAS/mitogen-activated protein kinase pathway in the skin, in the hair follicle proliferation and cell cycle, suggesting new perspectives in understanding the pathogenesis of idiopathic hirsutism.

The endoplasmic reticulum (ER) stress-mediated pathway is involved in a wide range of human neurodegenerative disorders. Hence, molecules that regulate the ER stress response represent potential candidates as drug targets to tackle these diseases. In previous studies we demonstrated that upon acetylation the reticulon-1C (RTN-1C) variant of the reticulon family leads to inhibition of histone deacetylase (HDAC) enzymatic activity and endoplasmic reticulum stress-dependent apoptosis. Here, by microarray analysis of the whole human genome we found that RTN-1C is able to specifically regulate gene expression, modulating transcript clusters which have been implicated in the onset of neurodegenerative disorders. Interestingly, we show that some of the identified genes were also modulated in vivo in a brain-specific mouse model overexpressing RTN-1C. These data provide a basis for further investigation of RTN-1C as a potential molecular target for use in therapy and as a specific marker for neurological diseases., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The early detection of genomic biomarkers (e.g. RNAs) through analysis of circulating blood cells could have a substantial impact on biomedicine, particularly in monitoring clinical trials, drug toxicity and doping in athletes. To achieve this goal, it is essential to develop methods that are sufficiently sensitive to detect biomarker alterations during normal biologic processes, pathogenic processes, and or in response to therapeutic or other intervention. Using a low density microarray (AndroChip 2) we detected a transcriptional profiling signature of 190 genes related to androgen and insulin metabolism pathway, in peripheral blood mononuclear cell (PBMC) in subjects with different intensities of sports activities. We demonstrated that androgen and insulin gene transcriptional levels are independent to sports activity and therefore potentially suitable for drug monitoring and/or drug doping (such as anabolic androgen steroid AAS abuse) and or gene doping.

The present experiments were designed to characterize by microarray analysis the transcriptional responses of human keratinocytes (HaCat) to TNF-α and IL-1 β, given alone or in combination, in order to better understand the mechanisms underlying inflammatory, immune responses and cell death in which both cytokines play a pathophysiological role. Significant differences in the percentage and quality of genes dysregulated by TNF-α and IL-1 β were shown. Both cytokines activated a series of genes involved in inflammatory, immune response as well as in cell death. In our experimental conditions, TNF-α, in contrast to IL-1 β, did not induce a significant level of apoptosis in keratinocytes. However, given together both cytokines produced a significant decrease in apoptotic cells and synergistic transcriptional response which was due to the activation of several specific genes occurring after application of each cytokine. TNF-α and IL-1 β evoked apoptotic effect and transcriptional responses were linked to the stimulation of their specific receptors since a pre-treatment with monoclonal antibodies vs TNF-α and/or IL-1 β receptors was able to significantly reduce them.

Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia, and prostate cancer. Although testosterone is the main androgen secreted from the testes, dihydrotestosterone (DHT), a more potent androgen converted from testosterone by 5alpha-reductase isozymes, type I and II, is the major androgen in the prostate cells. The aim of this study is to investigate the cellular and molecular effects of dutasteride, a potent inhibitor of 5alpha-reductase type I and type II, in androgen-responsive (LNCaP) and androgen-unresponsive (DU145) human prostate cancer(PCa) cell lines. The expression pattern of 190 genes, selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling, were analysed using a low density home-made oligoarray (AndroChip 2). Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested. AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed (FC >or= +/-1.5). Eight of these genes, were overexpressed and three were underexpressed. Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen (HSD17B1;HSD17B3;CYP11B2), androgen receptor and androgen receptor co-regulators (AR;CCND1), and signal transduction(ERBB2; V-CAM; SOS1) whereas, underexpressed genes (KLK3; KLK2; DHCR24) were androgen-regulated genes (ARGs). No differentially expressed genes were scored in DU145. Microarray data were confirmed by quantitative real-time PCR assay (QRT-PCR). These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology.

22q11 deletion syndrome (22q11DS) is a developmental anomaly caused by a microdeletion on human chromosome 22q11. Although mouse models indicate that Tbx1 is the gene responsible for the syndrome, the phenotypic spectrum of del22q11 patients is complex suggesting that gene-gene and gene-environment interactions are operative in delineating the pathogenesis of 22q11DS. In order to study the regulatory effects of 22q11 haploinsufficiency during development, the expression pattern of the orthologous MM16 genes was analysed in total embryos at different stages (from 4.5 dpc to 14.5 dpc; corresponding to pharyngeal development) by using a low-density oligonucleotide microarray (the "22q11DS-chip"). This microarray consists of 39 mouse genes orthologous to the 22q11 human ones and 29 mouse target genes selected on the basis of their potential involvement in biological pathways regarding 22q11 gene products. Expression level filtering and statistical analysis identified a set of genes that was consistently differentially expressed (FC>+/-2) during specific developmental stages. These genes show a similar profile in expression (overexpression or underexpression). Quantitative real-time PCR analyses showed an identical expression pattern to that found by microarrays. A bioinformatic screening of regulative sequence elements in the promoter region of these genes, revealed the existence of conserved transcription factor binding sites (TFBSs) in co-regulated genes which are functionally active at 4.5, 8.5 and 14.5 dpc. These data are likely to be helpful in studying developmental anomalies detected in del22q11 patients.