Search Results (67)

Background: North Carolina Macular Dystrophy (NCMD) is a non-progressive inherited macular dystrophy characterized by marked phenotypic variability. The genetic etiology of NCMD remains largely unknown, and only a limited number of families have been reported in Europe. Methods: We performed an in-depth investigation of an Italian family affected by NCMD using an integrated approach that combined SNP-array analysis, whole-exome sequencing, and long-read whole-genome sequencing. Additionally, we conducted a comprehensive review of NCMD-related literature. Results: We identified a novel 98 Kb duplication involving both PRDM13 and CCNC genes in a three-generation kindred, where the proband exhibited severe macular alterations, while all other affected family members presented with a milder clinical phenotype. A review of the literature suggests different genotype–phenotype correlations and similar penetrance for duplications and single-nucleotide variants (SNVs) in described families. Specifically, smaller duplications may be associated with more severe phenotypes, while SNVs exhibit high phenotypic variability. Conclusions: In this study, we describe the first NCMD Italian family, in which the integration of second- and third-generation sequencing methods enabled the identification of a novel pathogenic PRDM13 and CCNC duplication, thereby expanding the mutational spectrum of NCMD. Overall, these findings, together with the literature review, highlight the importance of selecting appropriate genetic testing approaches that allow the detection of non-coding variants and CNVs and thus enable accurate diagnosis and effective clinical management of patients and their families. Full article

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons with a phenotypic and genetic heterogeneity and elusive molecular mechanisms. With the present pilot study, we investigated different genetic mutations (C9orf72, TARDBP, and KIF5A) associated with ALS by generating induced pluripotent stem cells (iPSCs) from peripheral blood of ALS patients and healthy donors. iPSCs showed the typical morphology, expressed stem cell markers both at RNA (OCT4, SOX2, KLF4, and c-Myc) and protein (Oct4, Sox2, SSEA3, and Tra1-60) levels. Moreover, embryoid bodies expressing the three germ-layer markers and neurospheres expressing neural progenitor markers were generated. Importantly, the transcriptomic profiles of iPSCs and neurospheres were analyzed to highlight the differences between ALS patients and healthy controls. Interestingly, the differentially expressed genes (DEGs) shared across all ALS iPSCs are linked to extracellular matrix, highlighting its importance in ALS progression. In contrast, ALS neurospheres displayed widespread deficits in neuronal pathways, although these DEGs were varied among patients, reflecting the disease’s heterogeneity. Overall, we generated iPSC lines from ALS patients with diverse genetic backgrounds offering a tool for unravelling the intricate molecular landscape of ALS, paving the way for identifying key pathways implicated in pathogenesis and the disease’s phenotypic variability. Full article

The production and reproduction of small ruminants, such as sheep and goats, living under extensive range-grazing conditions may be influenced by the availability of nutrients and the mineral content of forage. This study evaluated the biodistribution of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), sodium (Na) and zinc (Zn) in whole blood, serum, blood clots, plasma, plasma sediments and hair in sheep and goats. Forty clinically healthy, nonpregnant female sheep and goats were enrolled in the study. Hair and blood samples were performed in duplicate to assess mineral concentration in biological substrates using a Thermo Scientific iCAP- Q ICP-MS spectrometer (Omaha, Ne, USA). Higher levels of Ca, Cu, Fe, Mg, and Na were observed in blood and blood clots than in serum, plasma, plasma sediments and hair in sheep and goats. A significant effect of species was observed for all the bioactive element concentrations in the investigated substrates (p < 0.05). The results revealed positive correlations between serum and plasma for all investigated elements in sheep (p < 0.0001) and for Mn and Na in goats (p < 0.001), as well as between serum and blood for Ca, Fe, Mg and Mn in sheep (p < 0.0001) and for Ca and Mn in goats (p < 0.001). Plasma and blood showed a positive correlation for Ca, Fe, and Mn (p < 0.001) in sheep, and for Fe, Mn, Na, and Zn (p < 0.0001) in goats. These findings elucidate differences in biodistribution between sheep and goats, offering valuable insights for livestock production. Full article

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe₂S₂ iron–sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII. Full article

Chronic disfiguring skin conditions profoundly affect patients’ quality of life (QoL) due to their physical, psychological, and emotional consequences. Although the presence of depression and anxiety symptomatology in dermatological patients is well established, the specific roles of emotional dysregulation, dysmorphophobic concerns, and hopelessness in this population require further investigation. This study aimed for the following: (1) to assess symptoms of emotional dysregulation, dysmorphophobic concerns, and hopelessness in hospitalized patients with severe dermatological diseases; (2) analyze whether emotional dysregulation mediates the relationship between dysmorphophobic concerns and hopelessness. A cross-sectional study was conducted with 120 hospitalized dermatology patients. Patients completed standardized measures, including the Emotional Dysregulation Scale (EDs), Beck Hopelessness Scale (BHS), and the Questionario sul Dismorfismo Corporeo “Body Dysmorphic Disorder Questionnaire” (QDC). Disease severity and pain perception were assessed using the Physician Global Assessment (PGA) and the Numerical Rating Scale (NRS). Significant associations were observed between emotional dysregulation, dysmorphophobic concerns, and hopelessness. Emotional dysregulation partially mediated the relationship between dysmorphophobic concerns and hopelessness (indirect effect: b = 0.013, CI [0.004, 0.026]). Higher dysmorphophobic concerns were associated with emotional dysregulation, which, in turn, predicted greater hopelessness. Emotional dysregulation seems to play a critical role in the relationship between dysmorphophobic concerns and hopelessness in dermatological patients. Full article

Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers. Approximately 20% of patients with NSCLC are diagnosed with stage IIIA–IIIB disease, for which the optimal treatment remains unclear. Meta-analyses reveal that neoadjuvant/perioperative ICI–chemotherapy significantly improves pathological complete response (pCR), overall survival (OS), major pathological response (MPR), and R0 rate compared to standard neoadjuvant chemotherapy. Resectability is achieved when R0 resection can be performed after surgery. Radiographic downstaging often does not correspond to surgical downstaging. In fact, intra-operative fibrosis due to chemo-immunotherapy (synonymous with ICI–chemotherapy) can create adhesions and consequent difficult planes for dissection. Thus, pneumonectomy cannot be avoided. Even the suspicion of N2 after neoadjuvant treatment is considered a limitation of upfront surgery because of the risk of pneumonectomy. The aim of this review is to explore the literature on the technical strategies for surgical excision of NSCLC after chemo-immunotherapy, addressing even the most challenging scenarios. Full article

In high-energy physics, resistive plate chamber (RPC) detectors operating in avalanche mode make use of a high-performance gas mixture. Its main component, Tetrafluoroethane (C₂H₂F₄), is classified as a fluorinated greenhouse gas. The RPC EcoGas@GIF++ collaboration is pursuing an intensive R&D on new gas mixtures for RPCs to explore eco-friendly alternatives complying with recent European regulations. The performance of different RPC detectors has been evaluated at the CERN Gamma Irradiation Facility with Tetrafluoropropene (C₃H₂F₄)-CO₂-based gas mixtures. A long-term ageing test campaign was launched in 2022, and since 2023, systematic long-term performance studies have been carried out thanks to dedicated beam tests. The results of these studies are discussed together with their future perspectives. Full article

Introduction: Psoriasis (PSO) and atopic dermatitis (AD) have traditionally been considered distinct diseases, respectively, mediated by T-helper 1 (Th1) and the T-helper 2 (Th2) immune pathway. In recent years, there has been a growing body of evidence highlighting an overlap between the two conditions, such as Asian AD, pediatric PSO, or “psoriasis dermatitis/PSOREMA”. Moreover, psoriasis dermatitis can be induced by therapeutic interventions. For instance, anti-IL-4/IL-13 monoclonal antibodies, commonly used to treat AD, can induce psoriasiform reactions by inhibiting the Th2 pathway, thereby unmasking Th1/Th17-driven PSO. Conversely, anti-TNFα and anti-IL-17 therapies, effective for PSO, may induce eczematous reactions promoting a switch toward Th2-driven inflammation. Janus Kinase Inhibitors (JAK-i) and IL-23 antagonists may represent valid therapeutic options for managing psoriasis dermatitis. JAK-i exert broader immunomodulatory effects, inhibiting both Th1 and Th2 pathways; however, they require careful monitoring due to potential adverse events. In contrast, IL-23 antagonists specifically suppress the IL-23/IL-17 axis inhibiting the p19 subunit of IL-23 and could represent a safer option for patients with psoriasis dermatitis. Materials and Methods/Results: We present a series of five cases of psoriasis dermatitis, including both patients who had the condition from the onset and those who developed it during treatment, with tailored therapeutic strategies based on individual patient profiles, comorbidities, and the specific characteristics of their overlapping disease presentation. Conclusion: JAK-i and IL-23 antagonists are both valid therapeutic options for managing psoriasis dermatitis, but with different immunomodulatory effects and safety profiles. Future research should focus on a better understanding of the immune pathway and identifying specific biomarkers of psoriasis dermatitis, to optimize therapeutic strategies. Full article

Background and Objectives: The impact of lifestyle on lower urinary tract symptoms has been deeply evaluated in recent years; however, studies in the young population are missing. The aim of this study is to evaluate the impact of alcohol intake, tobacco and cannabinoid smoking, physical activity, and dietary regime on urinary symptoms and sexual function in young adults under 30 years of age. Methods: A prospectively enrolled population of healthy young adults of both sexes under 30 years of age was selected. Young people with comorbidities were excluded. All participants were assessed by completing an anonymous questionnaire which included questions on medical history, lifestyle, smoking and alcohol intake, urinary symptoms, and sexual function only in male subjects. The questionnaire was postponed in case there was an acute pathology. Results: Overall, 802 young adults were prospectively enrolled, of whom 44% were male and 56% female, with a median age of 26 (23/28) years. In our population, 580/818 (70.9%) subjects presented an IPSS ≥ 3. In the analysis of the association between urinary symptoms and smoking, smokers presented urinary symptoms more frequently than nonsmokers (76% vs. 61%; p < 0.05). No association between urinary symptoms and alcohol intake, cannabinoid smoking, physical activity, and dietary regimen was recorded. On multivariable analysis, smokers had an almost doubled risk of urinary symptoms compared to nonsmokers (OR: 1.78; p = 0.001). Conclusions: In conclusion, we demonstrated how even in the young population there can be a correlation between LUTSs and different lifestyles. Full article

OBJECTIVE. The optimal surgical approach for thymoma resection is still an object of debate. The increasing experience in robotic-assisted thoracic surgery (RATS) has led to the progressive affirmation of this technique as a valid alternative to Sternotomy, Thoracotomy and Video-Assisted Thoracic Surgery (VATS) in this setting. The present study aims to compare the post-operative and short-term results of RATS Thymectomy for thymoma with those of other main surgical approaches (sternotomy, thoracotomy and VATS) from a high-volume single center. METHODS. Between May 2021 and September 2023, 40 consecutive patients underwent RATS Thymectomy for stage I to limited-stage III thymoma in our center. Three homogenous groups of patients who received thymoma resection through main alternative approaches (sternotomy, thoracotomy, VATS) over the last 5 years, were identified in order to perform a comparative analysis. Data including surgery duration, associated resections, conversion rate, overall morbidity, tumor size, radicality of resection, post-operative pain, length of hospital stay and cosmetic results were retrospectively collected and compared between the RATS and each control group. RESULTS. Mean tumor size was higher in the sternotomy group, but not significantly. The mean operative time of RATS interventions was significantly lower than that of sternotomy and VATS. It was significantly shorter compared to thoracotomy if excluding docking-undocking time. A higher rate of associated adjacent structures resection was reported in the sternotomy group (p = 0.005). Conversion rate was significantly higher in the VATS group (p = 0.026) compared to RATS. Post-operative pain at 24 and 48 h was significantly lower in the RATS group compared to the others. Improved cosmetics results were reported after RATS compared to sternotomy (p = 0.0001) and thoracotomy (p = 0.001) groups, with a trend towards better results compared to VATS (p = 0.05). Length of hospital stay was shorter in the RATS group with a significant difference vs. the sternotomy group (p < 0.001). CONCLUSIONS. These results from a single center confirm the safety and efficacy of RATS for the treatment of limited stage thymoma. An advantage in terms of operative outcomes, post-operative pain, cosmetic results and hospital stay was observed if compared to the alternative approaches. The short-term oncologic outcome was excellent based on the high complete resection rate of the tumor. Full article

Background/Objectives: The failure of physiological left-right (LR) patterning, a critical embryological process responsible for establishing the asymmetric positioning of internal organs, leads to a spectrum of congenital abnormalities characterized by laterality defects, collectively known as “heterotaxy”. MMP21 biallelic variants have recently been associated with heterotaxy syndrome and congenital heart defects (CHD). However, the genotype–phenotype correlations and the underlying pathogenic mechanisms remain poorly understood. Methods: Patients harboring biallelic MMP21 missense variants who underwent diagnostic genetic testing for CHD or heterotaxy were recruited at the Institute for Maternal and Child Health—I.R.C.C.S. “Burlo Garofolo”. Additionally, a literature review on MMP21 missense variants was conducted, and clinical data from reported patients, along with molecular data from in silico and modeling tools, were collected. Results: A total of 18 MMP21 missense variants were reported in 26 patients, with the majority exhibiting CHD (94%) and variable extra-cardiac manifestations (64%). In our cohort, through Whole-Exome Sequencing (WES) analysis, the missense p.(Met301Ile) variant was identified in two unrelated patients, who both presented with heterotaxy syndrome. Conclusions: Our comprehensive analysis of MMP21 missense variants supports the pathogenic role of the p.(Met301Ile) variant and provides significant insights into the disease pathogenesis. Specifically, missense variants are distributed throughout the gene without clustering in specific regions, and phenotype comparisons between patients carrying missense variants in compound heterozygosity or homozygosity do not reveal significant differences. These findings may suggest a potential loss-of-function mechanism for MMP21 missense variants, especially those located in the catalytic domain, and highlight their critical role in the pathogenesis of heterotaxy syndrome. Full article

COVID-19-related persistent olfactory dysfunction (OD) presents remarkable interindividual differences, and little is known about the host genetic factors that are involved in its etiopathogenesis. The goal of this study was to explore the genetic factors underpinning COVID-19-related OD through the analysis of Whole Genome Sequencing data of 153 affected subjects, focusing on genes involved in antiviral response regulation. An innovative approach was developed, namely the assessment of the association between a “gene score”, defined as the ratio of the number of homozygous alternative variants within the gene to its length, and participants’ olfactory function. The analysis highlighted how an increased gene score in the ACE2 gene is associated with a worse olfactory performance, while an increased gene score in the IFI44 and NDUFAF4 genes is associated with a better olfactory function. Considering the physiological role of the proteins encoded by these genes, it can be hypothesized that a reduced expression of ACE2 may be associated with a protracted and severe inflammatory response in the olfactory epithelium, thus worsening patients’ smell abilities. Conversely, an increased gene score in IFI44 and NDUFAF4 might be associated with a decreased inflammatory response, thus correlating with a better olfactory performance. Overall, this study identified new host genetic factors that may play a pivotal role in determining COVID-19-related OD heterogeneity, possibly enabling more personalized and effective clinical management for affected individuals. Full article

Objectives: The choice of the best Video-Assisted Thoracic Surgery (VATS) surgical approach is still debated. Surgeons are often faced with the choice between innovation and self-confidence. The present study reports the experience of a high-volume single institute, comparing data of uni-portal, bi-portal and tri-portal VATS, to find out the safest and most effective mini-invasive approach, leading surgeon’s choice. Methods: Between 2015 and 2022, a total of 210 matched patients underwent VATS lobectomy for early-stage cancer, using uni-portal (fifth intercostal space), bi-portal (seventh space for optic and the fifth), and tri-portal (seventh and the fifth/four) access. Patients were matched for age, BPCO, smoke, comorbidities, lesions (size and staging) to obtain three homogenous groups (A: uni-portal; B: bi-portal; C: tri-portal). The surgeons had comparable expertise. Data were retrospectively collected from institutional database and analyzed. Results: No differences were detected considering time of surgery, length of hospital stay, complications, conversion rate, specific survival, and days of chest tube length of stay. Better results on chest tube removal were described in group A (mean 1.1 days) compared to B (mean 2.6 days) and C (mean 4.7 days); nevertheless, they not statistically significant (p = 0.106). Conclusions: No significant differences among the groups were described, except for the reduction in chest tube permanence in group A. This allows to hypothesize an enhanced recovery after surgery in this group but the different approaches in this series seem to guarantee comparable safety and effectiveness. Considering no superiority of one method above the others, the best suggested approach should be the one for which the surgeon feels more confident. Full article

Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC’s specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment. Full article

Background: In recent decades, there has been a startling rise in the number of cancer patients worldwide, which has led to an amazing upsurge in the development of novel anticancer treatment candidates. On a positive note, arylpiperazines have garnered attention in cancer research due to their potential as scaffolds for developing anticancer agents. These compounds exhibit a diverse array of biological activities, including cytotoxic effects against cancer cells. Indeed, one of the key advantages of arylpiperazines lies in their ability to interact with various molecular targets implicated in cancer pathogenesis. Aim: Here, we focus on the chemical structures of several arylpiperazine derivatives, highlighting their anti-proliferative activity in different tumor cell lines. The modular structure, diverse biological activities, and potential for combination therapies of arylpiperazine compounds make them valuable candidates for further preclinical and clinical investigations in the fight against cancer. Conclusion: This review, providing a careful analysis of different arylpiperazines and their biological applications, allows researchers to refine the chemical structures to improve potency, selectivity, and pharmacokinetic properties, thus advancing their therapeutic potential in oncology. Full article