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Abstract Background Allgrove disease is a rare genetic syndrome characterized by adrenal insufficiency, alacrimia, achalasia and complex neurological involvement. Allgrove disease is due to recessive mutations in the AAAS gene, which encodes for the nucleoporin Aladin, implicated in the nucleocytoplasmic transport. The adrenal insufficiency has been suggested to rely on adrenal gland-ACTH resistance. However, the link between the molecular pathology affecting the nucleoporin Aladin and the glucocorticoid deficiency is still unknown. Results By analyzing postmortem patient’s adrenal gland, we identified a downregulation of Aladin transcript and protein. We found a downregulation of Scavenger receptor class B-1 (SCARB1), a key component of the steroidogenic pathway, and SCARB1 regulatory miRNAs (mir125a, mir455) in patient’s tissues. With the hypothesis of an impairment in the nucleocytoplasmic transport of the SCARB1 transcription enhancer cyclic AMP-dependent protein kinase (PKA), we detected a reduction of nuclear Phospho-PKA and a cytoplasmic mislocalization in patient’s samples. Conclusions These results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.

Background: Coronavirus disease-19 (COVID-19) has spread worldwide since December 2019 and was officially declared a pandemic in March 2020. Due to the rapid transmission and the high fatality rate, drastic emergency restrictions were issued, with a negative impact on routine clinical activities. In particular, in Italy, many authors have reported a reduction in the number of breast cancer diagnoses and critical problems in the management of patients who accessed the breast units during the dramatic first months of the pandemic. Our study aims to analyze the global impact of COVID-19 in the two years of the pandemic (2020–2021) on the surgical management of breast cancer by comparing them with the previous two years. Methods: In our retrospective study, we analyzed all cases of breast cancer diagnosed and surgically treated at the breast unit of “Città della Salute e della Scienza” in Turin, Italy, making a comparison between the 2018–2019 pre-pandemic period and the 2020–2021 pandemic period. Results: We included in our analysis 1331 breast cancer cases surgically treated from January 2018 to December 2021. A total of 726 patients were treated in the pre-pandemic years and 605 in the pandemic period (−121 cases, 9%). No significant differences were observed regarding diagnosis (screening vs. no screening) and timing between radiological diagnosis and surgery for both in situ and invasive tumors. There were no variations in the breast surgical approach (mastectomy vs. conservative surgery), while a reduction in axillary dissection compared to the sentinel lymph node in the pandemic period was observed (p-value < 0.001). Regarding the biological characteristics of breast cancers, we observed a greater number of grades 2–3 (p-value = 0.007), pT stage 3–4 breast cancer surgically treated without previous neoadjuvant chemotherapy (p-value = 0.03), and a reduction in luminal B tumors (p-value = 0.007). Conclusions: Overall, we report a limited reduction in surgical activity for breast cancer treatment considering the entire pandemic period (2020–2021). These results suggest a prompt resumption of surgical activity similar to the pre-pandemic period.

Panicum coloratum var. coloratum is a subtropical grass for potentially increasing forage production in lowly productive environments where cattle-raising activities have been relocated. Heritability was estimated for characters related to salinity tolerance under saline and non-saline conditions to explore the possibility of improving tolerance by selection. From a base germplasm collected in a very harsh environment, heritability and gain after selection were calculated using 2 recombination units: individual and phenotypic family mean (PFM). Heritability estimates were very low for all characters both in saline and non-saline conditions, suggesting a complex genetic control of salinity tolerance, with a high proportion of non-additive genetic effects. Estimates were higher using individual selection than with PFM and expected genetic gains were higher for individual selection. When compared in both saline and non-saline conditions, predicted means were greater than for plants of cv. Klein, the most common cultivar in use. It appears that the analyzed germplasm would be a valuable source of genes to be included in breeding programs to increase salinity tolerance in Panicum coloratum.

Abstract Background In Pompe disease, an inherited metabolic muscle disorder, severe diaphragmatic weakness often occurs. Enzyme replacement treatment is relatively ineffective for respiratory function, possibly because of irreversible damage to the diaphragm early in the disease course. Mildly impaired diaphragmatic function may not be recognized by spirometry, which is commonly used to study respiratory function. In this cross-sectional study, we aimed to identify early signs of diaphragmatic weakness in Pompe patients using chest MRI. Methods Pompe patients covering the spectrum of disease severity, and sex and age matched healthy controls were prospectively included and studied using spirometry-controlled sagittal MR images of both mid-hemidiaphragms during forced inspiration. The motions of the diaphragm and thoracic wall were evaluated by measuring thoracic cranial-caudal and anterior–posterior distance ratios between inspiration and expiration. The diaphragm shape was evaluated by measuring the height of the diaphragm curvature. We used multiple linear regression analysis to compare different groups. Results We included 22 Pompe patients with decreased spirometry results (forced vital capacity in supine position

Functional traits are powerful tools for distinguishing between plants with different resource acquisition strategies. Fast-growing plants normally dominate resource-rich habitats and present trait values associated with high productivity, such as high specific leaf area (SLA), short leaf lifespan, and rapid leaf elongation rate (LER). In contrast, slow-growing species have a higher leaf weight ratio (LWR), leaf lifespan (LLS), and phyllochron, which are useful traits for survival in stressful and unfertile environments, but are normally thought to be incompatible with high productivity, even under fertile conditions. We tested the hypothesis that slow-growing forage grasses have demographic parameters (tiller population density and canopy density) that offset their slow individual traits, making them as productive as fast-growing species when grown in fertile soil. Species with contrasting growth strategies (Arrhenatherum elatius L. and Festuca arundinacea Schreb cv. Quantum II, fast and slow-growing species, respectively) were cultivated in 45 m2 field plots and subjected to the same cutting regime and nitrogen supply level. Functional traits and canopy attributes were continuously measured during 8 growing cycles after the establishment of the swards. A. elatius had higher SLA, LER, leaf senescence, and leaf appearance rates, whereas F. arundinacea had higher LLS and LWR values. Conversely, there were no differences in relative growth rate or forage accumulation. F. arundinacea was able to offset their plant functional traits, typically associated with slow-growing grasses, with some demographic parameter like higher tiller population density, allowing it to be as productive as the fast-growing A. elatius when both were grown in fertile soil. Therefore, we suggest cautionary use of traditional plant functional traits to explain and predict the annual productivity of slow-growing grasses. [ABSTRACT FROM AUTHOR]

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

Abstract Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3–0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss‐of‐function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss‐of‐function activates the mTOR‐ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole‐cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2‐silenced human endothelial cells and in both cells and tissues from an endothelial‐specific CCM3‐knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial‐to‐mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.

O artigo versa sobre diversas questões relativas ao acordo de leniência previsto na Lei n. 12.529/2011 e Lei n. 12.846/2013. Discorre-se sobre sua origem, seu desenvolvimento no Brasil, seus requisitos legais, sobre sua relação com a responsabilidade empresarial e individual, sobre os conflitos de interesse no âmbito da organização empresarial, sobre questões processuais penais, incluído a pertinência ou não da participação do Ministério Público na celebração de acordo de leniência, além de seus possíveis reflexos no âmbito da improbidade administrativa.