Search

Abstract Background Individuals whose gender identity differs from the biological sex and the social norms are defined as transgender. Sometimes transgender undergo gender affirming hormone therapy, which lasts for the entire life making essential to evaluate its potential long-term effects. Moreover, transgender can represent a susceptible sub-group of population and specific attention is needed in risk assessment, including the development of targeted animal models. Aim of the study is the implementation of a rodent demasculinizing–feminizing model through the setting of appropriate dose of hormone therapy and the selection of specific biomarkers to evaluate the sex transition. Specific attention is paid to thyroid homeostasis due to the close link with reproductive functions. Four male adult rats/group were subcutaneously exposed to three doses plus control of β-estradiol valerate plus cyproterone acetate at: 0.045 + 0.2 (low), 0.09 + 0.2 (medium) and 0.18 + 0.2 (high) mg/dose, five times/week. The doses were selected considering the most recent recommendations for transgender woman. Sperm count, histopathological analysis (testis, liver, thyroid), testosterone, estradiol, triiodothyronine and thyroid-stimulating hormone serum levels and gene expression of sex dimorphic CYP450 were evaluated. Results The doses induced feminizing–demasculinizing effects: decreased testosterone serum levels at the corresponding cisgender, increased estradiol, impairment of male reproductive function and reversal of sex-specific CYP liver expression. However, the medium and high doses induced marked liver toxicity and the low dose is considered the best choice, also for long-term studies in risk assessment. The alterations of thyroid indicated follicular cell hypertrophy supported by increased thyroid-stimulating hormone serum levels at the higher doses. Conclusions The implementation of animal models that mimic the effects of gender affirming hormone therapy is essential for supporting clinical studies in transgender people and filling data gap in order to ensure an appropriate risk assessment and a more accurate, personalized care for transgender people.

Summary: Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. Recent evidence suggests diversity in dopamine signaling, yet it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here, we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. Our findings show that reward information and behavioral parameters are not only heterogeneously encoded but also differentially distributed across populations of dopamine neurons. Retrograde tracing and fiber photometry suggest that populations of dopamine neurons projecting to different striatal regions convey distinct signals. These data, supported by computational modeling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate specialized roles of different striatal regions.

Geriatric assessment management is a multidimensional tool used to evaluate prognosis for clinical outcomes and targets for interventions in older adults with cancer receiving chemotherapy. In this review, we evaluated the possible application of geriatric assessment management (GAM) in hematological malignancies. In older patients with Diffuse Large B Cell Lymphoma, GAM might be helpful in both predicting planned hospital admissions and improving quality of life. In chronic myeloid leukemia, the Charlson Comorbidity Index demonstrates how comorbidities could affect treatment compliance and overall outcomes. In multiple myeloma, the application of different scores such as the International Myeloma Working Group Frailty Index and the Revised Myeloma Comorbidity Index can identify frail patients who need suitable interventions in treatment plan (reducing drug dose or changing treatment). Therefore, including GAM in the management plan of older patients with hematological malignancies may direct and optimize cancer care.

The term congenital lung malformation (CLM) is used to describe a wide range of pathological conditions with different imaging and clinical manifestations. These anomalies stem from abnormal embryological lung development, potentially occurring across various stages of prenatal life. Their natural history can be variable, presenting in a wide range of severity levels and encompassing asymptomatic individuals who remain so until adulthood, as well as those who experience respiratory distress in the neonatal period. Through the PubMed database, we performed an extensive review of the literature in the fields of congenital lung abnormalities, including their diagnostic approach and findings. From our RIS-PACS database, we have selected cases with a final diagnosis of congenital lung malformation. Different diagnostic approaches have been selected, including clinical cases studied using plain radiograph, CT scan, prenatal ultrasound, and MR images. The most encountered anomalies can be classified into three categories: bronchopulmonary anomalies (congenital pulmonary airway malformations (CPAMs), congenital lobar hyperinflation, bronchial atresia, and bronchogenic cysts), vascular anomalies (arteriovenous malformation), and combined lung and vascular anomalies (scimitar syndrome and bronchopulmonary sequestration). CLM causes significant morbidity and mortality; therefore, the recognition of these abnormalities is necessary for optimal prenatal counseling and early peri- and postnatal management. This pictorial review aims to report relevant imaging findings in order to offer some clues for differential diagnosis both for radiologists and pediatric consultants.

It is of meaningful importance to evaluate the performance of all the nuclear facilities, and particularly those part of such buildings where spent nuclear fuel (SNF) is stored to assess what kinds of consequences are anomalous/abnormal or to determine what types of accident events may occur. In this preliminary study, the strategies adopted for the management of SNF, and the risk related to them are discussed. The aim of this study is to evaluate the total radioactivity inventory characterising Ukrainian nuclear facilities, including storage facilities. The dataset used to calculate the total activity associated with nuclear fuel is provided and discussed. For the evaluation, it is considered that a SNF pool in VVER-1000 is designed to store 687 fuel assemblies, and 670 are in VVER-440. When it is half full, which is the case for 15 Ukrainian units, it will store about 2200 tU containing up to 1·1019 Bq of 137Cs, 7·1018 Bq of 90Sr, and 1·1019 Bq of TUE. This study focuses particularly on the total activity of the SNF stored at the Zaporozhye plant, the biggest nuclear plant in Europe, and the risk posed by the potential loss that cooling the plant could incur because of pond water level variation. The results of the analysis of the Zaporozhye NPP behaviour suggest that the water flow rate which keeps the SNF pool temperature constant is about 200,000 m3·day−1. Therefore, the water level in the pond should not be lower than 1.5–2 m; otherwise, the plant will need an additional source of water of more than 200,000 m3 per day to guarantee safe storage of SNF.

Triterpenoids, such as ganoderic acid, and polysaccharides, including β-D-glucans, α-D-glucans, and α-D-mannans, are the main secondary metabolites of the medicinal fungus Ganoderma lucidum. There is evidence of the effects of ganoderic acid in hematological malignancies, whose mechanisms involve the stimulation of immune response, the macrophage-like differentiation, the activation of MAP-K pathway, an IL3-dependent cytotoxic action, the induction of cytoprotective autophagy, and the induction of apoptosis. In fact, this compound has been tested in twenty-six different human cancer cell types and has shown an anti-proliferative activity, especially in leukemia, lymphoma, and myeloma lines. Moreover, research clarified the capability of molecules from Ganoderma lucidum to induce mitochondrial damage in acute promyelocytic leukemia cells, without cytotoxic effects in normal mononuclear cells. Active lipids extracted from the spores of this fungus have also been shown to induce apoptosis mediated by downregulation of P-Akt and upregulation of caspases-3, -8, and -9. Among in vivo studies, a study in BALB/c mice injected with WEHI-3 leukemic cells suggested that treatment with Ganoderma lucidum promotes differentiation of T- and B-cell precursors, phagocytosis by PBMCs, and NK cell activity. Our review presents data revealing the possibility of employing Ganoderma lucidum in hematological malignancies and incorporating it into clinical practice.

Abstract Background To describe long-term outcomes in JDM using patient questionnaires and link to longitudinal, prospectively collected data for each patient within the Juvenile Dermatomyositis Cohort and Biomarker Study, UK and Ireland (JDCBS) to determine outcome predictors. Methods JDCBS participants aged ≥ 16y completed the SF36, HAQ and a questionnaire regarding current disease features, medications, education and employment. Data collected from the JDCBS included disease subtype, demographics, clinical and laboratory features. Intensity indices were calculated for physician VAS, modified skin DAS, CMAS and MMT8 by dividing area under the curve (AUC) from longitudinal score trajectories by duration of study follow-up (y). Relationships between questionnaire and JDCBS clinical / laboratory data were investigated fitting statistical models appropriate for cross sectional and longitudinal data. Results Of 190 questionnaires sent, 84 (44%) were returned. Average age of respondents was 20.6 years (SD 3.9), time since diagnosis was 12.4 years (SD 5.0), age at onset was 9.2 years (SD 4.3), female to male ratio 4.25:1. Forty-nine (59%) self-reported persistently active disease, 54 (65%) were still taking immunosuppressive medication. 14/32 at school/higher education reported myositis adversely affecting academic results. 18–24 year-olds were twice as likely to be unemployed compared the UK population (OR = 0.456, 95% CI 0.24, 0.84, p = 0.001). Participants ≥ 18 years were three times as likely to be living with a parent/guardian (OR = 3.39, p

Intensive agricultural practices, such as pesticides use, may negatively affect bee health and hive products. Glyphosate is one of the most widely used polar pesticides applied in crops for weed control. In this study, honey samples, collected from beekeeping farms located in the Lombardy and Emilia-Romagna regions in Italy in the framework of regional monitoring plans activated from 2020 to 2022, were analyzed for the presence of residues of polar pesticides. The analytical method based on ion chromatography coupled to high-resolution mass spectrometry was applied to quantify glyphosate, glufosinate, ethephon, fosetyl aluminum, and their related metabolites. Residues of glyphosate were detected in around 28% of analyzed honey samples. Observations on the distribution of the honey-production-site locations suggest that honey samples originating from the provinces within the Lombardy region, where the agricultural sector is highly developed, were more affected by glyphosate contamination than the samples collected from the areas with low agricultural activity, where no glyphosate residues were detected over the three years of the monitoring program.

Abstract Connective tissue diseases (CTDs) include a spectrum of disorders that affect the connective tissue of the human body; they include autoimmune disorders characterized by immune-mediated chronic inflammation and the development of fibrosis. Lung involvement can be misdiagnosed, since pulmonary alterations preceded osteo-articular manifestations only in 20% of cases and they have no clear clinical findings in the early phases. All pulmonary structures may be interested: pulmonary interstitium, airways, pleura and respiratory muscles. Among these autoimmune disorders, rheumatoid arthritis (RA) is characterized by usual interstitial pneumonia (UIP), pulmonary nodules and airway disease with air-trapping, whereas non-specific interstitial pneumonia (NSIP), pulmonary hypertension and esophageal dilatation are frequently revealed in systemic sclerosis (SSc). NSIP and organizing pneumonia (OP) may be found in patients having polymyositis (PM) and dermatomyositis (DM); in some cases, perilobular consolidations and reverse halo-sign areas may be observed. Systemic lupus erythematosus (SLE) is characterized by serositis, acute lupus pneumonitis and alveolar hemorrhage. In the Sjögren syndrome (SS), the most frequent pattern encountered on HRCT images is represented by NSIP; UIP and lymphocytic interstitial pneumonia (LIP) are reported with a lower frequency. Finally, fibrotic NSIP may be the interstitial disease observed in patients having mixed connective tissue diseases (MCTD). This pictorial review therefore aims to provide clinical features and imaging findings associated with autoimmune CTDs, in order to help radiologists, pneumologists and rheumatologists in their diagnoses and management.

A white matter pathway (termed, MOLT) connecting the parahippocampal place area and the medial early visual cortex contributes to visuospatial learning in humans.

Lymphomas are a heterogeneous group of pathologies that result from clonal proliferation of lymphocytes. They are classified into Hodgkin lymphoma and non-Hodgkin lymphoma; the latter develops as a result of B, T, or NK cells undergoing malignant transformation. It is believed that diet can modulate cellular redox state and that oxidative stress is implicated in lymphomagenesis by acting on several biological mechanisms; in fact, oxidative stress can generate a state of chronic inflammation through the activation of various transcription factors, thereby increasing the production of proinflammatory cytokines and causing overstimulation of B lymphocytes in the production of antibodies and possible alterations in cellular DNA. The purpose of our work is to investigate the results of in vitro and in vivo studies on the possible interaction between lymphomas, oxidative stress, and diet. A variety of dietary regimens and substances introduced with the diet that may have antioxidant and antiproliferative effects were assessed. The possibility of using nutraceuticals as novel anticancer agents is discussed; although the use of natural substances in lymphoma therapy is an interesting field of study, further studies are needed to define the efficacy of different nutraceuticals before introducing them into clinical practice.

May-Thurner syndrome (MTS) belongs to a group of uncommon vascular syndromes. It consists in left common iliac vein (LCIV) compression between the right common iliac artery (RCIA) anteriorly and the lumbar spine posteriorly. A compression of LCIV by the left common iliac artery (LCIA) or by both iliac arteries were described. We present a rare case of “double MTS” which consist in double stenosis of LCIV by both RCIA and LCIA. Double MTS can cause acute or chronic DVT; this latter could be clinical manifest or well compensated.A 58-year-old woman with chronic mild pelvic pain underwent Doppler Ultrasound (US) of the pelvis and lower extremity vessels which showed thrombosis of both LCIV and ipsilateral common femoral vein caused by the extrinsic compression by both common iliac arteries against the spine. CT angiography confirmed the US data and ruled out other causes of compression. CT scan also showed the development of a natural venous femoro-femoral bypass which allowed to counteract the venous stasis and compensate venous drainage.Therefore, we decide for a long-term prophylaxis with anticoagulant drugs and doppler US follow-up at 6 months.In conclusion, doppler US is a non-invasive, low-cost, repeatable and sensitive method which allows to diagnose MTS and associated DVT. It may be considered the first level exam which allows to easily detect pelvic vascular compression syndrome.

It is reported that about 10% of cystic fibrosis (CF) patients worldwide have nonsense (stop) mutations in the CFTR gene, which cause the premature termination of CFTR protein synthesis, leading to a truncated and non-functional protein. To address this issue, we investigated the possibility of rescuing the CFTR nonsense mutation (UGA) by sequence-specific RNA editing in CFTR mutant CFF-16HBEge, W1282X, and G542X human bronchial cells. We used two different base editor tools that take advantage of ADAR enzymes (adenosine deaminase acting on RNA) to edit adenosine to inosine (A-to-I) within the mRNA: the REPAIRv2 (RNA Editing for Programmable A to I Replacement, version 2) and the minixABE (A to I Base Editor). Immunofluorescence experiments show that both approaches were able to recover the CFTR protein in the CFTR mutant cells. In addition, RT-qPCR confirmed the rescue of the CFTR full transcript. These findings suggest that site-specific RNA editing may efficiently correct the UGA premature stop codon in the CFTR transcript in CFF-16HBEge, W1282X, and G542X cells. Thus, this approach, which is safer than acting directly on the mutated DNA, opens up new therapeutic possibilities for CF patients with nonsense mutations.

The well-being of skin and mucous membranes is fundamental for the homeostasis of the body and thus it is imperative to treat any lesion quickly and correctly. In this view, polyphenols might assist and enhance a successful wound healing process by reducing the inflammatory cascade and the production of free radicals. However, they suffer from disadvantageous physico–chemical properties, leading to restricted clinical use. In this work, a complex mixture of PEGylated lipid, Glyceryl monoester, 18-β-Glycyrrhetinic Acid and Menthol was designed to entrap Resveratrol (RSV) as the active ingredient and further produce lipid nanoparticles (LNPs) by homogenization followed by high-frequency sonication. The nanosystem was properly characterized in terms of particle size (DLS, SEM), zeta potential, drug loading, antioxidant power (DPPH), release behaviour, cytocompatibility, wound healing and antibiofilm properties. The optimized lipid mixture was homogeneous, melted at 57–61 °C and encapsulated amorphous RSV (4.56 ± 0.04% w/w). The RSV-loaded LNPs were almost monodispersed (PDI: 0.267 ± 0.010), with nanometric size (162.86 ± 3.12 nm), scavenger properties and suitable DR% and LE% values (96.82 ± 1.34% and 95.17 ± 0.25%, respectively). The release studies were performed to simulate the wound conditions: 1-octanol to mimic the lipophilic domains of biological tissues (where the First Order kinetic was observed) and citrate buffer pH 5.5 according to the inflammatory wound exudate (where the Korsmeyer–Peppas kinetic was followed). The biological and microbiological evaluations highlighted fibroblast proliferation and migration effects as well as antibiofilm properties at extremely low doses (LNPs: 22 μg/mL, corresponding to RSV 5 µM). Thus, the proposed multicomponent LNPs could represent a valuable RSV delivery platform for wound healing purposes.

Gliomas are the prevalent forms of brain cancer and derive from glial cells. Among them, astrocytomas are the most frequent. Astrocytes are fundamental for most brain functions, as they contribute to neuronal metabolism and neurotransmission. When they acquire cancer properties, their functions are altered, and, in addition, they start invading the brain parenchyma. Thus, a better knowledge of transformed astrocyte molecular properties is essential. With this aim, we previously developed rat astrocyte clones with increasing cancer properties. In this study, we used proteomic analysis to compare the most transformed clone (A-FC6) with normal primary astrocytes. We found that 154 proteins are downregulated and 101 upregulated in the clone. Moreover, 46 proteins are only expressed in the clone and 82 only in the normal cells. Notably, only 11 upregulated/unique proteins are encoded in the duplicated q arm of isochromosome 8 (i(8q)), which cytogenetically characterizes the clone. Since both normal and transformed brain cells release extracellular vesicles (EVs), which might induce epigenetic modifications in the neighboring cells, we also compared EVs released from transformed and normal astrocytes. Interestingly, we found that the clone releases EVs containing proteins, such as matrix metalloproteinase 3 (MMP3), that can modify the extracellular matrix, thus allowing invasion.

Background and Objectives: to describe current scientific knowledge regarding the treatment options in advanced oropharyngeal cancer. The standard care for advanced oropharyngeal cancer (OPSCC) has been chemoradiotherapy, although surgical approaches followed by adjuvant treatment have been proposed. The best therapy for each patient should be decided by an interdisciplinary tumour-board. Different strategies should be considered for the specific patient’s treatment: surgery, chemotherapy and radiation therapy or combinations of them. The treatment choice is influenced by tumour variability and prognostic factors, but it also depends on cancer extension, extranodal extension, nervous invasion, human papilloma virus (HPV) presence, making the decisional algorithm not always clear. HPV-related OPSCC is strongly associated with a favourable overall survival (OS) and disease-free survival rate (DSS); by contrast, HPV-negative OPSCC often flags a worse prognosis. Consequently, the American Joint Committee on Cancer (AJCC) differentiates OPSCC treatment and prognosis based on HPV status. Methods: we carried out a review of current scientific literature to analyze the different indications and limitations of surgical treatment options in OPSCC stage III and IV. Conclusion: robotic surgery or open approaches with reconstructive flaps can be considered in advanced stages, resulting in the de-intensification of subsequent systemic therapy and fewer related side effects. Furthermore, in the event of the primary failure of systemic therapy or disease recurrence, the surgical approach constitutes an additional therapeutic option which lengthens patient survival functions.

Transgender (TG) describes individuals whose gender identity differs from the social norms. TG people undergoing gender-affirming hormone therapy (HT) may be considered a sub-group of the population susceptible to environmental contaminants for their targets and modes of action. The aim of this study is to set appropriate HT doses and identify specific biomarkers to implement TG animal models. Four adult rats/group/sex were subcutaneously exposed to three doses of HT (plus control) selected starting from available data. The demasculinizing-feminizing models (dMF) were β-estradiol plus cyproterone acetate, at 0.09 + 0.33, 0.09 + 0.93 and 0.18 + 0.33 mg, respectively, five times/week. The defeminizing-masculinizing models (dFM) were testosterone (T) at 0.45, 0.95 and 2.05 mg, two times/week. Clitoral gain and sperm count, histopathological analysis of reproductive organs and liver, hormone serum levels and gene expression of sex-dimorphic CYP450 were evaluated. In the dMF model, the selected doses—leading to T serum levels at the range of the corresponding cisgender—induced strong general toxicity and cannot be used in long-term studies. In the dFM model, 0.45 mg of T represents the correct dose. In addition, the endpoints selected are considered suitable and reliable to implement the animal model. The sex-specific CYP expression is a suitable biomarker to set proper (de)masculinizing/(de)feminizing HT and to implement TG animal models.

Polymyositis and dermatomyositis are autoimmune idiopathic systemic inflammatory diseases, characterized by various degrees of muscle inflammation and typical cutaneous lesions—the latter found in dermatomyositis. The underlying pathogenesis is characterized by a high level of uncertainty, and recent studies suggest diseases may have different immunopathological mechanisms. In polymyositis, components of the cellular immune system are involved, whereas in dermatomyositis, the pathogenesis is mainly mediated by the humoral immune response. The interstitial lung disease occurs in one-third of polymyositis and dermatomyositis patients associated with worse outcomes, showing an estimated excess mortality rate of around 40%. Lung involvement may also appear, such as a complication of muscle weakness, mainly represented by aspiration pneumonia or respiratory insufficiency. The clinical picture is characterized, in most cases, by progressive dyspnea and non-productive cough. In some cases, hemoptysis and chest pain are found. Onset can be acute, sub-acute, or chronic. Pulmonary involvement could be assessed by High Resolution Computed Tomography (HRCT), which may identify early manifestations of diseases. Moreover, Computed Tomography (CT) appearances can be highly variable depending on the positivity of myositis-specific autoantibodies. The most common pathological patterns include fibrotic and cellular nonspecific interstitial pneumonia or organizing pneumonia; major findings observed on HRCT images are represented by consolidations, ground-glass opacities, and reticulations. Other findings include honeycombing, subpleural bands, and traction bronchiectasis. In patients having Anti-ARS Abs, HRCT features may develop with consolidations, ground glass opacities (GGOs), and reticular opacities in the peripheral portions; nonspecific interstitial pneumonia or nonspecific interstitial pneumonia mixed with organizing pneumonia have been reported as the most frequently encountered patterns. In patients with anti-MDA5 Abs, mixed or unclassifiable patterns are frequently observed at imaging. HRCT is a sensitive method that allows one not only to identify disease, but also to monitor the effectiveness of treatment and detect disease progression and/or complications; however, radiological findings are not specific. Therefore, aim of this pictorial essay is to describe clinical and radiological features of interstitial lung diseases associated with polymyositis and dermatomyositis, emphasizing the concept that gold standard for diagnosis and classification–should be based on a multidisciplinary approach.

Neurodegenerative diseases affect millions of people worldwide and the presence of various physiological barriers limits the accessibility to the brain and reduces the efficacy of various therapies. Moreover, new carriers having targeting properties to specific brain regions and cells are needed in order to improve therapies for the brain disorder treatment. In this study, for the first time, Myelin nanoVesicles (hereafter defined MyVes) from brain-extracted myelin were produced. The MyVes have an average diameter of 100–150 ​nm, negative zeta potential, spheroidal morphology, and contain lipids and the key proteins of the myelin sheath. Furthermore, they exhibit good cytocompatibility. The MyVes were able to target the white matter and interact mainly with the microglia cells. The preliminary results here presented allow us to suppose the employment of MyVes as potential carrier to target the white matter and microglia in order to counteract white matter microglia-related diseases.

Liquid biopsy is one of the fastest emerging fields in cancer evaluation. Circulating tumour cells and tumour-originated DNA in plasma have become the new targets for their possible employ in tumour diagnosis, and liquid biopsy can define tumour burden without invasive procedures. Multiple Myeloma, one of the most frequent hematologic tumors, has been the target of therapeutic progresses in the last few years. Bone marrow aspirate is the traditional tool for diagnosis, prognosis, and genetic evaluation in multiple myeloma patients. However, this painful procedure presents a relevant drawback for regular disease examination as it requires an invasive practice. Moreover, new data demonstrated that a sole bone marrow aspirate is incapable of expressing the multifaceted multiple myeloma genetic heterogeneity. In this review, we report the emerging usefulness of the assessment of circulating tumour cells, cell-free DNA, extracellular RNA, cell-free proteins, extracellular vesicles, and tumour-educated platelets to evaluate the changing mutational profile of multiple myeloma, as early markers of disease, reliable predictors of prognosis, and as useful tools to perform less invasive monitoring in multiple myeloma.

Aquaporins are transmembrane molecules regulating the transfer of water and other compounds such as ions, glycerol, urea, and hydrogen peroxide. Their alteration has been reported in several conditions such as cancer. Tumor progression might be enhanced by aquaporins in modifying tumor angiogenesis, cell volume adaptation, proteases activity, cell–matrix adhesions, actin cytoskeleton, epithelial–mesenchymal transitions, and acting on several signaling pathways facilitating cancer progression. Close connections have also been identified between the aquaporins and hematological malignancies. However, it is difficult to identify a unique action exerted by aquaporins in different hemopathies, and each aquaporin has specific effects that vary according to the class of aquaporin examined and to the different neoplastic cells. However, the expression of aquaporins is altered in cell cultures and in patients with acute and chronic myeloid leukemia, in lymphoproliferative diseases and in multiple myeloma, and the different expression of aquaporins seems to be able to influence the efficacy of treatment and could have a prognostic significance, as greater expression of aquaporins is correlated to improved overall survival in leukemia patients. Finally, we assessed the possibility that modifying the aquaporin expression using aquaporin-targeting regulators, specific monoclonal antibodies, and even aquaporin gene transfer could represent an effective therapy of hematological malignancies.

Currently, no commercially available drugs have the ability to reverse cachexia or counteract muscle wasting and the loss of lean mass. Here, we report the methodology used to develop Physiactisome—a conditioned medium released by heat shock protein 60 (Hsp60)—overexpressing C2C12 cell lines enriched with small and large extracellular vesicles. We also present evidence supporting its use in the treatment of cachexia. Briefly, we obtain a nanovesicle-based secretion by genetically modifying C2C12 cell lines with an Hsp60-overexpressing plasmid. The secretion is used to treat naïve C2C12 cell lines. Physiactisome activates the expression of PGC-1α isoform 1, which is directly involved in mitochondrial biogenesis and muscle atrophy suppression, in naïve C2C12 cell lines. Proteomic analyses show Hsp60 localisation inside isolated nanovesicles and the localisation of several apocrine and merocrine molecules, with potential benefits for severe forms of muscle atrophy. Considering that Physiactisome can be easily obtained following tissue biopsy and can be applied to autologous muscle stem cells, we propose a potential nanovesicle-based anti-cachexia drug that could mimic the beneficial effects of exercise. Thus, Physiactisome may improve patient survival and quality of life. Furthermore, the method used to add Hsp60 into nanovesicles can be used to deliver other drugs or active proteins to vesicles.

Effectual cell-to-cell communication is essential to the development and differentiation of organisms, the preservation of tissue tasks, and the synchronization of their different physiological actions, but also to the proliferation and metastasis of tumor cells. Tunneling nanotubes (TNTs) are membrane-enclosed tubular connections between cells that carry a multiplicity of cellular loads, such as exosomes, non-coding RNAs, mitochondria, and proteins, and they have been identified as the main participants in healthy and tumoral cell communication. TNTs have been described in numerous tumors in in vitro, ex vivo, and in vivo models favoring the onset and progression of tumors. Tumor cells utilize TNT-like membranous channels to transfer information between themselves or with the tumoral milieu. As a result, tumor cells attain novel capabilities, such as the increased capacity of metastasis, metabolic plasticity, angiogenic aptitude, and chemoresistance, promoting tumor severity. Here, we review the morphological and operational characteristics of TNTs and their influence on hematologic malignancies’ progression and resistance to therapies, focusing on acute and chronic myeloid and acute lymphoid leukemia. Finally, we examine the prospects and challenges for TNTs as a therapeutic approach for hematologic diseases by examining the development of efficient and safe drugs targeting TNTs.

Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old. A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects. As far as we are concerned, it is difficult to make wide-ranging conclusions/assumptions based on these observations in view of the relatively small sample size of LLIs. However, this is an important starting point. Larger-scale future studies will be required to clarify these findings including the link with other systemic inflammatory and antioxidant markers.

Colorectal cancer (CRC) develops by genetic and epigenetic alterations. However, the molecular mechanisms underlying metastatic dissemination remain unclear and could benefit from multi-omics investigations of specific protein families. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in ECM remodeling and the processing of bioactive molecules. Increased MMP expression promotes the hallmarks of tumor progression, including angiogenesis, invasion, and metastasis, and is correlated with a shortened survival. Nevertheless, the collective role and the possible coordination of MMP members in CRC are poorly investigated. Here, we performed a multi-omics analysis of MMP expression in CRC using data mining and experimental investigations. Several databases were used to deeply mine different expressions between tumor and normal tissues, the genetic and epigenetic alterations, the prognostic value as well as the interrelationships with tumor immune-infiltrating cells (TIICs). A special focus was placed on to MMP2 and MMP9: their expression was correlated with immune markers and the interaction network of co-expressed genes disclosed their implication in epithelial to mesenchymal transition (EMT) and immune response. Finally, the activity levels of MMP2 and MMP9 in a cohort of colon cancer samples, including tissues and the corresponding sera, was also investigated by zymography. Our findings suggested that MMPs could have a high potency, as they are targeted in colon cancer, and might serve as novel biomarkers, especially for their involvement in the immune response. However, further studies are needed to explore the detailed biological functions and molecular mechanisms of MMPs in CRC, also in consideration of their expression and different regulation in several tissues.

Today, 46% of operating Nuclear Power Plants (NPP) have a lifetime between 31 and 40 years, while 19% have been in operation for more than 40 years. Long Term Operation (LTO) is an urgent requirement for all of the nuclear industry. The aim of this study is to assess the performance of a reactor pressure vessel (RPV) subjected to a station blackout (SBO) event. Alterations suffered by the material properties and creep at elevated temperatures are considered. In this study, coupling between MELCOR and Finite Element Method (FEM) codes is carried out. In the Finite Element (FE) model, the combined effects of ageing and creep are implemented through degraded material properties and a viscoplastic model. The reliability of the model is validated by comparing the FOREVER/C1 experimental results. The results show that the RPV lower head bends downwards with a maximum radial expansion of about 260 mm and RPV thermomechanical properties are reduced by more than 50% at high temperatures. The effects of ageing, creep and long heat-up strongly affect the resistance of the RPV system until the point of compromising it in the absence of/delayed emergency intervention. Aged RPV at end-of-life may collapse earlier, and in less time, with the same accidental conditions.

The readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein.

Interaction between cancer cells and their microenvironment is central in defining the fate of cancer development. Tumour cells secrete signals (cytokines, chemokines, growth factors) that modify the surrounding area, while the niche supplies structures and activities necessary for tumour maintenance and growth. Hyaluronan (HA) is a glycosaminoglycan that constitute cancer cell niche and is known to influence tumour functions such as proliferation, migration and neoangiogenesis. The knowledge of the factors regulating HA synthesis and size is crucial in understanding the mechanisms sustaining tumour development. Here we show that a yet uncharacterized protein secreted by breast tumour cell lines, named c10orf118 (accession number NM_018017 in NCBI/BLAST, and Q7z3E2 according to the Uniprot identifier), with a predicted length of 898 amino acids, can induce the secretion of HA by stromal fibroblasts through the up-regulation of the hyaluronan synthase 2 gene (HAS2). Intracellularly, this protein is localized in the Golgi apparatus with a possible role in vesicle maturation and transport. The expression of c10orf118 was verified in breast cancer patient specimens and was found to be associated with the presence of estrogen receptor that characterizes a good patient survival. We suggest c10orf118 as a new player that influences the HA amount in breast cancer microenvironment and is associated with low aggressiveness of cancer.

Heat shock proteins (HSPs) are a well-characterized molecular chaperones protein family, classified into six major families, according to their molecular size. A wide range of tumors have been shown to express atypical levels of one or more HSPs, suggesting that they could be used as biomarkers. However, the collective role and the possible coordination of HSP members, as well as the prognostic significance and the functional implications of their deregulated expression in breast cancer (BC) are poorly investigated. Here, we used a systematic multi-omics approach to assess the HSPs expression, the prognostic value, and the underlying mechanisms of tumorigenesis in BC. By using data mining, we showed that several HSPs were deregulated in BC and significantly correlated with a poor or good prognosis. Functional network analysis of HSPs co-expressed genes and miRNAs highlighted their regulatory effects on several biological pathways involved in cancer progression. In particular, these pathways concerned cell cycle and DNA replication for the HSPs co-expressed genes, and miRNAs up-regulated in poor prognosis and Epithelial to Mesenchymal Transition (ETM), as well as receptors-mediated signaling for the HSPs co-expressed genes up-regulated in good prognosis. Furthermore, the proteomic expression of HSPs in a large sample-set of breast cancer tissues revealed much more complexity in their roles in BC and showed that their expression is quite variable among patients and confined into different cellular compartments. In conclusion, integrative analysis of multi-omics data revealed the distinct impact of several HSPs members in BC progression and indicate that collectively they could be useful as biomarkers and therapeutic targets for BC management.

Combining global experience, comprehensive aging knowledge, and predictive methodologies provides ideal prerequisites for the long-term operation strategy (LTO) of a nuclear power plant (NPP). Applying management strategies with an understanding of the ways in which structures relevant for the plant safety perform and interact in their operating environments is of meaningful importance for operating the plant beyond its originally licensed service life. In performing aging studies on the nuclear systems, structure, and components (SSCs), the results are crucial for demonstrating the safety and reliability of the NPP beyond 30 years of nominal operation. In this study, the synergistic effect of a creep mechanism with the alteration suffered by piping material is analyzed by means of MSC©MARC finite element code. Nonlinear analyses were performed to calculate the effects of the long operational period on a primary pipe, assess its degradation, and determine its residual functionality. In these analyses, both homogeneous and inhomogeneous pipe wall thinning are considered, as well as the operating or expected thermal–mechanical loads. The obtained results indicate that thermo–mechanical loads are responsible for pipe deformation, which develops and increases as the transient progresses. Furthermore, an excessive (general or local) wall thinning may determine a dimensional change of the pipe, even causing bending or buckling.

Two mononuclear Pd(II) complexes [PdCl2(pfptp)] (1) and [PdCl2(pfhtp)] (2), with ligands 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), were synthesized and structurally characterized. The two complexes showed a bidentate coordination of the ligand occurring through N atom of pyridine ring and N4 atom of 1,2,4-triazole. Both complexes showed antimicrobial activity when tested against both Gram-negative and Gram-positive bacterial strains.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the transmembrane conductance regulator (CFTR) protein. Some CF patients are compound heterozygous or homozygous for nonsense mutations in the CFTR gene. This implies the presence in the transcript of premature termination codons (PTCs) responsible for a truncated CFTR protein and a more severe form of the disease. Aminoglycoside and PTC124 derivatives have been used for the read-through of PTCs to restore the full-length CFTR protein. However, in a precision medicine framework, the CRISPR/dCas13b-based molecular tool “REPAIRv2” (RNA Editing for Programmable A to I Replacement, version 2) could be a good alternative to restore the full-length CFTR protein. This RNA editing approach is based on the targeting of the deaminase domain of the hADAR2 enzyme fused to the dCas13b protein to a specific adenosine to be edited to inosine in the mutant mRNA. Targeting specificity is allowed by a guide RNA (gRNA) complementarily to the target region and recognized by the dCas13b protein. Here, we used the REPAIRv2 platform to edit the UGA PTC to UGG in different cell types, namely IB3-1 cells, HeLa, and FRT cells engineered to express H2BGFPopal and CFTRW1282X, respectively.

Regenerative medicine aims to repair damaged, tissues or organs for the treatment of various diseases, which have been poorly managed with conventional drugs and medical procedures. To date, multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self-healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects, especially for mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) in damaged tissue restore are not dependent on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release extracellular vesicles (EVs). EVs play a fundamental role in cell-to-cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms through which MSCs and iPSCs-derived EVs carry out their therapeutic action and their possible application for the treatment of several diseases.