Search

The HECT‐type E3 ubiquitin WWP1 (also known as NEDD4‐like E3 ubiquitin‐protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin‐interacting protein (TXNIP)‐mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin‐dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in AML blasts reduces Trx activity and increases ROS production, hence inducing cellular oxidative stress. Increased ROS generation in WWP1‐depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up‐take and consumption. Hence, a contribution to the increased cell death observed in WWP1‐depleted cells also possibly arises from the attenuation of glucose up‐take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP‐dependent deregulation of redox homeostasis in WWP1‐overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.

Resistance, tolerance, and persistence to antibiotics have mainly been studied at the level of a single microbial isolate. However, in recent years it has become evident that microbial interactions play a role in determining the success of antibiotic treatments, in particular by influencing the occurrence of persistence and tolerance within a population. Additionally, the challenge of resuscitation (the capability of a population to revive after antibiotic exposure) and pathogen clearance are strongly linked to the small size of the surviving population and to the presence of fluctuations in cell counts. Indeed, while large population dynamics can be considered deterministic, small populations are influenced by stochastic processes, making their behaviour less predictable. Our study argues that microbe-microbe interactions within a community affect the mode, tempo, and success of persister resuscitation and that these are further influenced by noise. To this aim, we developed a theoretical model of a three-member microbial community and analysed the role of cell-to-cell interactions on pathogen clearance, using both deterministic and stochastic simulations. Our findings highlight the importance of ecological interactions and population size fluctuations (and hence the underlying cellular mechanisms) in determining the resilience of microbial populations following antibiotic treatment.

Este estudio explora la producción científica sobre conexión social (CS) mediante un análisis bibliométrico de 94 artículos obtenidos de las bases de datos SCOPUS, Dialnet y SciELO. La CS se define como un sentimiento de pertenencia y cercanía en relaciones interpersonales, desarrollado a partir de experiencias sociales internalizadas en diversos contextos. Estos estudios examinan la productividad por autor, colaboración entre investigadores, temáticas y distribución geográfica de las publicaciones. Los resultados indican un aumento en la investigación sobre CS desde 2016, alcanzando su pico en 2022, posiblemente vinculado a la pandemia de COVID-19 y la mayor atención en la CS como respuesta al aislamiento social. La investigación está liderada por autores de Estados Unidos, con menor participación de Australia y Europa, mientras que América Latina muestra escasa representación, evidenciando una brecha regional en la producción científica. La CS se asocia principalmente con la salud mental y el bienestar psicológico, mientras que otras áreas, como el desarrollo cognitivo y las diferencias culturales, son menos exploradas. Metodológicamente, la mitad de los estudios son correlacionales, con escasos diseños experimentales y longitudinales, lo que limita la comprensión de los efectos causales de la CS. Se concluye que el campo requiere mayor diversidad metodológica, colaboración interdisciplinaria y representación regional para profundizar en los mecanismos de la CS y su impacto en la salud y el bienestar en distintos contextos.

This study explores the potential of rabbits as a sustainable solution for poverty alleviation and food security in Burkina Faso, a country facing socio-economic and environmental challenges. In the context of limited resources and employment opportunities, rabbits offer advantages such as small size, short generation interval and high reproductive capacity. The research focuses on characterising the morphology of Burkina Faso’s local rabbit population, comparing it with two Italian breeds: a local medium-growing breed called Leprino di Viterbo (LV) and a fast-growing hybrid (a crossbred New Zealand × California, NZC). Utilising path analysis and principal component analysis, the study identifies key morphometric traits crucial for breeding programs and examines the influence of specific traits on body weight (BW) gain and heat stress resilience through ‘Transpiration Indexes.’ Findings highlight the importance of variables like chest girth (CG), abdominal girth (AG), rump width (RW) and nose to shoulders length (NSL) in influencing body weight (BW) and reveal significant size and shape differences among the breeds. The study suggests potential climate adaptation in Burkina Faso’s rabbit population, providing practical insights for breeding programs in resource-constrained regions. This research not only advances scientific understanding but also provides practical insights for breeding programs in resource-constrained regions, emphasising the importance of certain morphological traits for heat dissipation.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the NF1 gene. Patients harboring these mutations are predisposed to a spectrum of peripheral nerve sheath tumors (PNSTs) originating from Schwann cells, of which malignant peripheral nerve sheath tumors (MPNSTs) are the deadliest, with limited treatment options. Therefore, an unmet need still exists for more effective therapies directed at these aggressive malignancies. Cold atmospheric plasma (CAP) is a reactive oxygen species (ROS) and reactive nitrogen species (RNS) generating ionized gas that has been proposed to be a potential therapeutic modality for cancer. In this study, we sought to determine the effects of CAP on NF1-associated PNSTs. Utilizing established mouse and human cell lines to interrogate the effects of CAP in both in vitro and in vivo settings, we found that NF1-associated PNSTs were highly sensitive to CAP exposure, resulting in cell death. To our knowledge, this is the first application of CAP to NF1-associated PNSTs and provides a unique opportunity to study the complex biology of NF1-associated tumors.

Pineal cysts are benign, nonneoplastic lesions of the pineal gland, often identified incidentally on MRI scans. Although these cysts are usually asymptomatic, they can occasionally enlarge and compress adjacent structures, leading to neurological complications such as obstructive hydrocephalus and Parinaud's syndrome. The underlying mechanisms of pineal cyst development remain largely unclear, although inflammation - common in rheumatological conditions such as fibromyalgia - and mechanical stress have been suggested as contributing factors. In addition, the incomplete blood-brain barrier of the pineal gland raises the possibility that chronic lithium therapy, commonly used for psychiatric disorders and also known for its hyperplastic effects, could facilitate cysts formation through lithium accumulation and epithelial stimulation.We report the case of a 49-year-old woman with bipolar disorder on long-term lithium treatment who presented with a pineal cyst and clinical symptoms consistent with fibromyalgia. A review of the literature highlights possible links between pineal cyst formation, systemic inflammation associated with rheumatological disorders and prolonged lithium exposure.Although the hyperplastic properties of lithium in glandular tissue are well documented, there is no conclusive evidence directly linking lithium use to the development of pineal cysts in humans. The possibility of cystic growth driven by the pro-inflammatory environment of fibromyalgia remains plausible and warrants further investigation of the complex interactions between lithium therapy, systemic inflammation and pineal cystogenesis, particularly in patients with coexisting rheumatological and psychiatric disorders.

Acute myeloid leukemia (AML) is a heterogeneous blood-related neoplasm that predominantly afflicts older adults with a poor prognosis due to their physical condition and the presence of medical accompanying comorbidities, adverse biological disease features, and suitability for induction intensive chemotherapy and allogenic stem cells transplantation. Recent research into the molecular and biological factors contributing to disease development and progression has led to significant advancements in treatment approaches for older patients with AML. This review article discusses the latest biological and therapeutic developments that are transforming the management of AML in older adults.

Thalassa montezumae Mulsant is a coccinellid species recently discovered as predator of the pine tortoise scale Toumeyella parvicornis. In this study, the complete mitochondrial genome of T. montezumae collected in Turks and Caicos Islands in 2023 was sequenced using next-generation sequencing techniques. The circular mitochondrial genome is 16,981 bp long and contains 13 protein coding genes, 22 transfer RNA, and 2 rRNA genes. Gene order is identical to that of other Coccinellidae. Phylogenetic analysis confirms structure of Coccinellidae families and tribes.

Bony hemangiomas are benign vascular lesions with an expansive growth; usually they tend to obliterate the entire bony cavity. They are typical lesion of the spinal bones, but they can rarely arise within other bones of the neurocranium. Diabetic microangiopathy is a condition characterized by the development of aberrant vessel tangles anastomosed to each other due to dysregulated neoangiogenesis. We report the case of a 56-year-old woman, suffering from type 2 diabetes mellitus, admitted to the neurology department due to a reported worsening of paresthesias and dysesthesias of the upper and lower limbs. She performed a contrast-enhanced brain CT scan that showed the presence, at the level of the right mastoid process, of an hypervascular angioma. A subsequent MRI study of the brain and spine showed the presence of multiple bone angiomas, at the level of the right frontal theca and C7, Th3, and Th7 vertebral bodies. Due to the absence of further symptoms and clinical and radiological signs of intracranial compression, the patient did not perform surgery. A radiological follow-up was advised. Although possible pathophysiological correlations between diabetes and vertebral hemangiomas are mentioned in literature, vascular lesions of this type involving vertebrae and skull base simultaneously can be discovered in a patient with chronic diabetic disease. As long as these lesions remain asymptomatic, surgical treatment is not indicated, and the patient is followed over time with radiological follow-up.

This paper uses digital approaches to investigate Priene’s (Turkey) archaeological area. The city was built ex novo, after a catastrophic earthquake around 350 BC, on a new site facing the Mediterranean Sea. The city suffered a slow decline following centuries of development and was abandoned after the 12th century. The remains of Priene were discovered in the 17th century, and different excavations and studies have been conducted in the last few centuries. The city’s remains have been studied from various archaeological and historical points of view. It is documented that the city suffered different earthquakes during its existence, as demonstrated by the partial restorations and damage patterns visible within the remains. This contribution offers a methodological and interdisciplinary approach for studying and enhancing archaeological heritage. This paper presents the preliminary results of the first comprehensive digital acquisition of the Aegean city of Priene. The digitization approaches here described focused on digital acquisition and 3D modeling restitution in the form of virtual reconstructions of two monumental buildings: the Doric Stoa near the Temple of Athena Polias and the Theater. The procedure was complementary to the analysis and comprehension of previous numerous studies carried out by British and German institutions, where digital acquisition and restitution techniques have led to the validation of previously obtained results. For the first time, digital models have been used as tools for accessing heterogeneous knowledge, and they have been incorporated into the discourse of archeological studies. Indeed, the interdisciplinary team went beyond archaeological data to attempt to digitally reconstruct monumental complexes and conduct preliminary structural evaluations scientifically.

Background: Allergen immunotherapy (AIT) is the only treatment that modifies the natural course of allergies. However, AIT is only used in some eligible patients, is frequently underused, and only a few studies investigated this aspects. Understanding AIT utilization patterns might disclose information about why it is underused, thus providing valuable insights on how to broaden the positive impact it can have on the population. Methods: A questionnaire aiming to assess the trends of the use of AIT in Italy, patient health literacy on AIT, and the impact of respiratory allergies and AIT on patients' lives was submitted to patients affiliated with Respiriamo Insieme APS patient's association during the period between May and October 2023. Results: Nine hundred forty-four patients completed the questionnaire. Most patients reported to be affected by allergic rhinitis (81.1%), allergic asthma (45.4%), and/or allergic conjunctivitis (41.2%), and many of them presenting a combination of these diseases. Only 53.8% knew about AIT's existence, and AIT was proposed to only 33.1% of the 858 patients affected by allergic rhinitis and/or allergic asthma, of which 29.2% decided not to initiate the therapy. Common reasons for AIT refusal were related to indecisiveness (26.5%), costs (22.9%), and skepticism (19.3%). Among the remaining 70.8% who accepted to start AIT, 21.4% discontinued the treatment beforehand, on average 18.26 months from initiation. There was a high heterogeneity in the suggested duration of AIT, with 20.4% of patients receiving indications to continue AIT for less than 3 years. AIT positively impacted patients' lives as most patients who completed AIT found it effective and safe, and experienced a significant reduction in the workdays/schooldays lost due to disease exacerbations. Conclusions: The outcomes of this research pointed out a lot of misinformation surrounding AIT, calling for improvements in awareness and information on its efficacy and safety. Also, we noted a significant reduction in work/school days lost in patients who completed AIT and a good patient-reported safety and efficacy profile. We advocate for better economic accessibility through national-level standardization in treatment refundability. Notably, the collaboration with the patient association was crucial, and it would have been challenging to conduct this research otherwise.

For over a century after their discovery astrocytes were regarded merely as cells located among other brain cells to hold and give support to neurons. Astrocytes activation, “astrocytosis” or A1 functional state, was considered a detrimental mechanism against neuronal survival. Recently, the scientific view on astrocytes has changed. Accumulating evidence indicate that astrocytes are not homogeneous, but rather encompass heterogeneous subpopulations of cells that differ from each other in terms of transcriptomics, molecular signature, function and response in physiological and pathological conditions. In this review, we report and discuss the recent literature on the phenomic differences of astrocytes in health and their modifications in disease conditions, focusing mainly on the hippocampus, a region involved in learning and memory encoding, in the age-related memory impairments, and in Alzheimer’s disease (AD) dementia. The morphological and functional heterogeneity of astrocytes in different brain regions may be related to their different housekeeping functions. Astrocytes that express diverse transcriptomics and phenomics are present in strictly correlated brain regions and they are likely responsible for interactions essential for the formation of the specialized neural circuits that drive complex behaviors. In the contiguous and interconnected hippocampal areas CA1 and CA3, astrocytes show different, finely regulated, and region-specific heterogeneity. Heterogeneous astrocytes have specific activities in the healthy brain, and respond differently to physiological or pathological stimuli, such as inflammaging present in normal brain aging or beta-amyloid-dependent neuroinflammation typical of AD. To become reactive, astrocytes undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. Alterations of astrocytes affect the neurovascular unit, the blood–brain barrier and reverberate to other brain cell populations, favoring or dysregulating their activities. It will be of great interest to understand whether the differential phenomics of astrocytes in health and disease can explain the diverse vulnerability of the hippocampal areas to aging or to different damaging insults, in order to find new astrocyte-targeted therapies that might prevent or treat neurodegenerative disorders.

Abstract This Anaphylaxis Manifesto calls on communities to prioritise 10 practical actions to improve the lives of people at risk of serious allergic reactions. The Global Allergy and Asthma European Network and the European Federation of Allergy and Airways Diseases Patients' Associations (EFA) compiled patient‐centric priorities. We used qualitative consensus methods, research evidence and feedback from over 200 patient groups, stakeholder organisations and healthcare professionals. We encourage healthcare, education and food organisations to collaborate with people at risk of serious allergic reactions to tackle safety, anxiety and financial burdens for individuals and societies. Key priorities for prevention include awareness‐raising campaigns for the public and professionals, school and workplace initiatives and mandatory precautionary allergen labels on food. Priorities for improving immediate and long‐term management include educating healthcare professionals, patients and schools about when and how to use adrenaline, funding two approved adrenaline devices for everyone at risk, and facilitating access to allergy specialists. Integrated care pathways should include clinical and non‐clinical management options such as individualised risk assessment and quality of life assessment, self‐management plans, dietetic and psychosocial support and peer support. Organisations around the world are committing to work together towards these priorities.

Growing interest has emerged in the role of sex, as a biological variable that influences the immunopathogenesis of melanoma. Female patients exhibit significantly better disease outcomes compared to males, and antitumor immune responses and benefits of immunotherapy also differ between males and females. Preclinical and clinical studies suggest an association with a more immunogenic tumor microenvironment in women. However, the extent of sex-related differences in immune responses in melanoma remains unclear, highlighting the need for further research. Sex hormones play a role in determining the nature of melanoma tumor microenvironment, as estrogens and androgens have been shown to modulate immune responses, contributing to the differences observed between males and females. The generally more reactive and efficient female immune system may contribute to better antitumor responses. Conversely, males tend to have higher cancer incidence, potentially due to inherent immune-cellular and molecular variations. This review summarizes key findings on the influence of sex on melanoma in general, and more specifically on the melanoma tumor microenvironment and antitumor immune responses, to provide a comprehensive understanding of how sex influences melanoma progression and patients outcomes. Understanding these differences is crucial for developing more effective, personalized treatment strategies for melanoma patients.

Introduction: RET rearrangements occur in 1% to 2% NSCLCs. Since no clinically validated RET antibody is currently available, fluorescence in situ hybridization (FISH) is often used as a screening tool to identify patients likely to benefit from RET-targeted therapy. In this study, we performed a comprehensive review of publications in which RET-rearrangement testing was performed by FISH and compared the methods and results with our data. Methods: The findings of an electronic search for publications using RET-FISH in lung cancer were compared with the results obtained at the Grenoble University Hospital where 784 EGFR-, KRAS-, ALK-, and ROS1-negative NSCLCs were tested by RET break-apart FISH and confirmed by RNA-sequencing (RNA-seq). Results: Out of the 85 publications using RET-FISH analysis, 52 pertained to patients with lung cancer. The most often used positivity threshold was 15%. Six publications compared RET-FISH with at least one other molecular technique on at least eight samples, and the concordance was variable, from 5.9% to 66.7% for FISH-positive cases. Regarding our data, out of the 784 analyzed samples, 32 (4%) were positive by RET-FISH. The concordance between RET-FISH and RNA-seq in RET-FISH positive samples was 69%. Conclusions: Overall, both existing literature and our data suggest that RET-FISH testing can be used for rapid screening of RET rearrangements in NSCLC. Nevertheless, using an orthogonal technique such as RNA-seq to confirm RET-FISH-positive cases is essential for ensuring that only patients likely to benefit from RET-target therapy receive the treatment.

Background: Allergic rhinitis (AR) is a highly prevalent disease. We aimed to assess the symptoms that physicians who see patients with AR perceive as the most bothersome in their patients. Methods: We performed a cross-sectional study based on an online questionnaire sent to all members of the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative. The survey included questions on the physicians' perceptions of patients’ AR symptoms as well as of their own AR symptoms. Results: Among 401 respondents, 155 (38.7%) reported having AR. ARIA members reported nasal symptoms to be the most frequent (89.7%) and bothersome (80.0%) symptoms experienced by themselves. Likewise, nasal symptoms were reported by ARIA members as the most frequent (94.8% in members with AR vs 96.0% in members without AR) and bothersome (57.0% in members with AR vs 67.9% in members without AR) in their patients. We found a significant association (p = 0.001) between physicians’ own symptoms and those perceived as the most bothersome in their patients. Conclusion: Physicians perceive nasal symptoms to be the most frequent and the most bothersome symptoms in AR patients. The physicians' personal experiences with AR may influence their perception of patients’ symptoms.

The controlled expression of two or more proteins at a defined and stable ratio remains a substantial challenge, particularly in the bi- and multispecific antibody field. Achieving an optimal ratio of protein subunits can facilitate the assembly of multimeric proteins with high efficiency and minimize the production of by-products. In this study, we propose a solution based on alternative splicing, enabling the expression of a tunable and predefined ratio of two distinct polypeptide chains from the same pre-mRNA under the control of a single promoter. The pre-mRNA used in this study contains two open reading frames situated on separate exons. The first exon is flanked by two copies of the chicken troponin intron 4 (cTNT-I4) and is susceptible to excision from the pre-mRNA by means of alternative splicing. This specific design enables the modulation of the splice ratio by adjusting the strength of the splice acceptor. To illustrate this approach, we developed constructs expressing varying ratios of GFP and dsRED and extended their application to multimeric proteins such as monoclonal antibodies, achieving industrially relevant expression levels (>1 g/L) in a 14-day fed-batch process. The stability of the splice ratio was confirmed by droplet digital PCR in a stable pool cultivated over a 28-day period, while product quality was assessed via intact mass analysis, demonstrating absence of product-related impurities resulting from undesired splice events. Furthermore, we showcased the versatility of the construct by expressing two subunits of a bispecific antibody of the BEAT® type, which contains three distinct subunits in total.