"Caratterizzazione dell'impegno articolare di mano e polso in pazienti affetti da Lupus Eritematoso Sistemico: valutazione integrata mediante esame di Risonanza Magnetica Nucleare, ecografia articolare, clinimetrica e sierologia"

L’impegno articolare in corso di Lupus Eritematoso Sistemico (LES) è estremamente frequente e, benché storicamente considerato a prognosi benigna, oggi sappiamo come talvolta possa determinare dolore cronico, deformità articolari e quindi limitazione funzionale e ridotta qualità della vita. Sulla base di tali considerazioni abbiamo ipotizzato come un work-up completo, di tipo clinico, strumentale e sierologico, possa contribuire a caratterizzare al meglio l’impegno articolare in questi pazienti aiutandoci ad identificare precocemente i fattori prognostici negativi. Sono stati pertanto arruolati 79 pazienti affetti da LES indipendentemente dall’impegno d’organo o dalle manifestazioni cliniche di malattia e valutati mediante esame obiettivo, indici clinimetrici, sierologia, ecografia articolare e risonanza magnetica (tale metodica ha inoltre previsto un gruppo di controllo formato da 43 controlli sani). I risultati ottenuti indicano come l’artrite nel LES sia effettivamente frequente e spesso subclinica. A fronte di ciò abbiamo inoltre dimostrato come tale impegno articolare si traduca in un carico erosivo significativamente maggiore rispetto ai controlli sani confrontati per età e sesso con una potenziale progressione verso il dolore, le deformità e la disabilità funzionale. Tali dati suggeriscono la necessità di rivalutare l’impegno articolare in corso di LES identificando precocemente i pazienti con flogosi articolare o tendinea attiva per intraprendere sin dall’inizio una adeguata terapia di fondo

A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity

Genes encoding components of the PI3K–AKT–mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency. Significance: We report that a diverse set of cancer-associated MTOR mutations confer increased mTORC1/2 pathway activity and that cells harboring these mutations are highly sensitive to rapamycin in culture and in vivo. These findings are clinically relevant as the MTOR mutations characterized herein may serve as biomarkers for predicting tumor responses to mTOR inhibitors.Starr Cancer ConsortiumDavid H. Koch Institute for Integrative Cancer Research at MITAlexander and Margaret Stewart TrustNational Institutes of Health (U.S.) (Grant CA103866)National Institutes of Health (U.S.) (Grant CA129105)National Institutes of Health (U.S.) (Grant AI07389

NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumours grow despite suppression of NFS1, whereas metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the iron-sulfur co-factors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron-sulfur cluster maintenance robustly activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage

Barriers to Integrating Primary Care Services into Behavioral Health Agencies: A Policy Analysis

Background: This policy analysis explored the licensing requirements for primary care services compared with behavioral health and addiction services in agencies that were already licensed to provide the latter. This analysis looked at the challenges of doing so based on current New Jersey Department of Health regulations for licensing primary care facilities and Department of Human Services regulations for behavioral health and substance use treatment agencies. Creating an integrated health license moves agencies closer to providing whole person- centered care to vulnerable populations while enhancing quality of care and decreasing costs. Objectives: The purpose of this policy analysis was to assess the barriers to implementing primary care into certified community behavioral health clinics based on existing licensing regulations across two state departments and engage stakeholders to pass legislature to streamline licensing requirements. This policy analysis identified successes and barriers to integrating primary care into existing behavioral health agencies and made recommendations for agencies and legislators. A policy analysis was conducted on existing laws and bills at the state and federal levels that seek to integrate primary care into behavioral health agencies. Current licensing regulations for outpatient mental health and substance use agencies and primary care services were reviewed and overlaps and gaps in requirements were identified. Barriers, perceived or otherwise, in agencies that have not yet integrated primary care into practice were identified. Legislators were contacted regarding the regulation conflicts and encouraged to support the pending legislation to create a guidance for agencies to integrate primary care services. Methods: Extensive searches were done to identify regulations and waivers to regulations that were contradictory. A certified behavioral health community center that has integrated primary care was identified and an interview was conducted with a retired CEO to ascertain barriers and facilitators to the integration process. An agency wishing to integrate was interviewed regarding their knowledge of existing barriers and waivers to mitigate those challenges. Results: One bill requiring the Department of Health to create language to license behavioral health agencies to also provide primary care services has been pending since the 2021 legislative session. A bill passed in 2017 to create an integrated license, but no action has taken place on that, even though the Commissioners of Health and Human Services were given 180 days after the effective date of the act to create rules and regulations for said integrated license. This timeframe has come and gone. The pending legislation would be the completion of the 2017 bill. It has had different sponsors each session and has not had a companion Senate bill since its introduction in 2021. With the discovery of the shared clinical space waiver, a significant barrier to integrating primary care services into behavioral health agencies is potentially mitigated. Whether the legislation gets passed or not, the waiver opens the door for integrating services and. These findings were communicated to stakeholders, including elected officials who can advocate for legislation to enact new regulations and agencies who can advocate on behalf of patients to legislators regarding integrating care to improve healthcare delivery and cost effectiveness of care for Medicaid patients

Creating pre-Evaluation opportunity spaces in IRE sequences: Evidence from Italian L2 classrooms in a University Context.

This thesis explores L2 classroom teacher-fronted activities organised in Initiation-Response- Evaluation (IRE) sequences, during beginner and intermediate lessons of Italian at the University level. More specifically, the study analyses the ways in which teachers address a variety of pedagogical contingencies while simultaneously progressing the interaction. It is argued that the tripartite sequential structure provides the teachers with pre-evaluative moments - here defined as pre-Evaluation opportunity spaces - emerging between the student’s responsive move (R) and the teacher’s third positioned evaluation (E). The research draws upon 30 hours of video- and audio-recorded interactions from two University Italian L2 classrooms. The study is informed by multimodal Conversation Analysis and socio-interactional approaches to language learning. Classroom interaction is, thus, regarded as one institutional type of social interaction and - as such - is viewed as jointly achieved by participants, sequentially organised, and relentlessly negotiated on a moment-by-moment basis. The findings show that the teachers regularly exploit specific IRE sequential affordances, such as the inter-move space between the student’s responsive move and the teacher’s evaluation. In particular, the fine-grained analysis of the teachers’ multimodal conduct uncovers how such opportunity space arising between Response and Evaluation may be employed in order to invite peer-correction practices, manage shifting classroom participation frameworks, distribute agency in the L2 classroom, and orient to the omnirelevant property of sequential progressivity while attending to concurrent institutional pressures. Furthermore, the analysis unearths how such intra-move space might be organised through the mobilisation of different semiotic material, such as head nods, pointing gestures, gaze, and body orientation. The findings confirm the adaptive quality of the IRE sequence organisation as one fundamental infrastructure that embodies the reflexive relationship between pedagogy and interaction

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides

As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues1,2, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here, we developed a continuous flow culture apparatus (Nutrostat) for maintaining proliferating cells in low nutrient media for long periods of time and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNAi screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the upregulation of OXPHOS normally caused by glucose limitation as a result of either mtDNA mutations in Complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, anti-diabetic drugs that inhibit OXPHOS3,4, when cancer cells are grown in low glucose or as tumour xenografts. Remarkably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of Complex I function5. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors

Voice and Choice:Investigating the Role of Prosodic Variation in Request Compliance and Perceived Politeness Using Conversational TTS

As conversational Text-to-Speech (TTS) technologies become increasingly realistic and expressive, understanding the impact of prosodic variation on speech perception and social dynamics is crucial for enhancing conversational systems. This study explores the influence of prosodic features on listener responses to indirect requests using a specifically designed conversational TTS engine capable of controlling prosody, and generating speech across three different speaker profiles: female, male, and gender-ambiguous. We conducted two experiments to analyse how naturalistic variations in speech rate and vocal energy (projection) impact the likelihood of request compliance and perceived politeness. In the first experiment, we examined how prosodic modifications affect the perception of politeness in permission- and service requests. In the second experiment participants compared pairs of spoken requests, each rendered with different prosodic features, and chose which they were more likely to grant. Results indicate that both faster speech rates and higher projection increased the willingness to comply, though the extent of this influence varied by speaker gender. Higher projection in service request increases the chance of being granted more than in permission requests. Politeness has a demonstrated positive impact on the likelihood of requests being granted, this effect is stronger for the male voice compared to female and gender-ambiguous voices