HOPS/TMUB1 Enhances Apoptosis in TP53 Mutation-Independent Setting in Human Cancers.

TP53 mutations are prevalent in various cancers, yet the complexity of apoptotic pathway deregulation suggests the involvement of additional factors. HOPS/TMUB1 is known to extend the half-life of p53 under normal and stress conditions, implying a regulatory function. This study investigates, for the first time, the potential modulatory role of the ubiquitin-like-protein HOPS/TMUB1 in p53-mutants. A comprehensive analysis of apoptosis in the most frequent p53-mutants, R175, R248, and R273, in SKBR3, MIA PaCa2, and H1975 cells indicates that the overexpression of HOPS induces apoptosis at least equivalent to that caused by DNA damage. Immunoprecipitation assays confirm HOPS binding to p53-mutant forms. The interaction of HOPS/TMUB1 with p53-mutants strengthens its effect on the apoptotic cascade, showing a context-dependent gain or loss of function. Gene expression analysis of the MYC and TP63 genes shows that H1975 exhibit a gain-of-function profile, while SKBR3 promote apoptosis in a TP63-dependent manner. The TCGA data further corroborate HOPS/TMUB1's positive correlation with apoptotic genes BAX, BBC3, and NOXA1, underscoring its relevance in patient samples. Notably, singular TP53 mutations inadequately explain pathway dysregulation, emphasizing the need to explore additional contributing factors. These findings illuminate the intricate interplay among TP53 mutations, HOPS/TMUB1, and apoptotic pathways, providing valuable insights for targeted cancer interventions.

Adaptive Machine Learning Approach for Importance Evaluation of Multimodal Breast Cancer Radiomic Features.

Breast cancer holds the highest diagnosis rate among female tumors and is the leading cause of death among women. Quantitative analysis of radiological images shows the potential to address several medical challenges, including the early detection and classification of breast tumors. In the P.I.N.K study, 66 women were enrolled. Their paired Automated Breast Volume Scanner (ABVS) and Digital Breast Tomosynthesis (DBT) images, annotated with cancerous lesions, populated the first ABVS+DBT dataset. This enabled not only a radiomic analysis for the malignant vs. benign breast cancer classification, but also the comparison of the two modalities. For this purpose, the models were trained using a leave-one-out nested cross-validation strategy combined with a proper threshold selection approach. This approach provides statistically significant results even with medium-sized data sets. Additionally it provides distributional variables of importance, thus identifying the most informative radiomic features. The analysis proved the predictive capacity of radiomic models even using a reduced number of features. Indeed, from tomography we achieved AUC-ROC 89.9 % using 19 features and 92.1 % using 7 of them; while from ABVS we attained an AUC-ROC of 72.3 % using 22 features and 85.8 % using only 3 features. Although the predictive power of DBT outperforms ABVS, when comparing the predictions at the patient level, only 8.7% of lesions are misclassified by both methods, suggesting a partial complementarity. Notably, promising results (AUC-ROC ABVS-DBT 71.8 % - 74.1 % ) were achieved using non-geometric features, thus opening the way to the integration of virtual biopsy in medical routine.

Liver Regeneration and Immunity: A Tale to Tell.

The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.

Promote Community Engagement in Participatory Research for Improving Breast Cancer Prevention: The P.I.N.K. Study Framework.

Breast cancer (BC) has overtaken lung cancer as the most common cancer in the world and the projected incidence rates show a further increase. Early detection through population screening remains the cornerstone of BC control, but a progressive change from early diagnosis only-based to a personalized preventive and risk-reducing approach is widely debated. Risk-stratification models, which also include personal lifestyle risk factors, are under evaluation, although the documentation burden to gather population-based data is relevant and traditional data collection methods show some limitations. This paper provides the preliminary results from the analysis of clinical data provided by radiologists and lifestyle data collected using self-administered questionnaires from 5601 post-menopausal women. The weight of the combinations of women's personal features and lifestyle habits on the BC risk were estimated by combining a model-driven and a data-driven approach to analysis. The weight of each factor on cancer occurrence was assessed using a logistic model. Additionally, communities of women sharing common features were identified and combined in risk profiles using social network analysis techniques. Our results suggest that preventive programs focused on increasing physical activity should be widely promoted, in particular among the oldest women. Additionally, current findings suggest that pregnancy, breast-feeding, salt limitation, and oral contraception use could have different effects on cancer risk, based on the overall woman's risk profile. To overcome the limitations of our data, this work also introduces a mobile health tool, the Dress-PINK, designed to collect real patients' data in an innovative way for improving women's response rate, data accuracy, and completeness as well as the timeliness of data availability. Finally, the tool provides tailored prevention messages to promote critical consciousness, critical thinking, and increased health literacy among the general population.

The Four Homeostasis Knights: In Balance upon Post-Translational Modifications.

A cancer outcome is a multifactorial event that comes from both exogenous injuries and an endogenous predisposing background. The healthy state is guaranteed by the fine-tuning of genes controlling cell proliferation, differentiation, and development, whose alteration induces cellular behavioral changes finally leading to cancer. The function of proteins in cells and tissues is controlled at both the transcriptional and translational level, and the mechanism allowing them to carry out their functions is not only a matter of level. A major challenge to the cell is to guarantee that proteins are made, folded, assembled and delivered to function properly, like and even more than other proteins when referring to oncogenes and onco-suppressors products. Over genetic, epigenetic, transcriptional, and translational control, protein synthesis depends on additional steps of regulation. Post-translational modifications are reversible and dynamic processes that allow the cell to rapidly modulate protein amounts and function. Among them, ubiquitination and ubiquitin-like modifications modulate the stability and control the activity of most of the proteins that manage cell cycle, immune responses, apoptosis, and senescence. The crosstalk between ubiquitination and ubiquitin-like modifications and post-translational modifications is a keystone to quickly update the activation state of many proteins responsible for the orchestration of cell metabolism. In this light, the correct activity of post-translational machinery is essential to prevent the development of cancer. Here we summarize the main post-translational modifications engaged in controlling the activity of the principal oncogenes and tumor suppressors genes involved in the development of most human cancers.

Participation in Low Back Pain Management: It Is Time for the To-Be Scenarios in Digital Public Health.

Low back pain (LBP) carries a high risk of chronicization and disability, greatly impacting the overall demand for care and costs, and its treatment is at risk of scarce adherence. This work introduces a new scenario based on the use of a mobile health tool, the Dress-KINESIS, to support the traditional rehabilitation approach. The tool proposes targeted self-manageable exercise plans for improving pain and disability, but it also monitors their efficacy. Since LBP prevention is the key strategy, the tool also collects real-patient syndromic information, shares valid educational messages and fosters self-determined motivation to exercise. Our analysis is based on a comparison of the performance of the traditional rehabilitation process for non-specific LBP patients and some different scenarios, designed by including the Dress-KINESIS's support in the original process. The results of the simulations show that the integrated approach leads to a better capacity for taking on patients while maintaining the same physiotherapists' effort and costs, and it decreases healthcare costs during the two years following LBP onset. These findings suggest that the healthcare system should shift the paradigm towards citizens' participation and the digital support, with the aim of improving its efficiency and citizens' quality of life.

Epidemiology of SARS-CoV-2 Infection in Italy Using Real-World Data: Methodology and Cohort Description of the Second Phase of Web-Based EPICOVID19 Study.

Digital technologies have been extensively employed in response to the SARS-CoV-2 pandemic worldwide. This study describes the methodology of the two-phase internet-based EPICOVID19 survey, and the characteristics of the adult volunteer respondents who lived in Italy during the first (April-May 2020) and the second wave (January-February 2021) of the epidemic. Validated scales and ad hoc questionnaires were used to collect socio-demographic, medical and behavioural characteristics, as well as information on COVID-19. Among those who provided email addresses during phase I (105,355), 41,473 participated in phase II (mean age 50.7 years ± 13.5 SD, 60.6% females). After a median follow-up of ten months, 52.8% had undergone nasopharyngeal swab (NPS) testing and 13.2% had a positive result. More than 40% had undergone serological test (ST) and 11.9% were positive. Out of the 2073 participants with at least one positive ST, 72.8% had only negative results from NPS or never performed it. These results indicate that a large fraction of individuals remained undiagnosed, possibly contributing to the spread of the virus in the community. Participatory online surveys offer a unique opportunity to collect relevant data at individual level from large samples during confinement.

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy.

Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1-dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

Facing the National Recovery and Resilience Plan: Sources of Data, Indicators, and Participatory Strategies in Healthcare and Social Fields.

Innovation in governance and services should be the target of the Italian National Recovery and Resilience Plan. Monitoring processes, impacts, and outcomes requires a system of new indicators that are practical to collect. Secondary data sources, their availability, and their information potential should be evaluated, and primary sources should be implemented to supplement traditional disease surveillance. This work highlights the most relevant aspects for bridging the mismatching between complex community needs and current health/social supply and how those aspects could be faced. As a result, we propose a structured multi-phases process for setting the design and functionalities of a cooperative information system, built on the integration between secondary and primary data for informing policies about chronic low back pain (CLBP), a widely recognized determinant of disability and significant economic burden. In particular, we propose the Dress-KINESIS, a tool for improving community capacity development and participation that allows one to freely collect big health and social data and link it to existing secondary data. The system also may be able to monitor how the resources are distributed across different care sectors and suggest how to improve efficiency based on the patient's CLBP risk stratification. Moreover, it is potentially customizable in other fields of health.

Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity.

Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.

Hops/Tmub1 Heterozygous Mouse Shows Haploinsufficiency Effect in Influencing p53-Mediated Apoptosis.

HOPS is a ubiquitin-like protein implicated in many aspects of cellular function including the regulation of mitotic activity, proliferation, and cellular stress responses. In this study, we focused on the complex relationship between HOPS and the tumor suppressor p53, investigating both transcriptional and non-transcriptional p53 responses. Here, we demonstrated that Hops heterozygous mice and mouse embryonic fibroblasts exhibit an impaired DNA-damage response to etoposide-induced double-strand breaks when compared to wild-type genes. Specifically, alterations in HOPS levels caused significant defects in the induction of apoptosis, including a reduction in p53 protein level and percentage of apoptotic cells. We also analyzed the effect of reduced HOPS levels on the DNA-damage response by examining the transcript profiles of p53-dependent genes, showing a suggestive deregulation of the mRNA levels for a number of p53-dependent genes. Taken together, these results show an interesting haploinsufficiency effect mediated by Hops monoallelic deletion, which appears to be enough to destabilize the p53 protein and its functions. Finally, these data indicate a novel role for Hops as a tumor-suppressor gene in DNA damage repair in mammalian cells.

INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer.

Non-small-cell-lung cancer accounts for 80-85% of all forms of lung cancer as leading cause of cancer-related death in human. Despite remarkable advances in the diagnosis and therapy of lung cancer, no significant improvements have thus far been achieved in terms of patients' prognosis. Here, we investigated the role of INSL4 - a member of the relaxin-family - in NSCLC. We overexpressed INSL4 in NSCLC cells to analyse in vitro the growth rate and the tumourigenic features. We investigated the signalling pathways engaged in INSL4 overexpressing cells and the tumour growth ability by studying the tumour development in a patient derived tumour xenograft mouse model. We found an INSL4 cell growth promoting effect in vitro in H1299 cells and in vivo in NOD/SCID mice. Surprisingly, in NSCLC-A549 cells, INSL4 overexpression has not similar effect, despite huge basal INSL4-mRNA expression respect to H1299. The INSL4-mRNA analysis of eight different NSCLC-derived cell lines, revealed highly difference in the INSL4-mRNA amount. Transfection of NSCLC lines with INSL4-Myc showed huge level of INSL4-mRNA with a very low amount of protein expressed. Notably, similar discrepancy has been observed in NSCLC patients. However, in a cohort of NSCLC patients analysing a database, we found a significant inverse correlation between INSL4 expression and Overall Survival. By combining the in vitro and in vivo results, suggest that in patients whose NSCLC adenocarcinoma spontaneously expressed high levels of INSL4 post-transcriptional modifications affecting INSL4 do not allow to assess precision therapy in selected patients without consider protein INSL4 amount.

The P.I.N.K. Study Approach for Supporting Personalized Risk Assessment and Early Diagnosis of Breast Cancer.

Breast cancer is a clear example of excellent survival when it is detected and properly treated in the early stage. Currently, screening of this cancer relies on mammography, which may be integrated by new imaging techniques for more exhaustive evaluation. The Personalized, Integrated, Network, Knowledge (P.I.N.K.) study is a longitudinal multicentric study involving several diagnostic centres across Italy, co-ordinated by the Italian National Research Council and co-funded by the Umberto Veronesi Foundation. Aim of the study is to evaluate the increased diagnostic accuracy in detecting cancers obtained with different combinations of imaging technologies, and find the most effective diagnostic pathway matching the characteristics of an individual patient. The study foresees the enrolment of 50,000 women over the age of 40 years presenting for breast examination and providing informed consent to data handling. So far, the 15 participating centres across Italy have recruited a total of 22,848 patients. Based on the analyses of the first 175 histopathological-proven breast cancers, mammographic sensitivity was estimated to be 61.7% (n = 108 cancers), whereas diagnostic accuracy increased by 35.5% (n = 44 cancers) when mammography was integrated with other imaging modalities (ultrasound and/or digital breast tomosynthesis). Increase was mainly determined by ultrasound alone. Given the ongoing data collection and recruitment, the number of cancers detected is too low to allow any further in-depth analysis to explore links to patient characteristics. Past studies show that the uniform approach of population screening guidelines should be revised in favour of more personalised regimens, where known standards are integrated by imaging techniques most suitable for the individual's characteristics. With the ultimate goal of identifying early breast cancer detection strategies, our preliminary results suggest that integrated diagnostic approach could lead to a paradigm shift from an age-based regimen toward more specific and effective risk-based personalised screening regimens, in order to reduce mortality from breast cancer.

The Circadian Protein PER1 Modulates the Cellular Response to Anticancer Treatments.

The circadian clock driven by the daily light-dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other's expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy.

Functional expression and localisation of HOPS/TMUB1 in mouse lens.

Transparency represents the functional phenotype of eye lens. A number of defined steps including quiescence, proliferation, migration and cell differentiation culminates in cell elongation and organelle degradation, allowing the light to reach the retina. HOPS (Hepatocyte Odd Protein Shuttling)/TMUB1 (Trans Membrane Ubiquitin-like containing protein 1) is a nucleo-cytoplasmic shuttling protein, highly expressed both in vivo and in vitro proliferating systems, bearing a ubiquitin-like domain. The present study shows HOPS expression during the phases of lens cell proliferation and fiber differentiation, and its localisation in lens compartments. In lens, HOPS localises mainly in the nucleus of central epithelial cells. During mitosis, HOPS/TMUB1 shuttles to the cytoplasm and returns to the nucleus at the end of mitosis. The differentiating cells share distinct HOPS/TMUB1 localisation in transitional zone depending on the differentiation phases. HOPS/TMUB1 is observed in lens cortex and nucleus. Here, it is attached to fibers, having a structural function with crystallin proteins, probably acting in the ubiquitin-proteasome system.

Rapid COVID-19 Screening Based on Self-Reported Symptoms: Psychometric Assessment and Validation of the EPICOVID19 Short Diagnostic Scale.

BACKGROUND: Confirmed COVID-19 cases have been registered in more than 200 countries, and as of July 28, 2020, over 16 million cases have been reported to the World Health Organization. This study was conducted during the epidemic peak of COVID-19 in Italy. The early identification of individuals with suspected COVID-19 is critical in immediately quarantining such individuals. Although surveys are widely used for identifying COVID-19 cases, outcomes, and associated risks, no validated epidemiological tool exists for surveying SARS-CoV-2 infection in the general population. OBJECTIVE: We evaluated the capability of self-reported symptoms in discriminating COVID-19 to identify individuals who need to undergo instrumental measurements. We defined and validated a method for identifying a cutoff score. METHODS: Our study is phase II of the EPICOVID19 Italian national survey, which launched in April 2020 and included a convenience sample of 201,121 adults who completed the EPICOVID19 questionnaire. The Phase II questionnaire, which focused on the results of nasopharyngeal swab (NPS) and serological tests, was mailed to all subjects who previously underwent NPS tests. RESULTS: Of 2703 subjects who completed the Phase II questionnaire, 694 (25.7%) were NPS positive. Of the 472 subjects who underwent the immunoglobulin G (IgG) test and 421 who underwent the immunoglobulin M test, 22.9% (108/472) and 11.6% (49/421) tested positive, respectively. Compared to NPS-negative subjects, NPS-positive subjects had a higher incidence of fever (421/694, 60.7% vs 391/2009, 19.5%; P<.001), loss of taste and smell (365/694, 52.6% vs 239/2009, 11.9%; P<.001), and cough (352/694, 50.7% vs 580/2009, 28.9%; P<.001). With regard to subjects who underwent serological tests, IgG-positive subjects had a higher incidence of fever (65/108, 60.2% vs 43/364, 11.8%; P<.001) and pain in muscles/bones/joints (73/108, 67.6% vs 71/364, 19.5%; P<.001) than IgG-negative subjects. An analysis of self-reported COVID-19 symptom items revealed a 1-factor solution, the EPICOVID19 diagnostic scale. The following optimal scores were identified: 1.03 for respiratory problems, 1.07 for chest pain, 0.97 for loss of taste and smell 0.97, and 1.05 for tachycardia (ie, heart palpitations). These were the most important symptoms. For adults aged 18-84 years, the cutoff score was 2.56 (sensitivity: 76.56%; specificity: 68.24%) for NPS-positive subjects and 2.59 (sensitivity: 80.37%; specificity: 80.17%) for IgG-positive subjects. For subjects aged ≥60 years, the cutoff score was 1.28, and accuracy based on the presence of IgG antibodies improved (sensitivity: 88.00%; specificity: 89.58%). CONCLUSIONS: We developed a short diagnostic scale to detect subjects with symptoms that were potentially associated with COVID-19 from a wide population. Our results support the potential of self-reported symptoms in identifying individuals who require immediate clinical evaluations. Although these results come from the Italian pandemic period, this short diagnostic scale could be optimized and tested as a screening tool for future similar pandemics.

The Ins and Outs of HOPS/TMUB1 in biology and pathology.

Liver regeneration represents an outstanding tool to study not only proliferation, but also other important processes such as inflammation, regenerative response or stem cell biology. Several novel genes have been identified as being involved in the proliferation of residual hepatocytes. One of them, HOPS/TMUB1, is proving to be a significant player in the control of proliferation, both contributing to genomic stability and as a partner of essential molecules. HOPS is an ubiquitin-like protein, shuttling from nucleus to cytoplasm, and it is engaged in a number of biological and physiopathological functions. HOPS overexpression in tumour cell lines strongly reduces proliferation, arresting cell cycle in G0 /G1 . HOPS is involved in centrosome assembly and maintenance, and its knockdown causes genomic instability. Moreover, a direct interaction of HOPS with nucleophosmin (NPM) and p19Arf has been established, resulting in proper control of p19Arf stability and localization. These data indicate that HOPS acts as a functional bridge in the interaction between NPM and p19Arf , providing new mechanistic insight into how NPM and p19Arf will oppose cell proliferation. HOPS exerts a control in p53 stability, directing p53 mitochondrial apoptosis and cytoplasmic localization. HOPS plays a direct role as novel post-translational modifier of p53, much like SUMO or NEDD. HOPS is overexpressed in a high number of human tumours in patients affected by large intestinal, CNS, liver and oesophageal tumours. This review highlights HOPS involvement in distinct cellular functions, establishing its role as a key player in cell biology and pathology in a broader context.

Shifting the Paradigm: The Dress-COV Telegram Bot as a Tool for Participatory Medicine.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic management is limited by great uncertainty, for both health systems and citizens. Facing this information gap requires a paradigm shift from traditional approaches to healthcare to the participatory model of improving health. This work describes the design and function of the Doing Risk sElf-assessment and Social health Support for COVID (Dress-COV) system. It aims to establish a lasting link between the user and the tool; thus, enabling modeling of the data to assess individual risk of infection, or developing complications, to improve the individual's self-empowerment. The system uses bot technology of the Telegram application. The risk assessment includes the collection of user responses and the modeling of data by machine learning models, with increasing appropriateness based on the number of users who join the system. The main results reflect: (a) the individual's compliance with the tool; (b) the security and versatility of the architecture; (c) support and promotion of self-management of behavior to accommodate surveillance system delays; (d) the potential to support territorial health providers, e.g., the daily efforts of general practitioners (during this pandemic, as well as in their routine practices). These results are unique to Dress-COV and distinguish our system from classical surveillance applications.

HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6.

HOPS/Tmub1 is a ubiquitously expressed transmembrane ubiquitin-like protein that shuttles between nucleus and cytoplasm during cell cycle progression. HOPS causes cell cycle arrest in G0/G1 phase, an event associated to stabilization of p19Arf, an important tumor suppressor protein. Moreover, HOPS plays an important role in driving centrosomal assembly and maintenance, mitotic spindle proper organization, and ultimately a correct cell division. Recently, HOPS has been described as an important regulator of p53, which acts as modifier, stabilizing p53 half-life and playing a key role in p53 mediating apoptosis after DNA damage. NF-κB is a transcription factor with a central role in many cellular events, including inflammation and apoptosis. Our experiments demonstrate that the transcriptional activity of the p65/RelA NF-κB subunit is regulated by HOPS. Importantly, Hops-/- cells have remarkable alterations of pro-inflammatory responses. Specifically, we found that HOPS enhances NF-κB activation leading to increase transcription of inflammatory mediators, through the reduction of IκBα stability. Notably, this effect is mediated by a direct HOPS binding to the E3 ubiquitin ligase TRAF6, which lessens TRAF6 stability ultimately leading increased IKK complex activation. These findings uncover a previously unidentified function of HOPS/Tmub1 as a novel modulator of TRAF6, regulating inflammatory responses driven by activation of the NF-κB signaling pathway. The comprehension on how HOPS/Tmub1 takes part to the inflammatory processes in vivo and whether this function is important in the control of proliferation and tumorigenesis could establish the basis for the development of novel pharmacological strategies.

HOPS and p53: thick as thieves in life and death.

The oncosuppressor protein p53 plays a major role in transcriptionally controlling the expression of a number of genes, which in turn regulates many functions in response to DNA damage, oncogene triggering, oxidative, and additional cell stresses. A developing area of interest in p53 is the studies related to its cytoplasmic function(s). Many investigations revealed the significant role of p53 in the cytoplasm, acting in a transcriptional-independent manner in important processes related to cell homeostasis such as; apoptosis, autophagy, metabolism control, drug, and oxidative stress response. The studies on cytoplasmic p53 have shown intricate mechanisms by which posttranslational modifications allow p53 to perform its cytoplasmic functions. A number of ubiquitins, deubiquitins, and small ubiquitin-like proteins, have a pivotal role in controlling cytoplasmic stability and localization. Recently, HOPS/TMUB1 a novel small ubiquitin-like protein has been described as a vital molecule stabilizing p53 half-life, directing it to the mitochondria and favoring p53-mediated apoptosis. Furthermore, HOPS/TMUB1 competing with importin-α lessens p53 nuclear localization, thereby increasing cytoplasmic concentration. HOPS/TMUB1 as p53 modifiers could be attractive candidates to elucidate apoptosis or other important transcriptional-independent functions which are key in cancer research in order to develop new therapeutic approaches.