Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse model of lymphoma

Background: The genetic origins of chemotherapy resistance are well established; however the role of epigenetics in drug resistance is less well understood To investigate mechanisms of drug resistance we performed systematic genetic epigenetic and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by drug dose escalation   Methods: Dose escalation of the alkylating agent mafosfamide was used to create a series of increasingly drugresistant mouse Burkitt's lymphoma cell lines Whole genome sequencing DNA microarrays reduced representation bisulfite sequencing and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence mRNA expression CpG methylation and H3K27me3 occupancy respectively that were associated with increased resistance   Results: Our data suggest that acquired resistance cannot be explained by genetic alterations Based on integration of transcriptional profiles with transcription factor binding data we hypothesize that resistance is driven by epigenetic plasticity We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines Moreover we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance By integrating our results with data from the Immunological Genome Project (Immgenorg) we showed that these transcriptional changes track the B-cell maturation axis   Conclusions: Our data suggest a novel mechanism of drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosi

The Parkinson’s disease nurse specialist and subcutaneous apomorphine infusion. A scoping review of the literature

Objective: The aim of this scoping review is to outline the scientific evidence concerning the role of Parkinson’s disease nurse specialists (PDNS) to provide education and guidance to patients with Parkinson’s disease (PD) undergoing subcutaneous apomorphine therapy (CSAI). Introduction: PD affects approximately 1% of both men and women on a global scale, especially those aged 60 and above. Working within a multi-disciplinary team, the PDNS enhances adherence to the treatment regimen, even in a home-based setting. Inclusion criteria: Included studies involved participants over 18 years old, with texts in English or Italian. Exclusions covered research on alternative apomorphine administrations, brain stimulation, comparisons with other treatments, mood changes from apomorphine, or unrelated to PDNS training. Methods: We conducted a comprehensive literature review across databases such as Medline (via PubMed), The Cochrane Library, Scopus, Web of Science (WOS), and Google Scholar, sourcing relevant articles to identify primary indexed studies examining the interaction between nurse practitioners and PD patients undergoing subcutaneous apomorphine treatment; Results: The review encompasses twenty studies, revealing that specialized nursing education and training during the subcutaneous apomorphine therapy phase can effectively mitigate the considerable risks associated with treatment nonadherence. Conclusions: The collaboration of proficient and specialized nursing personnel, working alongside a multidisciplinary team, to deliver suitable training and education during CSAI, is instrumental in averting adverse outcomes and potential nonadherence issues, thereby enhancing the quality of life for both PD patients and their caregivers

Effects of Long COVID on Psycho-Physical Conditions in the Italian Population: A Statistical and Large Language Model Combined Description

Background: Long COVID refers to the persistence or development of signs and symptoms well after the acute phase of COVID-19. Objective of the study: To investigate the long-term outcomes of the SARS-CoV-2 infection in terms of psychological, social, and relational consequences within the Italian population. Materials and methods: We conducted an observational, cross-sectional, and multicenter study using an online questionnaire distributed to a sample of the Italian population. By utilizing the Short Form 12 Health Survey (SF-12) and the Hikikomori scale, we assessed perceived quality of life and social isolation, respectively. The questionnaire also included an open-answer question: “What will you remember about the pandemic period?”. We used generative artificial intelligence to analyze and summarize the corresponding answers. Results: A total of 1097 people participated in this study. A total of 79.3% (n = 870) of participants declared that they had been hospitalized and 62.8% (n = 689) received home care. Physical symptoms included headaches (43%, n = 472) and asthma (30.4%, n = 334). Additionally, 29.2% (n = 320) developed an addiction during the pandemic and, among these, 224 claimed internet addiction while 73 declared an emotional addiction. Furthermore, 51.8% (n = 568) experienced limitations in carrying out daily life activities. According to the Hikikomori scale, participants with positive SARS-CoV-2 infection exhibited higher levels of isolation compared to the others (p < 0.001). Participants without COVID-19 showed higher levels of emotional support (p < 0.001). Our semiautomatic analysis of the open-ended responses, obtained by a procedure based on a free large language model, allowed us to deduce and summarize the main feelings expressed by the interviewees regarding the pandemic. Conclusions: The data collected emphasize the urgent need to investigate the consequences of long COVID in order to implement interventions to support psychological well-being

Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy

Transgenic T-cell receptor (TCR) adoptive cell therapies recognizing tumor antigens are associated with robust initial response rates, but frequent disease relapse. This usually occurs in the setting of poor long-term persistence of cells expressing the transgenic TCR, generated using murine stem cell virus (MSCV) y-retroviral vectors. Analysis of clinical transgenic adoptive cell therapy products in vivo revealed that despite strong persistence of the transgenic TCR DNA sequence over time, its expression was profoundly decreased over time at the RNA and protein levels. Patients with the greatest degrees of expression suppression displayed significant increases in DNA methylation over time within the MSCV promoter region, as well as progressive increases in DNA methylation within the entire MSCV vector over time. These increases in vector methylation occurred independently of its integration site within the host genomes. These results have significant implications for the design of future viral-vector gene engineered adoptive cell transfer therapies

Low Back Pain in Italian Nurses: A Statistical Analysis of Disability and Work Productivity Impairment—An Observational Study

Background: Low back pain (LBP) is a common occupational health issue among nurses, significantly affecting quality of life and work productivity. Despite awareness, it remains a major cause of absenteeism and presenteeism, highlighting the need for targeted interventions. This study aimed to assess the prevalence of LBP among Italian nurses and its impact on quality of life and work productivity. Methods: A cross-sectional, multicenter observational study was conducted from May to October 2024 using an online questionnaire distributed to members of the Provincial Orders of Nursing Professions across Italy. The questionnaire included sociodemographic variables and three validated instruments: the Quebec Back Pain Disability Scale (QBPDS), the Oswestry Disability Index (ODI), and the Work Productivity and Activity Impairment Questionnaire (WPAI). Results: A total of 318 nurses participated, with the majority from Southern Italy (57.1%) and female (74.6%). LBP was reported by 57.5% of respondents. Nurses working in Critical Care and those with 30–40 years of experience had significantly higher QBPDS and ODI scores, indicating moderate disability. Nurses working 12 h shifts and those with job restrictions or medical prescriptions reported significantly higher disability levels (ODI > 29, p < 0.001). Nurses on pharmacological therapy reported moderate pain levels, while those engaging in regular physical activity had significantly lower pain symptoms (<20, p < 0.001). The WPAI results showed that 67.0% of nurses reported impaired work productivity due to LBP. Conclusions: LBP is extremely prevalent among Italian nurses, especially affecting physical well-being and, accordingly, the health care quality provided by them. Factors exacerbating this problem are wrong manual handling of loads, not exercising, poor nutrition, and smoking, as well as wrong posture. Fundamental in order to avoid the occurrence of this problem are preventive programs and ergonomic training

Clinical Features of Takotsubo Syndrome and Its Differential Diagnostic Criteria in Clinical Nursing Practice: A Review of the Literature

Purpose of Review: Takotsubo cardiomyopathy (TCM) is a heart disease that mimics the symptoms of a myocardial infarction (MI). The exact cause of TCM is unknown, but the main theory is that the syndrome is triggered by an excessive release of catecholamines, a consequence of factors related to stress or severe emotional distress. The aim of this review is to summarize the various scientific journal articles on the nursing differential diagnosis of TCM, on the specific nurse training (particularly the role of the Advanced Practice Nurse, APN), and on the nursing educational support for the patient after hospital discharge. Recent Findings: A literature review was conducted on Medline (via PubMed), Web of Science (WoS), Scopus, and Google Scholar databases. Relevant indexed articles that investigated the elements characterizing TCM in nursing differential diagnosis and the role of the APN were identified. Results: Sixteen studies were included in the review; they highlighted the role of the nurse in identifying and educating patients with TCM. Summary: Nurses must have a thorough understanding of the syndrome, the onset symptoms, the unusual characteristics, and the probable etiology of TCM in order to recognize and promptly treat patients affected by this syndrome and have the opportunity to educate them after hospital discharge to reduce the possibility of recurrence

Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia

Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is life threatening and occurs in up to 30% of MRSA bacteremia cases despite appropriate antimicrobial therapy. Isolates of MRSA that cause antibiotic-persistent methicillin-resistant S. aureus bacteremia (APMB) typically have in vitro antibiotic susceptibilities equivalent to those causing antibiotic-resolving methicillin-resistant S. aureus bacteremia (ARMB). Thus, persistence reflects host-pathogen interactions occurring uniquely in context of antibiotic therapy in vivo. However, host factors and mechanisms involved in APMB remain unclear. We compared DNA methylomes in circulating immune cells from patients experiencing APMB vs. ARMB. Overall, methylation signatures diverged in the distinct patient cohorts. Differentially methylated sites intensified proximate to transcription factor binding sites, primarily in enhancer regions. In APMB patients, significant hypomethylation was observed in binding sites for CCAAT enhancer binding protein-β (C/EBPβ) and signal transducer/activator of transcription 1 (STAT1). In contrast, hypomethylation in ARMB patients localized to glucocorticoid receptor and histone acetyltransferase p300 binding sites. These distinct methylation signatures were enriched in neutrophils and achieved a mean area under the curve of 0.85 when used to predict APMB using a classification model. These findings validated by targeted bisulfite sequencing (TBS-seq) differentiate epigenotypes in patients experiencing APMB vs. ARMB and suggest a risk stratification strategy for antibiotic persistence in patients treated for MRSA bacteremia

Variations in the Five Facets of Mindfulness in Italian Oncology Nurses according to Sex, Work Experience in Oncology, and Shift Work

Background: Oncology nurses support cancer patients in meeting their self-care needs, often neglecting their own emotions and self-care needs. This study aims to investigate the variations in the five facets of holistic mindfulness among Italian oncology nurses based on gender, work experience in oncology, and shift work. Method: A cross-sectional study was carried out in 2023 amongst all registered nurses who were employed in an oncology setting and working in Italy. Results: There were no significant differences in all five facets of holistic mindfulness (p ≥ 0.05) according to gender, work experience in the oncology field, and shift work. Conclusion: Could holistic mindfulness be defined as an intrinsic individual characteristic? Surely, more insights will be necessary to better define the holistic trend in oncology nursing

Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence

Complex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation

Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence

Complex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation