MRE11 nuclease is a central player in signaling and processing DNA damage, and in resolving stalled replication forks. Here, we describe the identification and characterization of new MRE11 inhibitors MU147 and MU1409. Both compounds inhibit MRE11 nuclease more specifically and effectively than the relatively weak state-of-the-art inhibitor mirin. They also abrogate double-strand break repair mechanisms that rely on MRE11 nuclease activity, without impairing ATM activation. Inhibition of MRE11 also impairs nascent strand degradation of stalled replication forks and selectively affects BRCA2-deficient cells. Herein, we illustrate that our newly discovered compounds MU147 and MU1409 can be used as chemical probes to further explore the biological role of MRE11 and support the potential clinical relevance of pharmacological inhibition of this nuclease.
- MeSH
- MRE11 Homologue Protein * metabolism antagonists & inhibitors MeSH
- Enzyme Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Drug Discovery MeSH
- DNA Repair drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Neurons in the CNS lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonizes PI3K signaling by hydrolyzing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores whether increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signaling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioral tests showed significant improvements in paw reaching, grip strength, and ladder-rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscle electromyography. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post SCI.
- MeSH
- Axons metabolism physiology MeSH
- Dependovirus genetics MeSH
- Class I Phosphatidylinositol 3-Kinases metabolism genetics MeSH
- Phosphatidylinositol 3-Kinases metabolism MeSH
- Genetic Vectors genetics MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Neurons metabolism MeSH
- Recovery of Function MeSH
- Spinal Cord Injuries * metabolism therapy genetics MeSH
- Pyramidal Tracts * metabolism MeSH
- Nerve Regeneration * MeSH
- Signal Transduction MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cardiorespiratory signals have long been treated as "noise" in functional magnetic resonance imaging (fMRI) research, with the goal of minimizing their impact to isolate neural activity. However, there is a growing recognition that these signals, once seen as confounding variables, provide valuable insights into brain function and overall health. This shift reflects the dynamic interaction between the cardiovascular, respiratory, and neural systems, which together support brain activity. In this review, we explore the role of cardiorespiratory dynamics-such as heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and changes in blood flow, oxygenation, and carbon dioxide levels-embedded within fMRI signals. These physiological signals reflect critical aspects of neurovascular coupling and are influenced by factors such as physiological stress, breathing patterns, and age-related changes. We also discuss the complexities of distinguishing these signals from neuronal activity in fMRI data, given their significant contribution to signal variability and interactions with cerebrospinal fluid (CSF). Recognizing the influence of these cardiorespiratory dynamics is crucial for improving the interpretation of fMRI data, shedding light on heart-brain and respiratory-brain connections, and enhancing our understanding of circulation, oxygen delivery, and waste elimination within the brain.
BACKGROUND: Accumulating evidence suggests that spontaneous preterm labor is a syndrome caused by multiple pathological processes. The breakdown of maternal-fetal tolerance has been proposed as a key mechanism of idiopathic spontaneous preterm labor, often viewed as a chronic inflammatory process resulting from the maternal immune system's impaired tolerance of the fetus from early pregnancy. Regulatory T cells are crucial for maintaining maternal-fetal tolerance. Even a partial reduction in their levels can disrupt this tolerance, leading to adverse pregnancy outcomes such as preterm labor. Given the complexity of the T lymphocyte-mediated immune response, identifying candidate signaling pathways involved in maternal-fetal tolerance is challenging. However, current literature highlights the importance of the functional and developmental markers FoxP3, CD45RA, Helios, and CD39 due to their immunosuppressive abilities essential for maintaining pregnancy. OBJECTIVE: This study aimed to determine whether changes in numbers of selected regulatory T cell subpopulations in the first trimester are associated with subsequent spontaneous preterm labor. STUDY DESIGN: This prospective study enrolled 43 women with early singleton pregnancies, excluding those with autoimmune diseases, diabetes mellitus (type 1, type 2), primary hypertension, or who had been treated with vaginal progesterone prior to sample collection. We analyzed regulatory T cell subpopulations in maternal circulation using the DURAClone IM T cell kit, focusing on the following subsets: CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-. RESULTS: Among the participants, 7 experienced spontaneous preterm labor between the 23rd and 33rd weeks of gestation, while 36 delivered at term. The preterm group showed a significant reduction in numbers of all analyzed regulatory T cell subpopulations: CD4+CD25+FoxP3+ (median 0.0410×10ˆ9/L vs median 0.0550×10ˆ9/L, P=.0217), CD4+CD25+FoxP3+CD45RA- (median 0.0310×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0216), CD4+CD25+FoxP3+Helios+ (median 0.0270×10ˆ9/L vs median 0.0370×10ˆ9/L, P=.0260), CD4+CD25+FoxP3+CD39- (median 0.0300×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0427). CONCLUSION: Early first trimester alterations in specific regulatory T cell subpopulations, including diminished levels of CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA-, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-, are associated with idiopathic spontaneous preterm labor. These findings suggest that early changes in these lymphocyte subpopulations may be linked to spontaneous preterm birth. This highlights the need for further research to understand the mechanisms underlying regulatory T-cell dynamics and their impact on pregnancy outcomes.
- MeSH
- Leukocyte Common Antigens metabolism MeSH
- Apyrase immunology MeSH
- Antigens, CD immunology MeSH
- Adult MeSH
- Forkhead Transcription Factors * metabolism MeSH
- Humans MeSH
- Young Adult MeSH
- Obstetric Labor, Premature * immunology MeSH
- Prospective Studies MeSH
- Pregnancy Trimester, First immunology MeSH
- T-Lymphocytes, Regulatory * immunology MeSH
- Pregnancy MeSH
- Ikaros Transcription Factor MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Introduction and Importance: Some experimental studies on brain injury associated with traumatic brain injury (TBI) and hypoxic-ischaemic encephalopathy (HIE) reveal a positive effect of hyperbaric oxygen therapy (HBOT). However, in clinical medicine, most of the scientific evidence available in the current literature relates only to TBI. Methods: The primary objective is to empirically assess the efficacy of HBOT in mitigating the symptoms of disability associated with brain injury in children, with a view to elucidating its therapeutic potential and clinical benefits. Outcomes: A total of 21 patients have been treated with HBOT. The mean age was 6±4.6 years. There were 12 cases (57%) of TBI, 8 cases (38%) of HIE and 1 case (5%) of ischaemic stroke. The mean initial Glasgow Coma Scale (GCS) at hospital admission immediately after accident was 3.3±0.9. The mean time from injury to HBOT was 5.2 ± 3.8 weeks. The mean number of HBOT exposures was 10±4.3. The mean GCS pre-HBOT was 10.7±3.7 and 12.3±3.4 (p=0.004) after post-HBOT, respectively. The mean Glasgow Outcome Scale (GOS) was 3.3±0.8 pre-HBOT, and 3.9±1.1 (p<0.001) after post-HBOT, respectively. Eighteen cases were included in response to HBOT assessment. Six cases (33%) were evaluated as large clinically significant response (CSR), 7 cases (39%) were evaluated as partial response with minimally important difference (MID). Five cases (28%) were evaluated as non-response. The results showed better response to HBOT in cases of starting HBOT up to 4 weeks (p=0.02) after the injury. There was no serious HBOT-related complication or injury. Conclusion: Results of our study demonstrate both clinical and statistically significant patient response to HBOT. Our data also suggest that the earlier HBOT started after diagnosis up to 4 weeks, the more pronounced patients' response to HBOT was achieved. The provision of HBOT to pediatric patients is feasible in large regional hyperbaric centers.
- MeSH
- Child MeSH
- Glasgow Coma Scale * MeSH
- Glasgow Outcome Scale MeSH
- Hyperbaric Oxygenation * methods MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Hypoxia-Ischemia, Brain * therapy MeSH
- Brain Injuries therapy MeSH
- Child, Preschool MeSH
- Retrospective Studies MeSH
- Brain Injuries, Traumatic therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: Systematic review and meta-analysis on laboratory studies aimed to answer whether there is a difference in fracture resistance and fracture mode of structurally compromised teeth restored with direct composite restorations reinforced with short glass-fiber or bidirectional polyethylene fiber substructure, and between the two different fiber-reinforcement types. METHODS: An electronic literature search was conducted in Medline, Scopus, Web of Science, Lilacs, Google Scholar, Cochrane Library, and University Library databases. The last search was conducted on 16 November 2023. Only studies looking at Ribbond-reinforced restorations and/ or the use of EverX Posterior within restorations were included. Data were categorized and analyzed based on specific outcome measures including fracture resistance and fracture mode. Data from individual studies were divided into premolars and molars for each material category and then collated to compare the mean differences in fracture resistance between control groups (composite restorations) and intervention groups (fiber-reinforced composite restorations). RESULTS: From the initial 1266 articles identified, 23 laboratory-based studies were included for quantitative analysis. Twenty articles had an overall low risk of bias and 3 had an overall unclear risk of bias. The pooled estimate of the effect favored the intervention groups as having statistically significant higher fracture resistance when compared to control groups. CONCLUSIONS: Both fiber types improve fracture resistance and the fracture mode of structurally compromised teeth is equally efficient. Application technique deserves attention. Ribbond could be placed in a single layer at the cavity floor, whereas EverX Posterior should replace missing dentin in an anatomically shaped way.
- MeSH
- Tooth Fractures * prevention & control MeSH
- Humans MeSH
- Polyethylenes MeSH
- Glass chemistry MeSH
- Composite Resins * therapeutic use chemistry MeSH
- Dental Restoration, Permanent * methods MeSH
- Dental Materials chemistry MeSH
- Dental Restoration Failure MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Research Support, Non-U.S. Gov't MeSH
- Systematic Review MeSH
IMPORTANCE: Advancements in molecular engineering have facilitated the creation of engineered T cells that express synthetic receptors, termed chimeric antigen receptors (CARs). This is promising not only in cancer treatment but also in addressing a spectrum of other conditions. This review provides a comprehensive overview of the current approaches and future potential of CAR T-cell therapy in the field of neurology, particularly for primary brain tumors and autoimmune neurological disorders. OBSERVATIONS: CAR T-cell therapy for glioblastoma is promising; however, first-in-human trials did not yield significant success or showed only limited success in a subset of patients. To date, the efficacy of CAR T-cell therapies has been demonstrated in animal models of multiple sclerosis, but larger human studies to corroborate the efficacy remain pending. CAR T cells showed efficacy in treatment of patients with relapsed or refractory aquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorders. Further studies with larger patient populations are needed to confirm these results. Success was reported also for treatment of cases with generalized myasthenia gravis using CAR T cells. Chimeric autoantibody receptor T cells, representing a modified form of CAR T cells directed against autoreactive B cells secreting autoantibodies, were used to selectively target autoreactive anti-N-methyl-d-aspartate B cells under in vitro and in vivo conditions, providing the basis for human studies and application to other types of autoimmune encephalitis associated with neuronal or glial antibodies. CONCLUSIONS AND RELEVANCE: CAR T cells herald a new era in the therapeutic landscape of neurological disorders. While their application in solid tumors, such as glioblastoma, has not universally yielded robust success, emerging innovative strategies show promise, and there is optimism for their effectiveness in certain autoimmune neurological disorders.
- MeSH
- Receptors, Chimeric Antigen * immunology MeSH
- Glioblastoma therapy immunology MeSH
- Immunotherapy, Adoptive methods trends MeSH
- Humans MeSH
- Brain Neoplasms therapy immunology MeSH
- Neurology trends methods MeSH
- Receptors, Antigen, T-Cell immunology MeSH
- T-Lymphocytes immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
IMPORTANCE: International guidelines lack consistency in their recommendations regarding routine imaging in the follow-up after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). Consequently, follow-up strategies differ between centers worldwide. OBJECTIVE: To compare clinical outcomes, including recurrence-focused treatment and survival, in patients with PDAC recurrence who received symptomatic follow-up or routine imaging after pancreatic resection in international centers affiliated with the European-African Hepato-Pancreato-Biliary Association (E-AHPBA). DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, international, cross-sectional study. Patients from a total of 33 E-AHPBA centers from 13 countries were included between 2020 and 2021. According to the predefined study protocol, patients who underwent PDAC resection and were diagnosed with disease recurrence were prospectively included. Patients were stratified according to postoperative follow-up strategy: symptomatic follow-up (ie, without routine imaging) or routine imaging. EXPOSURES: Symptomatic follow-up or routine imaging in patients who underwent PDAC resection. MAIN OUTCOMES AND MEASURES: Overall survival (OS) was estimated with Kaplan-Meier curves and compared using the log-rank test. To adjust for potential confounders, multivariable logistic regression was used to evaluate the association between follow-up strategy and recurrence-focused treatment. Multivariable Cox proportional hazard analysis was used to study the independent association between follow-up strategy and OS. RESULTS: Overall, 333 patients (mean [SD] age, 65 [11] years; 184 male [55%]) with PDAC recurrence were included. Median (IQR) follow-up at time of analysis 2 years after inclusion of the last patient was 40 (30-58) months. Of the total cohort, 98 patients (29%) received symptomatic follow-up, and 235 patients (71%) received routine imaging. OS was 23 months (95% CI, 19-29 months) vs 28 months (95% CI, 24-30 months) in the groups who received symptomatic follow-up vs routine imaging, respectively (P = .01). Routine imaging was associated with receiving recurrence-focused treatment (adjusted odds ratio, 2.57; 95% CI, 1.22-5.41; P = .01) and prolonged OS (adjusted hazard ratio, 0.75; 95% CI, 0.56-.99; P = .04). CONCLUSION AND RELEVANCE: In this international, prospective, cross-sectional study, routine follow-up imaging after pancreatic resection for PDAC was independently associated with receiving recurrence-focused treatment and prolonged OS.
- MeSH
- Carcinoma, Pancreatic Ductal * surgery mortality diagnostic imaging pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local * MeSH
- Survival Rate MeSH
- Pancreatic Neoplasms * surgery mortality MeSH
- Follow-Up Studies MeSH
- Pancreatectomy * MeSH
- Prospective Studies MeSH
- Cross-Sectional Studies MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
STUDY OBJECTIVES: Sleep-disordered breathing and diabetes mellitus (DM) are often concomitant; however, data on the impact of sleep-disordered breathing on mortality in the population with diabetes remain scarce. METHODS: The population from the Sleep Heart Health Study, a multicenter prospective observational study representing 5,780 patients with polysomnography and mortality data, including 453 patients with DM, was analyzed to assess the impact of sleep-disordered breathing variables and the presence of DM on all-cause, cardiovascular disease, and noncardiovascular disease associated mortality. Survival analysis and proportional hazard regression models were used to calculate the adjusted hazard ratios (aHRs) for mortality. RESULTS: Patients with DM and the average oxygen saturation > 91.4% had significantly lower all-cause (aHR 0.52, confidence interval [CI] 0.34-0.80) and cardiovascular disease mortality risk (aHR 0.44, CI 0.22-0.87) as compared with patients with oxygen saturation below this value. Apnea-hypopnea index > 31 (aHR 1.58, CI 1.10-2.28) and oxygen desaturation index > 13.3 (aHR 1.58, CI 1.10-2.25) were associated with increased all-cause mortality in participants with DM on treatment. Sleep efficiency and proportion of rapid eye movement sleep did not have any impact on mortality in patients with DM and thus differed significantly from individuals without DM, where increased all-cause mortality was observed in those with sleep efficiency < 81.4% (aHR 0.77, CI 0.68-0.87) or rapid eye movement sleep < 14.9% (aHR 0.78, CI 0.68-0.89). CONCLUSIONS: Patients with diabetes on treatment and moderate to severe sleep-disordered breathing experience increased all-cause mortality. Reduced average oxygen saturation predicted both all-cause and cardiovascular death in the population with diabetes. CITATION: Vichova T, Petras M, Waldauf P, Westlake K, Vimmerova-Lattova Z, Polak J. Sleep-disordered breathing increases mortality in patients with diabetes. J Clin Sleep Med. 2025;21(1):89-99.
- MeSH
- Diabetes Mellitus * mortality epidemiology MeSH
- Cardiovascular Diseases mortality MeSH
- Middle Aged MeSH
- Humans MeSH
- Polysomnography * statistics & numerical data MeSH
- Prospective Studies MeSH
- Aged MeSH
- Sleep Apnea Syndromes * mortality complications MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
INTRODUCTION AND OBJECTIVES: Type 1 diabetes is an autoimmune disease that destroys insulin-producing cells in the pancreas. Education is the cornerstone of effective diabetes care. In this implementation project, we aimed to improve compliance with best practices regarding type 1 diabetes educational interventions for adult hospitalized patients. METHODS: This project was guided by the JBI Evidence Implementation Framework. A baseline audit was conducted involving 20 nurses and 20 type 1 diabetes patients who received regular educational measures. Areas of non-compliance were identified and an improvement strategy was implemented. A follow-up audit was then conducted to evaluate the effectiveness of the improvement strategy. The project was conducted in Poland in 2021 in a tertiary referral unit that specializes in the diagnosis and treatment of diabetes. RESULTS: Substantial improvements were noted for all audit criteria after the implementation of strategies to address areas of non-compliance. Use of the education program improved from 0% to 100%. Compliance regarding patients receiving handouts and personalization of the program increased to 100%. We observed a significant improvement from 0% to 80% in the structuring of the program content. CONCLUSIONS: This project successfully improved the quality of education provided for type 1 diabetes patients in all relevant areas. We devised an education program, covering important aspects of diabetes education, with the patients reporting increased satisfaction with the personalized educational measures during their hospital stay. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A215.
- MeSH
- Diabetes Mellitus, Type 1 * therapy MeSH
- Adult MeSH
- Evidence-Based Practice MeSH
- Middle Aged MeSH
- Humans MeSH
- Patient Education as Topic * methods MeSH
- Quality Improvement MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Poland MeSH
