Search

Introduction: CACNA1A -related Hemiplegic Migraine (HM) is a rare neurological disorder distinguished by paroxysmal episodes of hemiparesis/hemiplegia with and without headache. Clinical features have been widely characterized, yet the impacts of the paroxysmal events on the patient and caregiver have not been thoroughly explored. Disease concept models are formal frameworks used to describe the lived experiences of patients and their families, offering a source for surrogate endpoints for clinical trials. Methods: We completed 13 semi-structured interviews with caregivers of 12 individuals diagnosed with CACNA1A -related HM. We methodically coded themes, grouping concepts into three domains. We measured the occurrence of concepts throughout all interviews and subgroups stratified by age categories. Results: Over 11 h of interviews yielded 2,018 references to 27 distinct concepts. Established symptoms such as seizures (87 references; including status epilepticus 27 references), hemiparesis/hemiplegia (24 references), and unconsciousness (17 references) were referenced, as well as previously underreported symptoms such as apneic episodes (32 references), lost ability to eat (13 references), and vascular access challenges (10 references). The symptom impacts were largely medical (294 references), followed by health (101 references), emotional (36 references), daily living (28 references), and social (26 references). Caregiver impacts were the most referenced domain (995 references), with the pivotal effects seen in caregiver requirements (355 references), emotional (245 references), HM treatments (179 references), daily living (148 references), and health support (135 references). Discussion: CACNA1A -related HM is a complex disorder defined by serious paroxysmal events that affects a broad range of social and clinical domains. We systematically classified symptoms and impacts from HM episodes, creating a disease concept model to help develop surrogate endpoints for future clinical trials, and identified two opportunities to improve patient management, including a written emergency protocol and a transition plan for adolescents approaching adulthood. [ABSTRACT FROM AUTHOR]

Simple Summary: This research examines how the loss of the Y chromosome (LoY) in men may contribute to the development and progression of certain cancers, particularly in the urinary system. Traditionally, the Y chromosome was primarily associated with male sex determination and sperm production, but recent studies suggest it plays a wider role in health and disease. LoY appears to disrupt immune function and increase genetic instability, factors that may heighten cancer risk and impact treatment outcomes. Our review highlights that LoY could serve as an early indicator of certain cancers and might help predict cancer behavior. Understanding LoY's role could lead to new diagnostic tools and treatments, especially for cancers where Y chromosome alterations are linked to poorer outcomes. Background: The Y chromosome (ChrY) is essential for male sex determination and spermatogenesis. However, recent studies have revealed its broader role in various physiological processes and disease susceptibility, including cancer. Methods: A comprehensive literature review was conducted using databases like MEDLINE, Scopus, Web of Science, and Google Scholar. The review included clinical and preclinical studies in animals and humans focusing on the role of LoY in urological tumors. Data on the frequency of LoY, its clinical implications, and underlying mechanisms were extracted and analyzed. Results: The evidence suggests that LoY is associated with an increased risk of urologic neoplasms, potentially serving as an early marker of genomic instability. Studies reveal that LoY in urologic cancers correlates with worse survival outcomes and may contribute to tumor progression. LoY may interfere with chromatin structure and epigenetic regulation, suggesting its role as a contributor to early tumorigenesis. Conclusions: LoY appears to be a structural aberration with unique biological and clinical relevance in urologic cancers, possibly serving as a biomarker for genomic instability. Further research is necessary to identify specific Y-linked genes affected by LoY, potentially informing targeted therapies and early diagnostic strategies for these cancers. [ABSTRACT FROM AUTHOR]

Background: Substance use disorder in the United States represents a complex and growing public health crisis, marked by increasing rates of overdose deaths and the misuse of prescription medications. There is a critical need for furthering the understanding of the molecular and genetic mechanisms that can lead to substance use disorder. Identifying significant variants in the kynurenine pathway could help identify therapeutic targets for intervention. Methods: The All of Us cohort builder evaluated the frequency of variants of four genes, TDO2, IDO1, IDO2, and KMO, encoding enzymes in the kynurenine pathway. The samples were broken into six cohorts: alcohol, cannabis, cocaine, opioid, other use disorder, and control. Using Chi-square analysis, the frequency of at least one copy of a variant allele was calculated. Results: Chi-square analysis showed a significant variation in genetic frequency (p-value < 0.005) in 14 of 18 polymorphisms analyzed. The cocaine cohort had the most significant variants (13), cannabis had 11, opioids had 3, other use disorders had 2, and alcohol had 1 significant variant. Conclusions: This study found associations of polymorphisms in the TDO2, IDO1, IDO2, and KMO genes of individuals with a substance use disorder. These results provide evidence of potential predictors of increased susceptibility to substance use disorder. [ABSTRACT FROM AUTHOR]

Background: PhenoMetaboDiff is a novel R package for computational analysis and visualization of data generated by Biolog Phenotype Mammalian Microarrays (PM-Ms). These arrays measure the energy production of mammalian cells in different metabolic environments, assess the metabolic activity of cells exposed to various drugs or energy sources, and compare the metabolic profiles of cells from individuals affected by specific disorders versus healthy controls. Methods: PhenoMetaboDiff has several modules that facilitate statistical analysis by sample comparisons using non-parametric Mann–Whitney U-test, the integration of the OPM package (an R package for analysing OmniLog® phenotype microarray data) for robust file conversion, and calculation of slope and area under the curve (AUC). In addition, the built-in visualization allows specific wells to be visualized in selected pathways for a particular time slice. Results: Compared to the standard OPM package, the features developed in PhenoMetaboDiff assess metabolic profiles by employing statistical tests and visualize the dynamic nature of the energy production in several conditions. Examples of how this package can be used are demonstrated for several rare disease conditions. The incorporation of a graphical user interface expands the utility of this program to both expert and novice users of R. Conclusions: PhenoMetaboDiff makes the deployment of the cutting-edge Biolog system available to any researcher. [ABSTRACT FROM AUTHOR]

Background/Objectives: Substance use disorder is a crisis impacting many people in the United States. This review aimed to identify the effect addictive substances have on the kynurenine pathway. Tryptophan is an essential amino acid metabolized by the serotonin and kynurenine pathways. The metabolites of these pathways play a role in the biological reward system. Addictive substances have been shown to cause imbalances in the ratios of these metabolites. With current treatment and therapeutic options being suboptimal, identifying biochemical mechanisms that are impacted during the use of addictive substances can provide alternative options for treatment or drug discovery. Methods: A systematic literature search was conducted to identify studies evaluating the relationship between substance use disorder and tryptophan metabolism through the kynurenine pathway. A total of 32 articles meeting eligibility criteria were used to review the relationship between the kynurenine pathway, tryptophan breakdown, and addictive substances. Results: The use of addictive substances dysregulates tryptophan metabolism and kynurenine metabolite concentrations. This imbalance directly affects the dopamine reward system and is thought to promote continued substance use. Conclusions: Further studies are needed to fully evaluate the metabolites of the kynurenine pathway, along with other options for treatment to repair the metabolite imbalance. Several possible therapeutics have been identified; drugs that restore homeostasis, such as Ro 61-8048 and natural products like Tinospora cordifolia or Decaisnea insignis, are promising options for the treatment of substance use disorder. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is characterized by persistent inflammation and is often associated with metabolic dysfunction-associated steatotic liver disease (MASLD). IBD patients are at risk of developing MASLD due to shared risk factors such as gut dysbiosis and systemic inflammation. The new MASLD nomenclature emphasizes the link between liver steatosis and cardiometabolic comorbidities. However, the prevalence of MASLD in IBD patients remains poorly explored. The main aim of this cross-sectional study is to assess the prevalence of ultrasound (US) and the clinical features of MASLD in patients with IBDs. Materials and Methods: We conducted a retrospective study enrolling 272 Italian IBD patients attending Renato Dulbecco Teaching Hospital in a period between 1 January 2021 and 31 December 2023. MASLD was diagnosed based on the presence of liver steatosis with cardiometabolic risk factors, using established guidelines. Demographic, clinical, and laboratory data were collected and analyzed. Statistical significance was determined at a p-value < 0.05. Results: Of the 272 IBD patients, 6% had non-alcoholic fatty liver disease (NAFLD), while 18% had MASLD. Patients with IBD-MASLD were significantly older, had higher body mass index, waist circumference, and triglyceride levels, and were more likely to have type 2 diabetes mellitus and hypertension compared to those with IBD-NAFLD. IBD-MASLD patients also showed higher disease activity scores and required more frequent surgical interventions. Bivariate logistic regression revealed triglyceride levels as a significant predictor of MASLD in IBD patients. Conclusions: MASLD is more prevalent in IBD patients, highlighting the importance of early detection of liver steatosis in this at-risk population. The association between MASLD and cardiometabolic risk factors underscores the need for a multidisciplinary approach to manage these patients effectively. Further studies in larger cohorts are necessary to confirm these findings and explore the pathophysiological mechanisms involved. [ABSTRACT FROM AUTHOR]

This critical review investigates the impact of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations on survival outcomes in non-small cell lung cancer (NSCLC) through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. In addition, this review explores the clinicopathologic characteristics of SMARCA4 mutations and their impact on various treatment modalities, including immune checkpoint inhibitors (ICIs) both with and without Kirsten rat sarcoma viral oncogene homolog (KRAS) co-mutations. The potential ineffectiveness of ICI treatment in NSCLC is explored through the impact of SMARCA4/KRAS co-mutations on the tumor microenvironment. Moreover, this NSCLC review consistently reported statistically worse overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT), and KRAS G12C inhibitors. Designing prospective clinical SMARCA4-mutated or SMARCA4/KRAS co-mutated NSCLC trials to evaluate targeted therapies and immunotherapy may lead to a better understanding of how to improve cancer patients' outcomes and survival rates. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic emphasized an urgent need for devices used in the self-collection of biospecimens in an evolving patient care system. The mailing of biospecimen self-collection kits to patients, with samples returned via mail, provides a more convenient testing regimen, but could also impart patient sampling variabilities. User compliance with device directions is central to downstream testing of collected biospecimens and clear instructions are central to this goal. Methods: Here, we performed an evaluation of 10 oral DNA collection devices involving either swab or saliva selfcollection and analyzed ease of use and comfort level with a device, as well as DNA recovery quantity/quality and sample stability. Results: We show that while these DNA quality/quantity metrics are comparable between devices, users prefer direct saliva collection over swab-based devices. Conclusions: This information is useful in guiding future experiments including their use in human RNA, microbial, or viral sample collection/recovery and their use in clinical testing. [ABSTRACT FROM AUTHOR]

Context.--The novel coronavirus disease 2019 (COVID-19) pandemic is significantly changing methodologic approaches in all branches of the health system. From a forensic point of view, this event is partly changing the manner in which forensic pathologists and all those who work in autopsy services operate, but above all, it is changing the patterns established for years by which cadavers are analyzed postmortem. Objective.--To present a review of the literature and a proposal for COVID-19 autopsy protocols. To contain the infection risk, a revision of all the protocols that until now have been applied to the examination of bodies that require autopsy services is required. Data Sources.--Currently, the diagnosis and postmortem analysis of positive or suspected COVID-19 cases plays a crucial role in scientific research. A review of the main recommendations proposed by international scien tific societies regarding the risk of infection during autopsy was carried out. Scientific papers currently available via the PubMed NCBI search engine on COVID-19 postmortem diagnosis were also examined. Conclusions.--Throughout the history of medicine, autopsy has been fundamental to the understanding of multiple pathogenic processes that are investigated postmortem. The purpose of the study is to propose an operating protocol that can be useful for all clinical and forensic autopsies, with particular reference to the correct methods to be applied to the examination of positive or suspected COVID-19 cases, regarding both the autopsy procedure and the collection and analysis of biological samples. (Arch Pathol Lab Med. 2020;144:1048-1056; doi: 10.5858/arpa.2020-0165-SA), Coronaviruses (Coronaviridae) are a large family of microorganisms existing in nature in the form of positive-strand RNA viruses that infect vertebrates. (1,2) The family includes the subfamily Orthocoronavirinae, to which [...]

The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1‐TPDS1) and a neurodevelopmental disorder known as Kury‐Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype–phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI® (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD. [ABSTRACT FROM AUTHOR]

The traditional Mediterranean diet, described for the first time by Ancel Keys in the 1960s, is inspired by the eating habits and traditional foodtypical of southern italy, southern spain, and crete, and currently represents one of the most important dietary health models worldwide. thehigh content of fibers and polyunsaturated fats in cereals, vegetables, legumes and olive oil, which are part of the Mediterranean diet, show anti-inflammatory and antioxidant properties, aim at reducing cellular oxidative stress, responsible for several chronic diseases. Moreover, this dietis characterized by low alcohol intake (mainly red wine) and low amounts of red meat and dairy products. From a nutritional intake perspective,the Mediterranean diet guarantees a correct assumption of proteins (10-15%), carbohydrates (55-60%) and fats (25%). importantly, a strongadherence to this dietary regimen modulates the gut microbiota composition, promote eubiosis and prevents several gut-liver axis diseases. Thepresent narrative review highlights the role of proteins in the Mediterranean diet, showing how plant-derived proteins have a protective effectagainst the development of cardiovascular, intestinal, liver, and metabolic diseases. [ABSTRACT FROM AUTHOR]