Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Diagnostics in Pediatric Brain Tumors: Impact on Diagnosis and Clinical Decision-Making — A Selected Case Series

Abstract Central nervous system (CNS) tumors account for the highest mortality among pediatric malignancies. Accurate diagnosis is essential for optimal clinical management. The increasing use of molecular diagnostics has opened up novel possibilities for more precise classification of CNS tumors. We here report a single-institutional collection of pediatric CNS tumor cases that underwent a refinement or a change of diagnosis after completion of molecular analysis that affected clinical decision-making including the application of molecularly informed targeted therapies. 13 pediatric CNS tumors were analyzed by conventional histology, immunohistochemistry, and molecular diagnostics including DNA methylation profiling in 12 cases, DNA sequencing in 8 cases and RNA sequencing in 3 cases. 3 tumors had a refinement of diagnosis upon molecular testing, and 6 tumors underwent a change of diagnosis. Targeted therapy was initiated in 5 cases. An underlying cancer predisposition syndrome was detected in 5 cases. Although this case series, retrospective and not population based, has its limitations, insight can be gained regarding precision of diagnosis and clinical management of the patients in selected cases. Accuracy of diagnosis was improved in the cases presented here by the addition of molecular diagnostics, impacting clinical management of affected patients, both in the first-line as well as in the follow-up setting. This additional information may support the clinical decision making in the treatment of challenging pediatric CNS tumors. Prospective testing of the clinical value of molecular diagnostics is currently underway.
Post-Exercise Whole Body Cryotherapy (−140 °C) Increases Energy Intake in Athletes

PURPOSE: The purpose of the present study was to investigate the effect of whole-body cryotherapy (WBC) treatment after exercise on appetite regulation and energy intake. METHODS: Twelve male athletes participated in two trials on different days. In both trials, participants performed high-intensity intermittent exercise. After 10 min following the completion of the exercise, they were exposed to a 3-min WBC treatment (−140 °C, WBC trial) or underwent a rest period (CON trial). Blood samples were collected to assess plasma acylated ghrelin, serum leptin, and other metabolic hormone concentrations. Respiratory gas parameters, skin temperature, and ratings of subjective variables were also measured after exercise. At 30 min post-exercise, energy and macronutrient intake were evaluated during an ad libitum buffet meal test. RESULTS: Although appetite-regulating hormones (acylated ghrelin and leptin) significantly changed with exercise (p = 0.047 for acylated ghrelin and p < 0.001 for leptin), no significant differences were observed between the trials. Energy intake during the buffet meal test was significantly higher in the WBC trial (1371 ± 481 kcal) than the CON trial (1106 ± 452 kcal, p = 0.007). CONCLUSION: Cold exposure using WBC following strenuous exercise increased energy intake in male athletes.
Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology

Objective To examine associations of average and change in late-life blood pressure (BP) with cerebrovascular and Alzheimer disease (AD) neuropathology in a large group of decedents followed longitudinally in vivo. Methods This clinical-pathologic study was derived from prospective, community-based cohort studies of aging with similar design and data collection. Measurements of systolic BP (SBP) and diastolic BP (DBP) were obtained annually (mean follow-up 8 years, SD = 4.8). Postmortem neuropathologic evaluations documented diseases of aging. Using regression analyses, we examined associations of average and decline in late-life SBP, and separately in DBP, with neuropathology. Results In 1,288 persons (mean age at death = 88.6 years; 65% women), the mean standardized person-specific SBP across the study was 134 (SD = 13) and DBP was 71 (SD = 8) mm Hg. The odds of brain infarcts were increased for participants with a higher mean SBP. Specifically, a person with a 1 SD SBP above the mean (147 vs 134 mm Hg) would have a 46% increased odds of having one or more infarcts, and an increased odds of gross infarct (46%) and microinfarct (36%). Furthermore, a more rapidly declining SBP slope over time increased the odds of one or more infarcts. Mean DBP, not slope, was related to brain infarcts. AD pathology analyses showed an association of a higher mean SBP with higher number of tangles (p = 0.038) but not plaques or other pathology (all p > 0.06). Changes in BP were not significantly related to AD pathology. Conclusions Higher average late-life SBP and DBP, and independently a faster decline in SBP, are associated with increasing number of brain infarcts, including gross and microinfarcts. We found some evidence for a relation of SBP with AD, specifically tangles. Both average and decline in BP are related to brain disease.
Cell-Derived Viral Genes Evolve under Stronger Purifying Selection in Rhadinoviruses

Viruses and hosts have been shown to capture genes from one another as part of the evolutionary arms race. Such genes offer a natural experiment on the effects of evolutionary pressure, since the same gene exists in vastly different selective environments. However, sequences of viral homologs often bear little similarity to the original sequence, complicating the reconstruction of their shared evolutionary history with host counterparts. In this study, we use a genus of herpesviruses as a model system to comprehensively investigate the evolution of host-derived viral genes, using a synthesis of genomics, phylogenetics, selection analysis, and nucleotide and amino acid modeling. ABSTRACT Like many other large double-stranded DNA (dsDNA) viruses, herpesviruses are known to capture host genes to evade host defenses. Little is known about the detailed natural history of such genes, nor do we fully understand their evolutionary dynamics. A major obstacle is that they are often highly divergent, maintaining very low sequence similarity to host homologs. Here we use the herpesvirus genus Rhadinovirus as a model system to develop an analytical approach that combines complementary evolutionary and bioinformatic techniques, offering results that are both detailed and robust for a range of genes. Using a systematic phylogenetic strategy, we identify the original host lineage of viral genes with high confidence. We show that although host immunomodulatory genes evolve rapidly compared to other host genes, they undergo a clear increase in purifying selection once captured by a virus. To characterize this shift in detail, we developed a novel technique to identify changes in selection pressure that can be attributable to particular domains. These findings will inform us on how viruses develop strategies to evade the immune system, and our synthesis of techniques can be reapplied to other viruses or biological systems with similar analytical challenges. IMPORTANCE Viruses and hosts have been shown to capture genes from one another as part of the evolutionary arms race. Such genes offer a natural experiment on the effects of evolutionary pressure, since the same gene exists in vastly different selective environments. However, sequences of viral homologs often bear little similarity to the original sequence, complicating the reconstruction of their shared evolutionary history with host counterparts. In this study, we use a genus of herpesviruses as a model system to comprehensively investigate the evolution of host-derived viral genes, using a synthesis of genomics, phylogenetics, selection analysis, and nucleotide and amino acid modeling.
Prediction and diversity of tracrRNAs from type II CRISPR-Cas systems

ABSTRACT Type II CRISPR-Cas9 systems require a small RNA called the trans-activating CRISPR RNA (tracrRNA) in order to function. The prediction of these non-coding RNAs in prokaryotic genomes is challenging because they have dissimilar structures, having short stems (3–6 bp) and non-canonical base-pairs e.g. G-A. Much of the tracrRNA is involved in base-pairing interactions with the CRISPR RNA, or itself, or in RNA-protein interactions with Cas9. Here we develop a new bioinformatic tool to predict tracrRNAs. On an experimentally verified test set the algorithm achieved a high sensitivity and specificity, and a low false discovery rate (FDR) on genome analysis. Analysis of representative RefSeq genomes (5462) detected 275 tracrRNAs from 165 genera. These tracrRNAs could be grouped into 15 clusters which were used to build covariance models. These clusters included Streptococci and Staphylococci tracrRNAs from the CRISPR-Cas9 systems which are currently used for gene editing. Compensating base changes observed in the models were consistent with the experimental structures of single guide RNAs (sgRNAs). Other clusters, for which there are not yet structures available, were predicted to form novel tracrRNA folds. These clusters included a large and divergent tracrRNA set from Bacteroidetes. These computational models contribute to the understanding of CRISPR-Cas biology, and will assist in the design of further engineered CRISPR-Cas9 systems. The tracrRNA prediction software is available through a galaxy web server.
A 10-year experience of linear accelerator-based stereotactic radiosurgery/radiotherapy (SRS/SRT) for paraganglioma: A single institution experience and review of the literature.

Objective Patients with paragangliomas were treated with LINAC-SRS/SRT in this retrospective review to evaluate tumor control, clinical control, and toxicity. Methods 16 patients (median age = 65) with paragangliomas were treated with LINAC-SRS/SRT. Patients were treated to a median dose of 25 Gy in 5 Fx and were evaluated for long-term tumor control, symptom control, and toxicity. Median follow-up was 44 months. Results 16 paragangliomas with a median PTV of 11.7 cc were treated as above. All but 2 lesions were controlled at last follow-up, with a 5-year control rate of 88%. Eighty-one percent of patients reported improved or resolved symptoms after treatment. Toxicities included grade 2 vertigo in 1 patient and grade 3 headache from hydrocephalus requiring ventriculoperitoneal shunt. Discussion Linear accelerator based SRS/SRT appears to be an effective treatment option for paragangliomas. Recurrences in this cohort occurred 4-5 years after treatment, highlighting the importance of long term follow up.
Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process

Hot-melt extrusion (HME) is a well-accepted and extensively studied method for preparing numerous types of drug delivery systems and dosage forms. It offers several advantages: no solvents are required, it is easy to scale up and employ on the industrial level, and, in particular, it offers the possibility of improving drug bioavailability. HME involves the mixing of a drug with one or more excipients, in general polymers and even plasticizers, which can melt, often forming a solid dispersion of the drug in the polymer. The molten mass is extruded and cooled, giving rise to a solid material with designed properties. This process, which can be realized using different kinds of special equipment, may involve modifications in the drug physicochemical properties, such as chemical, thermal and mechanical characteristics thus affecting the drug physicochemical stability and bioavailability. During process optimization, the evaluation of the drug solid state and stability is thus of paramount importance to guarantee stable drug properties for the duration of the drug product shelf life. This manuscript reviews the most important physicochemical factors that should be investigated while designing and optimizing a hot melt extrusion process, and by extension, during the different pre-formulation, formulation and process, and post-formulation phases. It offers a comprehensive evaluation of the chemical and thermal stability of extrudates, the solid physical state of extrudates, possible drug-polymer interactions, the miscibility/solubility of the drug-polymer system, the rheological properties of extrudates, the physicomechanical properties of films produced by hot melt extrusion, and drug particle dissolution from extrudates. It draws upon the last ten years of research, extending inquiry as broadly as possible.
CyberKnife® fixed cone and Iris™ defined small radiation fields: Assessment with a high‐resolution solid‐state detector array

Abstract Purpose The challenges of accurate dosimetry for stereotactic radiotherapy (SRT) with small unflattened radiation fields have been widely reported in the literature. In this case, suitable dosimeters would have to offer a submillimeter spatial resolution. The CyberKnife® (Accuray Inc., Sunnyvale, CA, USA) is an SRT‐dedicated linear accelerator (linac), which can deliver treatments with submillimeter positional accuracy using circular fields. Beams are delivered with the desired field size using fixed cones, the InCise™ multileaf collimator or a dynamic variable‐aperture Iris™ collimator. The latter, allowing for field sizes to be varied during treatment delivery, has the potential to decrease treatment time, but its reproducibility in terms of output factors (OFs) and dose profiles (DPs) needs to be verified. Methods A 2D monolithic silicon array detector, the “Octa”, was evaluated for dosimetric quality assurance (QA) for a CyberKnife system. OFs, DPs, percentage depth‐dose (PDD) and tissue maximum ratio (TMR) were investigated, and results were benchmarked against the PTW SRS diode. Cross‐plane, in‐plane and 2 diagonal dose profiles were measured simultaneously with high spatial resolution (0.3 mm). Monte Carlo (MC) simulations with a GEANT4 (GEometry ANd Tracking 4) tool‐kit were added to the study to support the experimental characterization of the detector response. Results For fixed cones and the Iris, for all field sizes investigated in the range between 5 and 60 mm diameter, OFs, PDDs, TMRs, and DPs in terms of FWHM measured by the Octa were accurate within 3% when benchmarked against the SRS diode and MC calculations. Conclusions The Octa was shown to be an accurate dosimeter for measurements with a 6 MV FFF beam delivered with a CyberKnife system. The detector enabled real‐time dosimetric verification for the variable aperture Iris collimator, yielding OFs and DPs consistent with those obtained with alternative methods.
Substance use in pregnancy: The medical challenge

Substance use contributes significantly to the global burden of disease. Growing numbers of women use nicotine, alcohol, and illicit substances. Women are the most vulnerable to problematic substance use in their reproductive years. The first 1000 days of life, starting at conception, have been established as a critical window of time for long-term health and development. Substance use in pregnancy is associated with negative pregnancy and child health outcomes. The impact of antenatal substance use on these outcomes needs to be considered within a challenging and complex context. This review provides an overview of the current literature on the impact of substances on pregnancy and child outcomes as well as the evidence and guidelines on screening and interventions for women using substances during pregnancy.
Management of acute appendicitis in an acute surgical unit: a cost analysis

The acute surgical unit (ASU) model of acute general surgery care offers efficient patient assessment, improved clinical outcomes and has been demonstrated to be cost‐efficient. Despite this, the management of acute appendicitis in our ASU was found to be highly cost‐negative. This study sought to identify the drivers of increased cost.
Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC + CD4+ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage

Combined anti‐retroviral therapy (cART) transformed HIV‐1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV‐induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV‐induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV‐1 infection.
Preeclampsia: risk factors and neonatal outcomes associated with early- versus late-onset diseases

Abstract Objective: This study examined the effects of early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) on short-term maternal and neonatal morbidity, as well as risk factors associated with early-onset and late-onset diseases. Method: This retrospective, cohort study included pregnant women who had been diagnosed with PE during pregnancy. Electronic medical records were reviewed for demographics and medical history, laboratory tests, and delivery data. The women were grouped according to EOPE (<34 weeks) and LOPE (≥34 weeks). Power analysis revealed that a sample size of 35 was sufficient for each PE group, under the assumptions of type I error (two-sided) of 5% and at least 80% power to detect a 30% difference in composite outcomes between EOPE and LOPE. Results: Among 101 patients, 35 (34.7%) had EOPE and 66 (65.3%) developed LOPE. Alpha fetoprotein (AFP) and unconjugated estriol (UE3) were higher in the early-onset group (p = .015 and p= .002, respectively) and might be predictors of EOPE. There was a positive correlation between gestational age at PE diagnosis and gestational age at delivery. Patients with EOPE delivered earlier than patients with LOPE did (p<.0001). Conclusions: Patients who developed EOPE had higher of AFP and UE3 values at their second trimester biochemical screening. These parameters might be predictors of EOPE. We found a positive correlation between early gestational age at PE diagnosis and preterm delivery.
Metabolic homeostasis: Oxidative phosphorylation and the metabolic requirements of higher plants and animals.

A model of oxidative phosphorylation and its regulation is presented that is consistent with the experimental data on metabolism in higher plants and animals. The variables that provide real time control of metabolic status are: intramitochondrial [NAD+]/[NADH], energy state ([ATP]/[ADP][Pi]), and local oxygen concentration ([O2]). ATP consumption and respiratory chain enzyme content are tissue specific (liver vs heart muscle) and the latter is modulated by chronic alterations in ATP consumption (i.e. endurance training etc). ATP consumption affects the energy state, which increases or decreases as necessary to match synthesis with consumption. [NAD+]/[NADH], local [O2], and respiratory chain content determine the energy state at which match of synthesis and utilization is achieved. Tissues vary widely in their ranges of ATP consumption. Expressed as the turnover of cytochrome c, the rates may change little (7 to 12 sec-1) (liver) or a lot (1 to >300 sec-1) (flight muscle of birds, bats, and insects). Ancillary metabolic pathways, including creatine or arginine kinase, glycerol phosphate shuttle, fatty acid and citric acid cycle dehydrogenases, are responsible for meeting tissue specific differences in maximal rate and range in ATP utilization without displacing metabolic homeostasis. Intramitochondrial [NAD+]/[NADH], [ATP], and [Pi] are adjusted to keep [ADP] and [AMP] similar for all tissues despite large differences in ranges in ATP utilization. This is essential because [ADP] and [AMP], particularly the latter, have major roles in regulating the activity of many enzymes and signaling pathways (AMP deaminase, AMP dependent protein kinases, etc) common to all higher plants and animals.
High‐Throughput Metabolomics by 1D NMR

Abstract Metabolomics deals with the whole ensemble of metabolites (the metabolome). As one of the ‐omic sciences, it relates to biology, physiology, pathology and medicine; but metabolites are chemical entities, small organic molecules or inorganic ions. Therefore, their proper identification and quantitation in complex biological matrices requires a solid chemical ground. With respect to for example, DNA, metabolites are much more prone to oxidation or enzymatic degradation: we can reconstruct large parts of a mammoth's genome from a small specimen, but we are unable to do the same with its metabolome, which was probably largely degraded a few hours after the animal's death. Thus, we need standard operating procedures, good chemical skills in sample preparation for storage and subsequent analysis, accurate analytical procedures, a broad knowledge of chemometrics and advanced statistical tools, and a good knowledge of at least one of the two metabolomic techniques, MS or NMR. All these skills are traditionally cultivated by chemists. Here we focus on metabolomics from the chemical standpoint and restrict ourselves to NMR. From the analytical point of view, NMR has pros and cons but does provide a peculiar holistic perspective that may speak for its future adoption as a population‐wide health screening technique.
The role of SAGA coactivator complex in snRNA transcription

ABSTRACT The general snRNA gene transcription apparatus has been extensively studied. However, the role of coactivators in this process is far from being clearly understood. Here, we have demonstrated that the Drosophila SAGA complex interacts with the PBP complex, the key component of the snRNA gene transcription apparatus, and is present at the promoter regions of the snRNA genes transcribed by both the RNA polymerase II and RNA polymerase III (U6 snRNA). We show that SAGA interacts with the Brf1 transcription factor, which is a part of the RNA polymerase III transcription apparatus and is present at promoters of a number of Pol III-transcribed genes. Mutations inactivating several SAGA subunit genes resulted in reduced snRNA levels in adult flies, indicating that SAGA is indeed the transcriptional coactivator for the snRNA genes. The transcription of the Pol II and Pol III-transcribed U genes was reduced by mutations in all tested SAGA complex subunits. Therefore, the transcription of the Pol II and Pol III-transcribed U genes was reduced by the mutations in the deubiquitinase module, as well as in the acetyltransferase module of the SAGA, indicating that the whole complex is essential for their transcription. Therefore, the SAGA complex activates snRNA genes suggesting its wide involvement in the regulation of gene transcription, and consequently, in the maintenance of cellular homeostasis.
Személyek lokalizálása és magasságuk becslése többszörös születés és halál dinamikával többkamerás környezetben

Kivonat A jelen cikk egy új eszközt mutat be személyek lokalizálásához többkamerás környezetben, kalibrált kamerákat használva. Ezenfelül becslést adunk az egyes személyek magasságára is. A bemutatott módszer bemenete jelenleg a testek előtér sziluettjei, de ez később könnyedén kicserérlhető más, széles körben alkalmazott, objektum (pl. fej, láb, test) detektáló eljárások kimeneteire. A módszer első lépésben az összes előtér képpontot a föld sı́kjára, valamint ezzel párhuzamos, különböző magasságú sı́kokra vetı́ti. Ezután jellemzőket nyerünk ki, melyek a kétdimenziós képlétrehozás fizikai tulajdonságain alapulnak. A végső konfigurációt (pozı́ciók és magasságok) egy iteratı́v sztochasztikus optimalizáló eljárással, a többszörös születés és halál dinamikával, kapjuk meg.