Clinical prediction models assessing response to radiotherapy for rectal cancer: protocol for a systematic review.

BackgroundRectal cancer has a high prevalence. The standard of care for management of localised disease involves major surgery and/or chemoradiotherapy, but these modalities are sometimes associated with mortality and morbidity. The notion of 'watch and wait' has therefore emerged and offers an organ-sparing approach to patients after administering a less invasive initial treatment, such as X-ray brachytherapy (Papillon technique). It is thus important to evaluate how likely patients are to respond to such therapies, to develop patient-tailored treatment pathways. We propose a systematic review to identify published clinical prediction models of the response of rectal cancer to treatment that includes radiotherapy and here present our protocol.MethodsIncluded studies will develop multivariable clinical prediction models which assess response to treatment and overall survival of adult patients who have been diagnosed with any stage of rectal cancer and have received radiotherapy treatment with curative intent. Cohort studies and randomised controlled trials will be included. The primary outcome will be the occurrence of salvage surgery at 1 year after treatment. Secondary outcomes include salavage surgery at at any reported time point, the predictive accuracy of models, the quality of the developed models and the feasibility of using the model in clinical practice. Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL will be searched from inception to 24 February 2022. Keywords and phrases related to rectal cancer, radiotherapy and prediction models will be used. Studies will be selected once the deduplication, title, abstract and full-text screening process have been completed by two independent reviewers. The PRISMA-P checklist will be followed. A third reviewer will resolve any disagreement. The data extraction form will be pilot-tested using a representative 5% sample of the studies reviewed. The CHARMS checklist will be implemented. Risk of bias in each study will be assessed using the PROBAST tool. A narrative synthesis will be performed and if sufficient data are identified, meta-analysis will be undertaken as described in Debray et al. DISCUSSION: This systematic review will identify factors that predict response to the treatment protocol. Any gaps for potential development of new clinical prediction models will be highlighted.Trial registrationCRD42022277704

99mTc-Labeled Iron Oxide Nanoparticles as Dual-Modality Contrast Agent: A Preliminary Study from Synthesis to Magnetic Resonance and Gamma-Camera Imaging in Mice Models

The combination of two imaging modalities in a single agent has received increasing attention during the last few years, since its synergistic action guarantees both accurate and timely diagnosis. For this reason, dual-modality contrast agents (DMCAs), such as radiolabeled iron oxide (namely Fe3O4) nanoparticles, constitute a powerful tool in diagnostic applications. In this respect, here we focus on the synthesis of a potential single photon emission computed tomography/magnetic resonance imaging (SPECT/MRI) DMCA, which consists of Fe3O4 nanoparticles, surface functionalized with 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD) and radiolabeled with 99mTc, [99mTc]Tc-DPD-Fe3O4. The in vitro stability results showed that this DMCA is highly stable after 24 h of incubation in phosphate buffer saline (~92.3% intact), while it is adequately stable after 24 h of incubation with human serum (~67.3% intact). Subsequently, [99mTc]Tc-DPD-Fe3O4 DMCA was evaluated in vivo in mice models through standard biodistribution studies, MR imaging and gamma-camera imaging. All techniques provided consistent results, clearly evidencing noticeable liver uptake. Our work documents that [99mTc]Tc-DPD-Fe3O4 has all the necessary characteristics to be a potential DMCA

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis

AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model

Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins

Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias

BACKGROUND: Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein. CONCLUSIONS/SIGNIFICANCE: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations

Effectiveness of school food environment policies on children's dietary behaviors: A systematic review and meta-analysis.

BACKGROUND: School food environment policies may be a critical tool to promote healthy diets in children, yet their effectiveness remains unclear. OBJECTIVE: To systematically review and quantify the impact of school food environment policies on dietary habits, adiposity, and metabolic risk in children. METHODS: We systematically searched online databases for randomized or quasi-experimental interventions assessing effects of school food environment policies on children's dietary habits, adiposity, or metabolic risk factors. Data were extracted independently and in duplicate, and pooled using inverse-variance random-effects meta-analysis. Habitual (within+outside school) dietary intakes were the primary outcome. Heterogeneity was explored using meta-regression and subgroup analysis. Funnel plots, Begg's and Egger's test evaluated potential publication bias. RESULTS: From 6,636 abstracts, 91 interventions (55 in US/Canada, 36 in Europe/New Zealand) were included, on direct provision of healthful foods/beverages (N = 39 studies), competitive food/beverage standards (N = 29), and school meal standards (N = 39) (some interventions assessed multiple policies). Direct provision policies, which largely targeted fruits and vegetables, increased consumption of fruits by 0.27 servings/d (n = 15 estimates (95%CI: 0.17, 0.36)) and combined fruits and vegetables by 0.28 servings/d (n = 16 (0.17, 0.40)); with a slight impact on vegetables (n = 11; 0.04 (0.01, 0.08)), and no effects on total calories (n = 6; -56 kcal/d (-174, 62)). In interventions targeting water, habitual intake was unchanged (n = 3; 0.33 glasses/d (-0.27, 0.93)). Competitive food/beverage standards reduced sugar-sweetened beverage intake by 0.18 servings/d (n = 3 (-0.31, -0.05)); and unhealthy snacks by 0.17 servings/d (n = 2 (-0.22, -0.13)), without effects on total calories (n = 5; -79 kcal/d (-179, 21)). School meal standards (mainly lunch) increased fruit intake (n = 2; 0.76 servings/d (0.37, 1.16)) and reduced total fat (-1.49%energy; n = 6 (-2.42, -0.57)), saturated fat (n = 4; -0.93%energy (-1.15, -0.70)) and sodium (n = 4; -170 mg/d (-242, -98)); but not total calories (n = 8; -38 kcal/d (-137, 62)). In 17 studies evaluating adiposity, significant decreases were generally not identified; few studies assessed metabolic factors (blood lipids/glucose/pressure), with mixed findings. Significant sources of heterogeneity or publication bias were not identified. CONCLUSIONS: Specific school food environment policies can improve targeted dietary behaviors; effects on adiposity and metabolic risk require further investigation. These findings inform ongoing policy discussions and debates on best practices to improve childhood dietary habits and health

Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies.

PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans

Immunocompatibility of a new dual modality contrast agent based on radiolabeled iron-oxide nanoparticles

Radiolabeled magnetic nanoparticles are promising candidates as dual-modality-contrast-agents (DMCA) for diagnostic applications. The immunocompatibility of a new DMCA is a prerequisite for subsequent in vivo applications. Here, a new DMCA, namely Fe3O4 nanoparticles radiolabeled with 68Ga, is subjected to immunocompatibility tests both in vitro and in vivo. The in vitro immunocompatibility of the DMCA relied on incubation with donated human WBCs and PLTs (five healthy individuals). Optical microscopy (OM) and atomic force microscopy (AFM) were employed for the investigation of the morphological characteristics of WBCs and PLTs. A standard hematology analyzer (HA) provided information on complete blood count. The in vivo immunocompatibility of the DMCA was assessed through its biodistribution among the basic organs of the mononuclear phagocyte system in normal and immunodeficient mice (nine in each group). In addition, Magnetic Resonance Imaging (MRI) data were acquired in normal mice (three). The combined OM, AFM and HA in vitro data showed that although the DMCA promoted noticeable activation of WBCs and PLTs, neither degradation nor clustering were observed. The in vivo data showed no difference of the DMCA biodistribution between the normal and immunodeficient mice, while the MRI data prove the efficacy of the particular DMCA when compared to the non-radiolabeled, parent CA. The combined in vitro and in vivo data prove that the particular DMCA is a promising candidate for future in vivo applications. © 2021, The Author(s)

Diereunisi ton allagon kai katagrafi ton problimaton tis neas genias ktimatografiseon

128 σ.Επιπλέον, η παρούσα διπλωματική εργασία ταξινομεί σε κατηγορίες τα προβλήματα που προκύπτουν από τις νέες τεχνικές προδιαγραφές. Τα προβλήματα αυτά χωρίζονται σε νομικά, τεχνικά, προβλήματα σύνταξης, λειτουργικά, προβλήματα χρηστών καθώς επίσης και συγκεκριμένα προβλήματα. Οι τεχνικές προδιαγραφές που αναφέρονται έχουν τροποποιήσει το υπάρχον νομικό πλαίσιο (όπως οι νόμοι 2308/95 και 3441/2006) και αναθεωρούνται ακόμα. Επομένως, ο στόχος της μελέτης αυτής είναι να αποκαλυφθούν οι διαφορές που προέρχονται από τις νέες προδιαγραφές που είναι σχετικές με τις θεσμικές αλλαγές καθώς επίσης και τη λειτουργία του Κτηματολογίου. Πολλά από τα στοιχεία που παρατίθενται στην εργασία έχουν συλλεχθεί από εταιρίες αναδόχων. Τέλος, τα προβλήματα αυτά του Κτηματολογίου που αφορούν το νέο νομικό πλαίσιο εξετάστηκαν περαιτέρω, μέσω χαρακτηριστικών περιπτώσεων. Τα αποτελέσματα της μελέτης αυτής παρουσιάζουν απαραίτητες αλλαγές που απαιτούνται προκριμένου να βελτιωθεί το τρέχον πρόγραμμα Κτηματολογίου, έτσι ώστε να εκπληρώνονται οι σύγχρονες ανάγκες των χρηστών.Furthermore, the study categorizes the problems that result from the new technical specifications as legal, technical, compilation problems, operational, users as well as specific problems. The technical specifications that are reported have amended the existing legal framework (such as laws 2308/95 and3441/2006) and are still under revision. Therefore, the aim of this study is to reveal the differences that derive from the new specifications concerning the institutional changes as well as the functionality of the Cadastre. The collected concerning the first and second stage of the project, derived by topographical firms. The cadastral problems that relate to the existing as well as to the new legal framework were further examined through characteristic cases. The results obtained, show necessary changes that are required in order to improve the ongoing cadastral project, fulfilling modern users needs.Αναστασία Δ. Καραγεώργο