Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.

The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.

Exploring the Potential of Zirconium-89 in Diagnostic Radiopharmaceutical Applications: An Analytical Investigation.

This study highlights the use of 89Zr-oxalate in diagnostic applications with the help of WinAct and IDAC2.1 software. It presents the biodistribution of the drug in various organs and tissues, including bone, blood, muscle, liver, lung, spleen, kidneys, inflammations, and tumors, and analyzes the maximum amount of nuclear transformation per Bq intake for each organ. The retention time of the maximum nuclear transformation and the absorbed doses of the drug in various organs and tissues are also examined. Data from clinical and laboratory studies on radiopharmaceuticals are used to estimate the coefficients of transition. The accumulation and excretion of the radiopharmaceutical in the organs is assumed to follow an exponential law. The coefficients of transition from the organs to the blood and vice versa are estimated using a combination of statistical programs and digitized data from the literature. WinAct and IDAC 2.1 software are used to calculate the distribution of the radiopharmaceutical in the human body and to estimate the absorbed doses in organs and tissues. The results of this study can provide valuable information for the biokinetic modeling of wide-spectrum diagnostic radiopharmaceuticals. The results show that 89Zr-oxalate has a high affinity for bones and a relatively low impact on healthy organs, making it helpful in targeting bone metastases. This study provides valuable information for further research on the development of this drug for potential clinical applications.

Lead-Free Ternary Glass for Radiation Protection: Composition and Performance Evaluation for Solar Cell Coverage.

Solar cells in superstrate arrangement need a protective cover glass as one of its main components. The effectiveness of these cells is determined by the cover glass's low weight, radiation resistance, optical clarity, and structural integrity. Damage to the cell covers brought on by exposure to UV irradiation and energetic radiation is thought to be the root cause of the ongoing issue of a reduction in the amount of electricity that can be generated by solar panels installed on spacecraft. Lead-free glasses made of xBi2O3-(40 - x)CaO-60P2O5 (x = 5, 10, 15, 20, 25, and 30 mol%) were created using the usual approach of melting at a high temperature. The amorphous nature of the glass samples was confirmed using X-ray diffraction. At energies of 81, 238, 356, 662, 911, 1173, 1332, and 2614 keV, the impact of various chemical compositions on gamma shielding in a phospho-bismuth glass structure was measured. The evaluation of gamma shielding revealed that the results of the mass attenuation coefficient of glasses increase as the Bi2O3 content increases but decrease as the photon energy increases. As a result of the study conducted on the radiation-deflecting properties of ternary glass, a lead-free low-melting phosphate glass that exhibited outstanding overall performance was developed, and the optimal composition of a glass sample was identified. The 60P2O5-30Bi2O3-10CaO glass combination is a viable option for use in radiation shielding that does not include lead.

Neuroprotective Effects of Black Pepper Cold-Pressed Oil on Scopolamine-Induced Oxidative Stress and Memory Impairment in Rats.

Oxidative stress is usually associated with many neurodegenerative diseases. In this study, the gas chromatography-mass spectrometry (GC-MS) analysis of cold-pressed oil (CPO) from black pepper (Piper nigrum) fruits was performed and its neuroprotective effects were evaluated for the first time. The analysis of CPO revealed the presence of the lignan sesamin (39.78%), the alkaloid piperine (33.79%), the monoterpene hydrocarbons 3-carene (9.53%) and limonene (6.23%), and the sesquiterpene ß-caryophyllene (10.67%). Black pepper hydrodistilled oil (HDO) was also comparatively analyzed by GC-MS to show the impact of oil isolation by two different methodologies on their components and class of compounds identified. HDO analysis revealed 35 compounds (99.64% of the total peak areas) mainly composed of monoterpene hydrocarbons (77.28%), such as limonene (26.50%), sabinene (21.36%), and ß-pinene (15.53%), and sesquiterpene hydrocarbons (20.59%) represented mainly by ß-caryophyllene (19.12%). Due to the low yield obtained for HDO (0.01% v/w), only CPO was chosen for the evaluation of its neuroprotective potential. Alzheimer-type dementia was induced in rats by scopolamine intraperitoneal injection (1.5 mg/kg/day) for seven days. CPO was administered orally (100 mg/kg) for a week before scopolamine administration and then concomitantly for another week. Donepezil (1 mg/kg, orally) was used as a reference drug. CPO administration significantly improved the rat behaviors as evaluated by the Morris water maze test, evident from prolongation in time spent in the platform quadrant (262.9%, compared to scopolamine) and increasing in the crossing time by 18.18% compared to the control group. The rat behavior tested by passive avoidance, showed prolongation in the step-through latency compared to control. Moreover, CPO significantly (p < 0.05) ameliorated the activities of antioxidant enzymes such as catalase, superoxide dismutase (SOD) and reduced malondialdehyde (MDA) equivalents by 22.48%, 45.41%, and 86.61%, respectively, compared to scopolamine. Furthermore, CPO administration decreased scopolamine-induced elevated acetylcholinesterase levels in rats' hippocampi by 51.30%. These results were supported by histopathological and in silico molecular docking studies. Black pepper oil may be a potential antioxidant and neuroprotective supplement.

The Influence of CoO/P2O5 Substitutions on the Structural, Mechanical, and Radiation Shielding of Boro-Phosphate Glasses.

A new glass system (50-x)P2O5-20B2O3-5Al2O3-25Na2O-xCoO was manufactured using a standard melt quenching procedure, where 1≤ x ≤ 12 mol%. The characteristics of boro-phosphate-glasses containing CoO have been studied. The effect of CoO on the radiation-protective properties of glasses was established. The density of the prepared glasses as a function of CoO increased. XRD was used to check the vitreous structure of samples. Fourier-transform infrared (FTIR) spectroscopy was used to study the structure of each sample. FTIR demonstrated that connections grew as CoO/P2O5 levels increased, and the FTIR spectra shifted to higher wavenumbers. The increment of CoO converts non-bridging oxygens associated with phosphate structural units into bridging oxygens. This process increases the concentration of BO4 structural units and creates new, strong and stable bonds B-O-P, i.e., there is polymerization of the boro-phosphate glass network. With an increase in the ratio of CoO/P2O5 in the produced samples, ultrasonic velocities and elastic moduli were observed to increase. The coefficients of linear and mass attenuation, the transmittance of photons in relation to the photon energy, the efficiency of radiation protection in relation to the photon energy, and the thickness of the absorber were modeled using these two methods (experimental and theoretical). From the obtained values, it can be concluded that the 12Co sample containing 12 mol% will play the most influential role in radiation protection. An increase in the content of cobalt-I oxide led to a significant increase in the linear and mass attenuation coefficient values, which directly contributes to the development of the radiation-protective properties of glass.

Spectrum of childhood interstitial and diffuse lung diseases at a tertiary hospital in Egypt.

BACKGROUND: Childhood interstitial and diffuse lung diseases (chILD) encompass a broad spectrum of rare pulmonary disorders. In most developing Middle Eastern countries, chILD is still underdiagnosed. Our objective was to describe and investigate patients diagnosed with chILD in a tertiary university hospital in Egypt. METHODS: We analysed data of consecutive subjects (aged <18 years) referred for further evaluation at the Children's Hospital, Ain Shams University (Cairo, Egypt). Diagnosis of chILD was made in accordance with the ChILD-EU criteria. The following information was obtained: demographic data, clinical characteristics, chest computed tomography findings, laboratory studies, spirometry, bronchoalveolar lavage and histopathology findings. RESULTS: 22 subjects were enrolled over 24 months. Median age at diagnosis was 7 years (range 3.5-14 years). The most common manifestations were dyspnoea (100%), cough (90.9%), clubbing (95.5%) and tachypnoea (90.9%). Systematic evaluation led to the following diagnoses: hypersensitivity pneumonitis (n=3), idiopathic interstitial pneumonias (n=4), chILD related to chronic granulomatous disease (n=3), chILD related to small airways disease (n=3), post-infectious chILD (n=2), Langerhans cell histiocytosis (n=2), idiopathic pulmonary haemosiderosis (n=2), granulomatous lymphocytic interstitial lung disease (n=1), systemic sclerosis (n=1) and familial interstitial lung disease (n=1). Among the subjects who completed the diagnostic evaluation (n=19), treatment was changed in 13 (68.4%) subjects. CONCLUSION: Systematic evaluation and multidisciplinary peer review of chILD patients at our tertiary hospital led to changes in management in 68% of the patients. This study highlights the need for an Egyptian chILD network with genetic testing, as well as the value of collaborating with international groups in improving healthcare for children with chILD.

The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics.

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that regulates metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we showed that SIRT5 was required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 was required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we found that SIRT5 was required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably included MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a druggable genotype-independent addiction in melanoma.

Translating complexity and heterogeneity of pancreatic tumor: 3D in vitro to in vivo models.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive type of cancer with an overall survival rate of less than 7-8%, emphasizing the need for novel effective therapeutics against PDAC. However only a fraction of therapeutics which seemed promising in the laboratory environment will eventually reach the clinic. One of the main reasons behind this low success rate is the complex tumor microenvironment (TME) of PDAC, a highly fibrotic and dense stroma surrounding tumor cells, which supports tumor progression as well as increases the resistance against the treatment. In particular, the growing understanding of the PDAC TME points out a different challenge in the development of efficient therapeutics - a lack of biologically relevant in vitro and in vivo models that resemble the complexity and heterogeneity of PDAC observed in patients. The purpose and scope of this review is to provide an overview of the recent developments in different in vitro and in vivo models, which aim to recapitulate the complexity of PDAC in a laboratory environment, as well to describe how 3D in vitro models can be integrated into drug development pipelines that are already including sophisticated in vivo models. Hereby a special focus will be given on the complexity of in vivo models and the challenges in vitro models face to reach the same levels of complexity in a controllable manner. First, a brief introduction of novel developments in two dimensional (2D) models and ex vivo models is provided. Next, recent developments in three dimensional (3D) in vitro models are described ranging from spheroids, organoids, scaffold models, bioprinted models to organ-on-chip models including a discussion on advantages and limitations for each model. Furthermore, we will provide a detailed overview on the current PDAC in vivo models including chemically-induced models, syngeneic and xenogeneic models, highlighting hetero- and orthotopic, patient-derived tissues (PDX) models, and genetically engineered mouse models. Finally, we will provide a discussion on overall limitations of both, in vitro and in vivo models, and discuss necessary steps to overcome these limitations to reach an efficient drug development pipeline, as well as discuss possibilities to include novel in silico models in the process.

Principles and guidelines in the management of ankle fractures in adults.

Ankle fractures are common injuries that have many physical and psychosocial complications. As a result, it is important to be aware of how these patients present and are managed perioperatively. Detailed guidelines from NICE and the British Orthopaedic Association have been produced on this topic, including recent developments such as the decision to weight-bear early after surgery and the use of virtual fracture clinics. This article provides an overview of the key perioperative factors that need to be considered in cases of ankle fracture and the relevant clinical guidelines.

An overview of the key principles and guidelines in the management of pelvic fractures.

Pelvic fractures are complex injuries with a range of different presentations depending on the mechanism of trauma. Due to the morbidity and mortality of pelvic fractures, patients require thorough investigation and timely management with multidisciplinary input. Various surgical and non-surgical techniques can be used to treat pelvic fractures, as well as any associated visceral injuries. Following repair, it is important to remain vigilant for postoperative complications such as infection, sexual and urinary dysfunction, chronic pain and adverse psychological health. This article summarises the relevant UK guidance and literature and presents them in a format that follows the patient's journey. In doing so, it highlights the key perioperative factors that need to be considered in cases of pelvic fracture.

Abdominal aortic aneurysms part two: Surgical management, postoperative complications and surveillance.

Large, symptomatic and ruptured abdominal aortic aneurysms are usually treated surgically if patients are deemed fit enough. This may be achieved through endovascular or open surgical repair. The type of treatment that a patient receives is dependant on many factors, such as the rupture status of the aneurysm. Each approach is also associated with different risks and postoperative complications. Multiple guidelines exist to inform the surgical management of abdominal aortic aneurysms. This literature review combines these recommendations and explores the evidence upon which they are based. In addition, it highlights the key perioperative considerations that need to be considered in cases of unruptured and ruptured abdominal aortic aneurysms.

Abdominal aortic aneurysms part one: Epidemiology, presentation and preoperative considerations.

An abdominal aortic aneurysm is an irreversible dilatation of the abdominal aorta. The majority of abdominal aortic aneurysms are asymptomatic and identified incidentally while investigating a separate pathology. Others are detected by national screening programmes and some present due to a growth or rupture. Symptomatic or ruptured aneurysms require urgent or emergency repair in patients fit for surgery. Perioperative practitioners should therefore be aware of how patients with abdominal aortic aneurysms present and are investigated, so that they can implement timely management. Guidelines have been recently updated to reflect this. This literature review discusses these recommendations and explores the evidence upon which they are based. The aim of this article is to highlight the important preoperative principles that need to be considered in cases of abdominal aortic aneurysm.

Interleukin-17 haplotyping predicts hepatocellular carcinoma in sofosbuvir, pegylated interferon-alpha-2a & ribavirin treated chronic hepatitis C patients.

Suspect has been directed towards some direct acting antivirals (DAAs) due to their reported association with hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients. The mechanisms behind HCC development, following CHC treatment, were not well understood and may be linked to genetic variabilities in different patients which affect several cytokine productions involved in angiogenesis and inflammation. Of these variabilities, is the genetic polymorphisms in the interleukin-17 (IL-17) A receptor gene. Being an important pleiotropic cytokine, this study aimed to investigate the association between haplotypes in IL-17A receptor rs2275913 and rs3819024 and development of HCC in CHC patients treated with either triple therapy (sofosbuvir (SOF), pegylated interferon-alpha-2a (Peg-IFNα-2a) & ribavirin(RBV)) or with dual therapy (Peg-IFNα-2a&RBV). A cohort of 100 CHC patients was recruited in this study. Samples were tested for single nucleotide polymorphism (SNPs) in IL-17A receptor (rs2275913 and rs3819024) using TaqMan Genotyping assay. Our results showed that the presence of G-G haplotype in IL-17A (rs2275913& rs3819024) is inversely associated with HCC development in patients receiving triple therapy. While, high serum AFP levels are directly associated with HCC development in patients receiving triple therapy. However, in patients receiving dual therapy, HCC development was only associated with high serum alpha fetoprotein (AFP) levels and was not correlated to any specific allele in our studied SNPs. Such results highlight the importance of IL17A receptor gene haplotyping in the prediction of HCC development in patients receiving triple therapy. These results will aid in performing tailored, personalized strategy for CHC treatment.

Tricuspid atresia: Where are we now?

Tricuspid atresia (TA) is a complex congenital heart disease that presents with cyanosis in the neonatal period. It is invariably fatal if left untreated and requires multiple stages of palliation. Early recognition and timely surgical intervention are therefore pivotal in the management of these infants. This literature review considers the pathophysiology, presentation, investigations, and classification of TA. Moreover, it discusses the evidence upon which the latest medical and surgical treatments are based, as well as numerous recent case reports. Further work is needed to elucidate the etiology of TA, clarify the role of pharmacotherapy, and optimize the surgical management that these patients receive.

Effect of vildagliptin and pravastatin combination on cholesterol efflux in adipocytes.

Many reports suggested that some statins are almost ineffective in reducing triglycerides or enhancing HDL-C plasma levels, although statin treatment was still efficacious in reducing LDL-C. In diabetic dyslipidemic patients, it may therefore be necessary to use a combination therapy with other drugs to achieve either LDL-C- and triglyceride-lowering or HDL-C-enhancing goals. Such ineffectiveness of statins can be attributed to their effect on the liver X receptor (LXR) which regulates the expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. A decrease in the expression of these transporters eventually leads to decreased cholesterol efflux from peripheral tissues leading to low levels of HDL-C. Although manipulating the LXR pathway may complement the effects of statins, LXR synthetic ligands as T091317 have shown significant hypertriglyceridemic action which limits their use. We recently found that the antidiabetic drug vildagliptin stimulates LXR expression leading to increased ABCB1/ABCG1 expression which improves cholesterol efflux from adipocytes. Therefore, a combination of vildagliptin and statin may provide a solution without the hypertriglyceridemic action observed with LXR agonist. We hypothesize that a combination of vildagliptin and pravastatin will improve cholesterol efflux in adipocytes. Statin-treated 3T3-L1 adipocytes were treated with vildagliptin, and the expression of LXR-ABCA1/ABCG1 cascade and the cholesterol efflux were then determined. Our data indicate that a combination of vildagliptin and pravastatin significantly induces the expression of LXR-ABCA1/ABCG1 cascade and improves cholesterol efflux (P > 0.05) in adipocytes. Our data may explain, at least in part, the improvement in HDL-C levels observed in patients receiving both medications. © 2016 IUBMB Life, 68(7):535-543, 2016.

A magnet built on bronchoscopic suction for extraction of tracheobronchial headscarf pins: a novel technique and review of a tertiary centre experience.

OBJECTIVES: Airway metal pins are one of the most commonly inhaled foreign bodies in Eastern societies in young females wearing headscarves. We innovated a modified bronchoscopic technique to extract tracheobronchial headscarf pins by the insertion of a magnet to allow an easy and non-traumatic extraction of the pins. The aim of this study was to assess the feasibility and safety of our new technique and compare it with our large previous experience with the classic bronchoscopic method of extraction of tracheobronchial headscarf pins. METHODS: We performed a study comparing our retrospective experience of classic bronchoscopic extraction from February 2004 to January 2014 and prospective experience with our modified technique using the magnet from January 2014 to June 2015. An institutional review board and new device approval were obtained. RESULTS: Three hundred and twenty-six procedures on 315 patients were performed during our initial 10-year experience. Of them, 304 patients were females. The median age of our group was 13 (0-62). The median time from inhalation to procedure was 1 day (0-1022). After introducing our modified new technique using the magnet, 20 procedures were performed. Nineteen were females. The median time of the procedure and the need to forcefully bend the pin for extraction were in favour of the new technique in comparison with our classic approach (2 vs 6 min; P < 0.001) (2 patients = 20% vs 192 = 58%; P < 0.001). The conversion rate to surgery was also in favour of the modified technique but did not reach statistical significance (0 = 0% vs 15 = 4.8%; P = 0.32). All patients who underwent the modified technique were discharged home on the same day of the procedure. No procedural complications were recorded. All remain well on a follow-up period of up to 14 months. CONCLUSIONS: Bronchoscopic extraction of tracheobronchial inhaled headscarf pins using a novel technique using homemade magnets was safer and simpler in comparison with our large experience with the classic approach. We advise the use of this device (or concept) in selected patients in centres dealing with this problem.

Glucagon-like peptide 1 (GLP-1)-based therapy upregulates LXR-ABCA1/ABCG1 cascade in adipocytes.

A promising treatment for obesity involves the use of therapeutic agents that increase the level of the glucagon-like peptide (GLP-1) which reduces appetite and food intake. Native GLP-1 is rapidly metabolized by the dipeptidyl peptidase-4 (DPP-4) enzyme and, as such, GLP-1 mimetics or DPP-4 inhibitors represent promising treatment approaches. Interestingly, obese patient receiving such medications showed improved lipid profiles and cholesterol homeostasis, however the mechanism(s) involved are not known. Members of the ATP-binding cassette (ABC) transporters, including ABCA1 and ABCG1, play essential roles in reverse cholesterol transport and in high density lipoprotein (HDL) formation. These transporters are under the transcriptional regulation of liver X receptor alpha (LXR-α). We hypothesize that GLP-1 mimetics and/or DPP-4 inhibitors modulate ABCA1/ABCG1 expression in adipocytes through an LXR-α mediated process and thus affecting cholesterol homeostasis. 3T3-L1 adipocytes were treated with the DPP-4 inhibitor vildagliptin (2 nM) or the GLP-1 mimetic exendin-4 (5 nM). Gene and protein expression of ABCA1, ABCG1 and LXR-α were determined and correlated with cholesterol efflux. Expression levels of interleukin-6 (IL-6), leptin and the glucose transporter-4 (GLUT-4) were also determined. Treatment with both medications significantly increased the expression of ABCA1, ABCG1, LXR-α and GLUT-4, decreased IL-6 and leptin, and improved cholesterol efflux from adipocytes (P < 0.05). Our data suggest that GLP-1-based therapy modulate ABCA1/ABCG1 expression in adipocytes potentially through an LXR-α mediated process.

Retrosternal goiter: the need for thoracic approach based on CT findings: surgeon's view.

BACKGROUND AND PURPOSE: The incidence of retrosternal goiter (RSG) varies from 2% to 26% of all thyroidectomies, depending on the defining criteria. There are no clear guidelines to identify patients that require an intrathoracic approach. So, we tried to correlate, between the size and/or anatomical site of the RSG based on preoperative CT findings and the surgical approaches used, aiming at defining those patients with RSG who are in need for thoracic approach. PATIENTS AND METHODS: Out of 1481 patients underwent thyroidectomy at the National Cancer Institute (NCI), Cairo University, between January 2000 and December 2009, only 73 (4.93%) of them had retrosternal extension. Demographic, clinical, operative, anatomical, and pathological data of patients with RSG were recorded and analyzed. RESULTS: The intraoperative extension of the goiter correlated with the extension seen in the CT in all except two patients. Laterality and longitudinal extension found in preoperative CT, correlated well with the surgical findings. The approach used was cervical in 66 cases (90.4%); combined approach in six patients (8.2%). Pure thoracic (full sternotomy) was used alone in one case (1.4%). Extension of the RSG down to or below the arch was associated with an increased risk of using a thoracic approach p<0.0001. CONCLUSION: Preoperative CT, can be used effectively to guide the indications for using a thoracic approach. Reaching the aortic arch or beyond and loss of fat planes in CT, recurrent and malignant disease, are significant risk factors for using a thoracic approach.