Effects of calorie restriction and IGF-1 receptor blockade on the progression of 22Rv1 prostate cancer xenografts.

Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe combined immunodeficient mice were subcutaneously injected with 22Rv1 cells and randomized to: (1) Ad libitum feeding/intraperitoneal saline (Ad-lib); (2) Ad-lib/20 mg/kg twice weekly, intraperitoneal ganitumab [anti-IGF-1R antibody (Ad-lib/Ab)]; (3) 40% calorie restriction/intraperitoneal saline (CR); (4) CR/ intraperitoneal ganitumab, (CR/Ab). CR and ganitumab treatment were initiated one week after tumor injection. Euthanasia occurred 19 days post treatment. Results showed that CR alone decreased final tumor weight, plasma insulin and IGF-1 levels, and increased apoptosis. Ganitumab therapy alone reduced tumor growth but had no effect on final tumor weight. The combination therapy (CR/Ab) further decreased final tumor weight and proliferation, increased apoptosis in comparison to the Ad-lib group, and lowered plasma insulin levels relative to the Ad-lib and Ad-lib/Ab groups. Tumor AKT activation directly correlated with plasma IGF-1 levels. In conclusion, whereas ganitumab therapy modestly affected 22Rv1 tumor growth, combining IGF-1R blockade with calorie restriction resulted in a significant decrease in final tumor weight and improved metabolic profile

Underwater Multirobot Cooperative Intervention MAC Protocol

This work introduces a Medium Access Control (MAC) protocol designed to allow a group of underwater robots that share a wireless communication channel to effectively communicate with each other. The goal of the Underwater Multirobot Cooperative Intervention MAC (UMCI-MAC) protocol presented in this work is to minimize the end to end delay and the jitter. The access to the medium in UMCI-MAC follows a Time Division Multiple Access (TDMA) strategy which is arbitrated by a master, which also has the capability to prioritize the transmission of some nodes over the rest of the network. Two experiments have been carried out with a team of four Autonomous Underwater Vehicles (AUV) in order to compare this protocol with Aloha-CS and S-FAMA MAC protocols used in Underwater Wireless Sensor Networks (UWSN). In the first experiment, the communications and the AUVs have been simulated using UWSim-NET. The objective of this experiment was to evaluate all three protocols in terms of delay, jitter, efficiency, collisions and throughput depending on the size of the data packet and the rate of packet delivery in the application layer for each robot. The results of this experiment proved that UMCI-MAC successfully avoids packet collisions and outperforms the other two protocols in terms of delay, jitter and efficiency. The second experiment consisted of a Hardware In The Loop (HIL) teleoperation of a team of four robots. One of the AUVs was a real BlueROV in a water tank, while the remaining AUVs and the communications were simulated with UWSim-NET. It demonstrates the impact of the MAC protocols in underwater acoustic links. Of the three MAC protocols evaluated in this work, UMCI-MAC was the only one which succeeded in the proposed teleoperation experiment. Thus demonstrating its suitability as a communications protocol in underwater cooperative robotics

Cooperative and Multimodal Capabilities Enhancement in the CERNTAURO Human–Robot Interface for Hazardous and Underwater Scenarios

The use of remote robotic systems for inspection and maintenance in hazardous environments is a priority for all tasks potentially dangerous for humans. However, currently available robotic systems lack that level of usability which would allow inexperienced operators to accomplish complex tasks. Moreover, the task’s complexity increases drastically when a single operator is required to control multiple remote agents (for example, when picking up and transporting big objects). In this paper, a system allowing an operator to prepare and configure cooperative behaviours for multiple remote agents is presented. The system is part of a human–robot interface that was designed at CERN, the European Center for Nuclear Research, to perform remote interventions in its particle accelerator complex, as part of the CERNTAURO project. In this paper, the modalities of interaction with the remote robots are presented in detail. The multimodal user interface enables the user to activate assisted cooperative behaviours according to a mission plan. The multi-robot interface has been validated at CERN in its Large Hadron Collider (LHC) mockup using a team of two mobile robotic platforms, each one equipped with a robotic manipulator. Moreover, great similarities were identified between the CERNTAURO and the TWINBOT projects, which aim to create usable robotic systems for underwater manipulations. Therefore, the cooperative behaviours were validated within a multi-robot pipe transport scenario in a simulated underwater environment, experimenting more advanced vision techniques. The cooperative teleoperation can be coupled with additional assisted tools such as vision-based tracking and grasping determination of metallic objects, and communication protocols design. The results show that the cooperative behaviours enable a single user to face a robotic intervention with more than one robot in a safer way

Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth

Chromobox 2 (CBX2) is a chromatin-binding component of polycomb repressive complex 1, which causes gene silencing. CBX2 expression is elevated in triple-negative breast cancer (TNBC), for which there are few therapeutic options. Here, we aimed to investigate the functional role of CBX2 in TNBC. CBX2 knockdown in TNBC models reduced cell numbers, which was rescued by ectopic expression of wild-type CBX2 but not a chromatin binding-deficient mutant. Blocking CBX2 chromatin interactions using the inhibitor SW2_152F also reduced cell growth, suggesting CBX2 chromatin binding is crucial for TNBC progression. RNA sequencing and gene set enrichment analysis of CBX2-depleted cells identified downregulation of oncogenic signalling pathways, including mTORC1 and E2F signalling. Subsequent analysis identified that CBX2 represses the expression of mTORC1 inhibitors and the tumour suppressor RBL2. RBL2 repression, in turn, inhibits DREAM complex activity. The DREAM complex inhibits E2F signalling, causing cell senescence; therefore, inhibition of the DREAM complex via CBX2 may be a key oncogenic driver. We observed similar effects in oestrogen receptor-positive breast cancer, and analysis of patient datasets suggested CBX2 inhibits RBL2 activity in other cancer types. Therapeutic inhibition of CBX2 could therefore repress mTORC1 activation and promote DREAM complex-mediated senescence in TNBC and could have similar effects in other cancer types

A Novel Missense Mutation, I890T, in the Pore Region of Cardiac Sodium Channel Causes Brugada Syndrome

Brugada syndrome (BrS) is a life-threatening, inherited arrhythmogenic syndrome associated with autosomal dominant mutations in SCN5A, the gene encoding the cardiac Na+ channel alpha subunit (Nav1.5). The aim of this work was to characterize the functional alterations caused by a novel SCN5A mutation, I890T, and thus establish whether this mutation is associated with BrS. The mutation was identified by direct sequencing of SCN5A from the proband's DNA. Wild-type (WT) or I890T Nav1.5 channels were heterologously expressed in human embryonic kidney cells. Sodium currents were studied using standard whole cell patch-clamp protocols and immunodetection experiments were performed using an antibody against human Nav1.5 channel. A marked decrease in current density was observed in cells expressing the I890T channel (from -52.0±6.5 pA/pF, n = 15 to -35.9±3.4 pA/pF, n = 22, at -20 mV, WT and I890T, respectively). Moreover, a positive shift of the activation curve was identified (V1/2 = -32.0±0.3 mV, n = 18, and -27.3±0.3 mV, n = 22, WT and I890T, respectively). No changes between WT and I890T currents were observed in steady-state inactivation, time course of inactivation, slow inactivation or recovery from inactivation parameters. Cell surface protein biotinylation analyses confirmed that Nav1.5 channel membrane expression levels were similar in WT and I890T cells. In summary, our data reveal that the I890T mutation, located within the pore of Nav1.5, causes an evident loss-of-function of the channel. Thus, the BrS phenotype observed in the proband is most likely due to this mutation. © 2013 Tarradas et al

Cerebral embolization associated with parenchymal seeding of the left atrial myxoma : Potential role of interleukin-6 and matrix metalloproteinases

Systemic embolization has been reported in up to 40% of patients with left atrial myxoma, half of them with cerebral involvement. However, development of intracerebral embolization associated with parenchymal seeding of the myxoma emboli is an extremely rare complication, with only 36 histologically diagnosed cases reported in the published literature. We describe a 69-year-old woman who arrived at the emergency service with hemiparesis associated with drug-resistant epilepsy and a medical history of resection of a left atrial myxoma 10 months previously. Cranial computed tomography revealed multiple large lesions of heterogeneous density and cystic components in the occipital lobes and posterior fossa parenchyma. Histopathological analyses after stereotactic biopsy of the occipital lesion revealed infiltrative myxoma cells with benign histological findings and uniform expression of calretinin similar to that of the primary cardiac myxoma. Additional immunohistochemical studies confirmed brain parenchymal seeding of the myxoma cells with strong expression of interleukin-6 (IL-6) and focal expression of matrix metalloproteinases-2 (MMP-2). Here, we discuss the clinicopathological features of intracerebral embolization of left atrial myxomas associated with progressive parenchymal seeding of the tumor emboli and the potential pathogenic role of IL-6 and MMPs.Peer reviewe

Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system

Arginine methylation is a post-translational modification that consists of the transfer of one or two methyl (CH3) groups to arginine residues in proteins. Several types of arginine methylation occur, namely monomethylation, symmetric dimethylation and asymmetric dimethylation, which are catalysed by different protein arginine methyltransferases (PRMTs). Inhibitors of PRMTs have recently entered clinical trials to target several types of cancer, including gliomas (NCT04089449). People with glioblastoma (GBM), the most aggressive form of brain tumour, are among those with the poorest quality of life and survival of anyone diagnosed with cancer. There is currently a lack of (pre)clinical research on the possible application of PRMT inhibitors to target brain tumours. Here, we set out to investigate the effects of clinically-relevant PRMT inhibitors on GBM biopsies. We present a new, low-cost, easy to fabricate perfusion device that can maintain GBM tissue in a viable condition for at least eight days post-surgical resection. Theminiaturised perfusion device enables the treatment of GBM tissue with PRMT inhibitors ex vivo, and we observed a two-fold increase in apoptosis in treated samples compared to parallel control experiments. Mechanistically, we show thousands of differentially expressed genes after treatment, and changes in the type of arginine methylation of the RNA binding protein FUS that are consistent with hundreds of differential gene splicing events. This is the first time that cross-talk between different types of arginine methylation has been observed in clinical samples after treatment with PRMT inhibitors

Prevalence of severe/morbid obesity and other weight status and anthropometric reference standards in Spanish preschool children: The PREFIT project

BACKGROUND: Childhood obesity has become a major health problem in children under the age of 5 years. Providing reference standards would help paediatricians to detect and/or prevent health problems related to both low and high levels of body mass and to central adiposity later in life. Therefore, the aim of this study was to examine the prevalence of different weight status categories and to provide sex- and age-specific anthropometry reference standards for Spanish preschool children. METHODS: A total of 3178 preschool children (4.59±0.87 years old) participated in this study. Prevalence of different degrees of obesity (mild, severe, and morbid) and other weight status categories were determined. RESULTS: Reference standards were obtained. Prevalence of overweight and obese preschool children in the Spanish population ranged from 21.4 to 34.8%. Specifically, the obesity prevalence was 3.5, 1.2, and 1.3% of these subjects were categorized as mild, severe, and morbid obese. Sex- and age-specific reference standards for anthropometric parameters are provided for every 0.25 years (i.e. every trimester of life). CONCLUSION: Our results show a high prevalence of overweight/obese preschoolers. The provided sex- and age-specific anthropometric reference standards could help paediatricians to track and monitor anthropometric changes at this early stage in order to prevent overweight/obesity.We thank the participation of the preschoolers, parents, and teachers in this study. We are grateful to Ms. Carmen Sainz-Quinn for assistance with the English language. This work is part of a Ph.D. Thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain. The PREFIT project takes place owing to the funding of the Ramón y Cajal grant held by FBO (RYC-2011-09011). C.C.-S. is supported by a grant from the Spanish Ministry of Economy and Competitiveness (BES-2014-068829). E.G.A. and F.B.O. are supported by a grant from the Spanish Ministry of Science and Innovation (RYC-2014-16390 and RYC-2011-09011, respectively). C.A.-B., A.P.-B., and G.S.-D. are supported by the Spanish Ministry of Education (FPU13/03137, FPU15/ 05337, and FPU13/04365, respectively). Additional funding was obtained from the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES) and by the Junta de Andalucia, Consejería de Conocimiento, Investigación y Universidades. In addition, funding was provided by the SAMID III network, RETICS, the PN I+D+I 2017-2021 (Spain), ISCIII-Sub-Directorate General for Research Assessment and Promotion, the European Regional Development Fund (ERDF) (RD16/0022, SOMM17/6107/UGR), the EXERNET Research Network on Exercise and Health in Special Populations (DEP2005- 00046/ACTI), the University of the Basque Country (GIU14/21), and the University of Zaragoza (JIUZ-2014-BIO-08)