The subcutaneous implantable cardioverter-defibrillator: A tertiary center experience

Background: The aim of the study was to evaluate subcutaneous implantable cardioverter-defibrillator (S-ICD) patients with regard to underlying etiology, peri-procedural outcome, appropriate/inappropriate shocks, and complications during follow-up. Methods: All patients who underwent S-ICD implantation from February 2013 to March 2017 at an academic hospital in Vienna were included. Medical records were examined and follow-up interrogations of devices were conducted. Results: A total of 79 S-ICD patients (58.2% males) with a mean age of 44.5 ± 17.2 years were followed for a mean duration of 12.8 ± 13.7 months. A majority of patients (58.2%) had S-ICD for primary prevention of sudden cardiac death. The most common of the 16 underlying etiologies were ischemic cardiomyopathy, non-ischemic cardiomyopathy, and idiopathic ventricular fibrillation. The lead was implanted to the left sternal border in 96.2% of cases, between muscular layers in 72.2%. Mean implant time was 45 min, 3 patients were induced, and all patients except one were programmed to two zones. Six (7.6%) patients experienced at least one appropriate therapy for ventricular arrhythmias and the time to first event ranged from 1 to 52 months. Seven patients experienced inappropriate shocks due to T-wave oversensing, atrial tachycardia with rapid atrioventricular conduction, external electromagnetic interference, and/or baseline oversensing due to lead movement. Four patients underwent revision for lead repositioning (n = 1), loose device suture (n = 1), and infection (n = 2). Conclusions: While S-ICDs are a feasible and effective treatment, issues remain with inappropriate shock and infection

Dissecting early mechanism of melanoma cell resistance to cytotoxic T lymphocyte attack

Les cellules de mélanome humain expriment différents antigènes tumoraux qui sont reconnus par les lymphocytes T cytotoxiques CD8 + (CTL) induisant des réponses spécifiques de la tumeur in vivo. Cependant, chez les patients atteints de mélanome l'efficacité de la réponse naturelle des CTL ou stimulée par thérapie est limitée. Les mécanismes sous-jacents de l'échec de la phase effectrice des CTL contre les mélanomes sont encore largement méconnus. Notre hypothèse est que l'efficacité limitée des CTL dans leur combat contre les tumeurs est le résultat d'une balance défavorable entre la capacité des CTL à tuer les tumeurs et une résistance tumorale intrinsèque à l'activité cytolytique des CTL. Au cours de ma thèse je me suis concentrée sur la dynamique moléculaire qui se produit à la synapse lytique afin de pouvoir identifier un mécanisme précoce mis en place par les cellules de mélanome face à l'attaque des CTL. En combinant l'utilisation d'approches de microscopie de pointe et des outils moléculaires, j'ai pu montrer que, lors de l'interaction avec les CTL, les cellules de mélanome humain subissent une activation de leur trafic vésiculaire endosomal et lysosomal, lequel est intensifié à la synapse lytique et corrèle avec la dégradation par la cathepsine de la perforine et un défaut de pénétration d'entrée du granzyme B. De plus, j'ai démontré que le blocage du trafic lysosomal dépendant de SNAP23, la modification du pH (intra-vésiculaire) et l'inhibition de l'activité lysosomale protéotlytique des cellules de mélanome permet de restaurer leur sensibilité à l'attaque des CTL. Nos résultats révèlent une stratégie sans précédent d' " auto-défense " des cellules de mélanome à la synapse immunologique basée sur une sécrétion lysosomale massive et sur la dégradation de la perforine sécrétée par les CTL. Ainsi pouvoir interférer avec cette stratégie synaptique d'auto-défense des cellules de mélanome pourrait contribuer à potentialiser les réponses des CTL et les immunothérapies chez les patients atteints de mélanome.Human melanoma cells express various tumor antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL) and elicit tumor-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying the failure of CTL effector phase against melanomas are still largely elusive. Our hypothesis is that the limited efficacy of CTL in their fight against tumors is the result of an unfavorable balance between CTL ability to kill tumors and an intrinsic tumor resistance to CTL cytolytic activity. During my thesis I focused on the molecular dynamics occurring at the lytic synapse in order to identify possible "early response-mechanism" of melanoma cells to CTL attack. Using a combination of cutting edge microscopy approaches and molecular tools, I showed that upon conjugation with CTL, human melanoma cells undergo an exacerbated late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Our results reveal an unprecedented strategy of melanoma cell "self-defense" at the immunologic synapse based on a lysosome secretory burst and perforin degradation at the lytic synapse. Interfering with this synaptic self-defense strategy might be instrumental to potentiate CTL-mediated therapies in melanoma patients

Monitoring Workers on Construction Sites using Data Fusion of Real-Time Worker’s Location, Body Orientation, and Productivity State

Traditionally, on-site construction production monitoring depends primarily on manual processes that are time-consuming and error-prone. State-of-the-art technologies have been utilized lately to improve these processes to support timely decisions pertinent to the productivity and safety of onsite operations. This research introduces a novel construction site monitoring system to track workers' location, body orientation, and productivity state. The developed system uses Bluetooth Low Energy (BLE) based reference transmitting beacons fixed on job sites and a set of receiving beacons mounted on workers’ hardhats, chests, and wrists. The system works via three modules, i.e. (i) RTLS (Real-Time Location System) module; (ii) body orientation detection module; and (iii) productivity state detection module. The RTLS module is developed to continuously track the location of the workers and subsequently extract the actual labor workspaces. The RTLS is explicitly designed for construction by satisfying requirements for widespread on-site adoption, including cost efficiency, deployability, scalability, adjustability to the construction site dynamism, and the expected accuracy. The main features of the developed RTLS are (i) substituting commonly used BLE receivers with BLE receiving beacons; (ii) proposing a modular infrastructure placement strategy; (iii) deploying Trilateration and Min-Max as localization techniques; (iv) post-processing the worker’s estimated locations. As per the body orientation detection module, it identifies workers' body orientation on the job sites, using the impacts of signal blockage by a human body to identify an approximate worker's body orientation. It works based on geometrical relationships and Received Signal Strength Indicator (RSSI) values between the chest-mounted receiving beacon and the reference transmitting beacons. Last but not least, the productivity state detection module determines workers' productivity state (i.e., direct work, support work, delay) and travel state, using the accelerometer sensor embedded in the body-mounted receiving beacons. Consequently, the collected data of the system modules are fused to augment real-time knowledge of workers' status on job sites

Combinatorial Expression Rules of Ion Channel Genes in Juvenile Rat (Rattus norvegicus) Neocortical Neurons

The electrical diversity of neurons arises from the expression of different combinations of ion channels. The gene expression rules governing these combinations are not known. We examined the expression of twenty-six ion channel genes in a broad range of single neocortical neuron cell types. Using expression data from a subset of twenty-six ion channel genes in ten different neocortical neuronal types, classified according to their electrophysiological properties, morphologies and anatomical positions, we first developed an incremental Support Vector Machine (iSVM) model that prioritizes the predictive value of single and combinations of genes for the rest of the expression pattern. With this approach we could predict the expression patterns for the ten neuronal types with an average 10-fold cross validation accuracy of 87% and for a further fourteen neuronal types not used in building the model, with an average accuracy of 75%. The expression of the genes for HCN4, Kv2.2, Kv3.2 and Caβ3 were found to be particularly strong predictors of ion channel gene combinations, while expression of the Kv1.4 and Kv3.3 genes has no predictive value. Using a logic gate analysis, we then extracted a spectrum of observed combinatorial gene expression rules of twenty ion channels in different neocortical neurons. We also show that when applied to a completely random and independent data, the model could not extract any rules and that it is only possible to extract them if the data has consistent expression patterns. This novel strategy can be used for predictive reverse engineering combinatorial expression rules from single-cell data and could help identify candidate transcription regulatory processes

Determination of the micromagnetic parameters in (Ga,Mn)As using domain theory

The magnetic domain structure and magnetic properties of a ferromagnetic (Ga,Mn)As epilayer with perpendicular magnetic easy-axis are investigated. We show that, despite strong hysteresis, domain theory at thermodynamical equilibrium can be used to determine the micromagnetic parameters. Combining magneto-optical Kerr microscopy, magnetometry and ferromagnetic resonance measurements, we obtain the characteristic parameter for magnetic domains $\lambda_c$, the domain wall width and specific energy, and the spin stiffness constant as a function of temperature. The nucleation barrier for magnetization reversal and the Walker breakdown velocity for field-driven domain wall propagation are also estimated

Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration.

Childhood neuroblastoma is one of the most common types of extra-cranial cancer affecting children with a clinical spectrum ranging from spontaneous regression to malignant and fatal progression. In order to improve the clinical outcomes of children with high-risk neuroblastoma, it is crucial to understand the tumorigenic mechanisms that govern its malignant behaviors. MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification has been implicated in the malignant, treatment-evasive nature of aggressive, high-risk neuroblastoma. In this study, we used a SILAC approach to compare the proteomic signatures of MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cells. Tumorigenic proteins, including fatty-acid binding protein 5 (FABP5), L1-cell adhesion molecule (L1-CAM), baculoviral IAP repeat containing 5 [BIRC5 (survivin)] and high mobility group protein A1 (HMGA1) were found to be significantly upregulated in the IMR-32 compared to the SK-N-SH cells and mapped to highly tumorigenic pathways including, MYC, MYCN, microtubule associated protein Tau (MAPT), E2F transcription factor 1 (E2F1), sterol regulatory element binding transcription factor 1 or 2 (SREBF1/2), hypoxia-inducible factor 1α (HIF-1α), Sp1 transcription factor (SP1) and amyloid precursor protein (APP). The transcriptional knockdown (KD) of MYCN, HMGA1, FABP5 and L1-CAM significantly abrogated the proliferation of the IMR-32 cells at 48 h post transfection. The early apoptotic rates were significantly higher in the IMR-32 cells in which FABP5 and MYCN were knocked down, whereas cellular migration was significantly abrogated with FABP5 and HMGA1 KD compared to the controls. Of note, L1-CAM, HMGA1 and FABP5 KD concomitantly downregulated MYCN protein expression and MYCN KD concomitantly downregulated L1-CAM, HMGA1 and FABP5 protein expression, while survivin protein expression was significantly downregulated by MYCN, HMGA1 and FABP5 KD. In addition, combined L1-CAM and FABP5 KD led to the concomitant downregulation of HMGA1 protein expression. On the whole, our data indicate that this inter-play between MYCN and the highly tumorigenic proteins which are upregulated in the malignant IMR-32 cells may be fueling their aggressive behavior, thereby signifying the importance of combination, multi-modality targeted therapy to eradicate this deadly childhood cancer