Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis

<p>Abstract</p> <p>Background</p> <p>The present study compares antiepileptic drugs and aromatase (CYP19) inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs) are needed, especially since every individual responds differently to given treatment options.</p> <p>Methods</p> <p>Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits.</p> <p>Results</p> <p>The pharmacophore model returned 73% (19 out of 26) of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62) of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses.</p> <p>Conclusions</p> <p>This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity, and the similarity analyses performed propose a number of antiepileptic compounds with high potential for aromatase inhibition.</p

Factors associated with extended remission in neovascular age-related macular degeneration on pro re nata treatment protocol.

AimTo show the characteristics and outcomes of patients with neovascular age-related macular degeneration (nAMD) who had extended remission (ER) while on a pro re nata (PRN) treatment protocol.MethodsThis was a retrospective case-control study of a consecutive series of patients with nAMD treated with a PRN antivascular endothelial growth factor (anti-VEGF) drug regimen. ER was defined as the absence of haemorrhage, intraretinal/subretinal fluid on optical coherence tomography and leakage on fluorescein angiography for 52 weeks after cessation of anti-VEGF therapy. Matching patients with nAMD who did not achieve ER were included as control group. Cox regression analysis was fitted to identify predictors of time to achieve ER and time to recurrence. A logistic regression analysis of baseline characteristics was used to identify predictors of achieving ER.ResultsOf 830 eyes treated with anti-VEGF monotherapy, 77 (9.2%) eyes achieved ER during a median follow-up of 236 weeks (range 70-525 weeks). Cox regression analysis showed that ER was achieved earlier in eyes with isolated intraretinal fluid (HR, 2.05; 95% CI 1.929 to 4.520; p=0.045) at presentation. Logistic regression analysis showed that type 3 choroidal neovascularisation (OR, 0.090; 95% CI 0.021 to 0.382; p=0.001), thinner choroid (OR, 0.993; 95% CI 0.988 to 0.998; p=0.004) and absence of macular atrophy (OR, 0.233; 95% CI 0.065 to 0.839; p=0.026) at baseline increased the likelihood of achieving ER.ConclusionER is achievable in 9.2% of patients under PRN therapy for nAMD. At presentation with nAMD, anatomical features on retinal imaging may predict the likelihood of achieving ER and a shorter time to achieve ER

Experimental Study of Choking Flow of Water at Supercritical Conditions

Les prochaines générations de réacteurs nucléaires vont opérer avec un fluide de refroidissement dont la pression sera près de 25 MPa et dont la température de sortie sera de 500°C à 625°C, selon le type de réacteur. En conséquence, l’enthalpie du flux de sortie de ces futurs réacteurs à eau supercritique, SCWR, «Supercritical Water-Cooled Reactors» sera beaucoup plus élevée que celle des réacteurs actuels. Cela permettra à l’efficacité des centrales nucléaires de passer d’environ 30-33% aujourd’hui jusqu’à 48%. Cependant, le comportement thermo-hydraulique de l’eau supercritique n’est pas encore bien compris sous de telles conditions d’écoulement, notamment en ce qui concerne par exemple les chutes de pression, la convection forcée, la détérioration du transfert de chaleur et le flux massique critique. Jusqu’à maintenant, seul un nombre très limité de recherches ont été effectuées utilisant des fluides en conditions supercritiques. De plus, ces recherches n’ont pas été effectuées dans des conditions représentatives des SCWR. Aussi, les données existantes au sujet du flux massique critique ont été recueillies lors d’expériences dont la pression de décharge était celle de l’atmosphère ambiante, et dans la plupart des cas en utilisant des fluides autres que l’eau. Il est à noter que la compréhension de l’écoulement critique des fluides supercritiques est essentielle pour effectuer les analyses de sûreté des futurs réacteurs nucléaires et pour concevoir leurs principaux composants mécaniques, par exemple, les valves de contrôle et les vannes de sûreté. Ainsi donc, une installation d’eau supercritique a été construite à l’École Polytechnique de Montréal pour effectuer des recherches sur le débit critique. Ce montage expérimental consiste en deux boucles fonctionnant en parallèle, servant à déterminer les conditions d’écoulement qui déclenchent le débit critique de l’eau supercritique. Cette installation est également en mesure d’effectuer des expériences de transfert de chaleur et de perte de pression utilisant de l’eau en conditions supercritiques. Dans cette thèse, seront présentés les résultats obtenus grâce à cette installation avec l’utilisation d’une section d’essais munie d’un orifice de 1 mm de diamètre interne et de 3,17 mm de longueur, et dont les rebords sont acérés. Ainsi, 545 points de données de flux massique critique ont été obtenus en conditions supercritiques, pour des pressions d’écoulement allant de 22,1 MPa à 32,1MPa, et à des températures d’écoulement allant de 50°C à 502°C, et ce pour des pressions de décharges 0,1 MPa à 3,6 MPa.----------Abstract Future nuclear reactors will operate at a coolant pressure close to 25 MPa and at outlet temperatures ranging from 500oC to 625°C. As a result, the outlet flow enthalpy in future Supercritical Water-Cooled Reactors (SCWR) will be much higher than those of actual ones which can increase overall nuclear plant efficiencies up to 48%. However, under such flow conditions, the thermal-hydraulic behavior of supercritical water is not fully known, e.g., pressure drop, forced convection and heat transfer deterioration, critical and blowdown flow rate, etc. Up to now, only a very limited number of studies have been performed under supercritical conditions. Moreover, these studies are conducted at conditions that are not representative of future SCWRs. In addition, existing choked flow data have been collected from experiments at atmospheric discharge pressure conditions and in most cases by using working fluids different than water which constrain researchers to analyze the data correctly. In particular, the knowledge of critical (choked) discharge of supercritical fluids is mandatory to perform nuclear reactor safety analyses and to design key mechanical components (e.g., control and safety relief valves, etc.). Hence, an experimental supercritical water facility has been built at École Polytechnique de Montréal which allows researchers to perform choking flow experiments under supercritical conditions. The facility can also be used to carry out heat transfer and pressure drop experiments under supercritical conditions. In this thesis, we present the results obtained at this facility using a test section that contains a 1 mm inside diameter, 3.17 mm long orifice plate with sharp edges. Thus, 545 choking flow of water data points are obtained under supercritical conditions for flow pressures ranging from 22.1 MPa to 32.1 MPa, flow temperatures ranging from 50°C to 502°C and for discharge pressures from 0.1 MPa to 3.6 MPa. Obtained data are compared with the data given in the literature including those collected with fluids other than water. It is also important to mention that present models used to predict supercritical choking flows have been developed for fluids under subcritical conditions. Even though none of these models were developed to handle the expansion of supercritical fluids, we tested some of the models (Homogenous Equilibrium Model, Modified-Homogeneous Equilibrium Model and Bernoulli equation) under supercritical conditions and compared their predictions with our data and those of other researchers, available in the literature. In addition, a simple polytropic model is proposed to estimate the critical flow rate of water

Bacillus Cereus Catheter Related Bloodstream Infection in a Patient with Acute Lymphoblastic Leukemia

Bacillus cereus infection is rarely associated with actual infection and for this reason single positive blood culture is usually regarded as contamination . However it may cause a number of infections, such catheter-related bloodstream infections. Significant catheter-related bloodstream infections (CRBSI) caused by Bacillus spp. are mainly due to B. cereus and have been predominantly reported in immunocompromised hosts. Catheter removal is generally advised for management of infection. In this report, catheter-related bacteremia caused by B. cereus in a patient with acute lymphoblast c leukemia (ALL) in Istanbul Medical Faculty was presented

Pars Plana Vitrectomy in Advanced Coats’ Disease

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Benchmarking Differential Privacy and Federated Learning for BERT Models

Natural Language Processing (NLP) techniques can be applied to help with the diagnosis of medical conditions such as depression, using a collection of a person's utterances. Depression is a serious medical illness that can have adverse effects on how one feels, thinks, and acts, which can lead to emotional and physical problems. Due to the sensitive nature of such data, privacy measures need to be taken for handling and training models with such data. In this work, we study the effects that the application of Differential Privacy (DP) has, in both a centralized and a Federated Learning (FL) setup, on training contextualized language models (BERT, ALBERT, RoBERTa and DistilBERT). We offer insights on how to privately train NLP models and what architectures and setups provide more desirable privacy utility trade-offs. We envisage this work to be used in future healthcare and mental health studies to keep medical history private. Therefore, we provide an open-source implementation of this work.Comment: 4 pages, 3 tables, 1 figur

Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates

The Cockayne syndrome B (CSB) protein—defective in a majority of patients suffering from the rare autosomal disorder CS—is a member of the SWI2/SNF2 family with roles in DNA repair and transcription. We demonstrate herein that purified recombinant CSB and the major human apurinic/apyrimidinic (AP) endonuclease, APE1, physically and functionally interact. CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP–DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein, as no CSB-dependent stimulation was observed with Escherichia coli endonuclease IV or an N-terminal truncated APE1 fragment. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. Moreover, human fibroblasts defective in CSB were found to be hypersensitive to both methyl methanesulfonate (MMS) and 5-hydroxymethyl-2′-deoxyuridine, agents that introduce base excision repair (BER) DNA substrates/intermediates

Cockayne syndrome group B protein has novel strand annealing and exchange activities

Cockayne syndrome (CS) is a rare inherited human genetic disorder characterized by UV sensitivity, severe neurological abnormalities and prageroid symptoms. The CS complementation group B (CSB) protein is involved in UV-induced transcription coupled repair (TCR), base excision repair and general transcription. CSB also has a DNA-dependent ATPase activity that may play a role in remodeling chromatin in vivo. This study reports the novel finding that CSB catalyzes the annealing of complementary single-stranded DNA (ssDNA) molecules with high efficiency, and has strand exchange activity. The rate of CSB-catalyzed annealing of complementary ssDNA is 25-fold faster than the rate of spontaneous ssDNA annealing under identical in vitro conditions and the reaction occurs with a high specificity in the presence of excess non-homologous ssDNA. The specificity and intrinsic nature of the reaction is also confirmed by the observation that it is stimulated by dephosphorylation of CSB, which occurs after UV-induced DNA damage, and is inhibited in the presence of ATPγS. Potential roles of CSB in cooperation with strand annealing and exchange activities for TCR and homologous recombination are discussed