Репозиторий Университета

© 2019 Elsevier B.V. Brain delivery of drugs by nanoparticles is a promising strategy that could open up new possibilities for the chemotherapy of brain tumors. As demonstrated in previous studies, the loading of doxorubicin in poly(lactide-co-glycolide) nanoparticles coated with poloxamer 188 (Dox-PLGA) enabled the brain delivery of this cytostatic that normally cannot penetrate across the blood-brain barrier in free form. The Dox-PLGA nanoparticles produced a very considerable anti-tumor effect against the intracranial 101.8 glioblastoma in rats, thus representing a promising candidate for the chemotherapy of brain tumors that warrants clinical evaluation. The objective of the present study, therefore, was the optimization of the Dox-PLGA formulation and the development of a pilot scale manufacturing process. Optimization of the preparation procedure involved the alteration of the technological parameters such as replacement of the particle stabilizer PVA 30–70 kDa with a presumably safer low molecular mass PVA 9–10 kDa as well as the modification of the external emulsion medium and the homogenization conditions. The optimized procedure enabled an increase of the encapsulation efficiency from 66% to >90% and reduction of the nanoparticle size from 250 nm to 110 nm thus enabling the sterilization by membrane filtration. The pilot scale process was characterized by an excellent reproducibility with very low inter-batch variations. The in vitro hematotoxicity of the nanoparticles was negligible at therapeutically relevant concentrations. The anti-tumor efficacy of the optimized formulation and the ability of the nanoparticles to penetrate into the intracranial tumor and normal brain tissue were confirmed by in vivo experiments.

© 2019 Elsevier B.V. Submicrocapsules were prepared from diethylaminoethyl dextran (DEAE-D), xanthan gum (XG) and bovine serum albumin (BSA) on oil cores by ultrasonic treatment. These capsules were modified with poly-L-lysine (PLL) via electrostatic adsorption. The behavior of the capsules was investigated at an air–water interface after their introduction into an aqueous subphase. The interaction of the capsules with 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) monolayer formed on the water surface (model cellular membrane) was studied both upon their introduction under the condensed monolayer and with the use of a dilute colloidal solution of the capsules as a subphase. Biodegradation of the proteinaceous capsules with subsequent oil-core release was demonstrated by influence of pronase. The Langmuir lipid monolayer was found to be a good model for investigation of drug release from the capsules in the presence of the cellular membrane.

© 2019, The Author(s). Background: In recent years, joint replacement surgery has gradually progressed towards the fast-track model, and early rehabilitation immediately after surgery is regarded fundamental for optimal recovery of function: the aim of the present study is to describe the efficacy in perioperative management of pain in patients undergoing total hip replacement surgery and treated with tapentadol or oxycodone/naloxone in combination with ketoprofene. Methods: Single-center retrospective study on patients with moderate-severe pain, referred to total hip replacement. Patients received either tapentadol (100 mg/twice-daily post-surgery – treatment group) or oxycodone/naloxone (10 mg/5 mg post-surgery – control group) plus ketoprofen 100 mg/ twice daily. Supplemental analgesia (paracetamol 1 g or morphine 0,1 mg/kg sc) was provided if needed. Pain at rest and pain during movement were evaluated on a daily basis for 4 days post-op, after which patients were usually discharged. All adverse events were reported and compared between the two groups. Results: 106 patients were analyzed in the tapentadol group and compared to 105 patients treated with oxycodone/naloxone. Both pain intensity at rest and upon movement were significantly lower in the tapentadol group at all follow-up times (p < 0.001). Throughout T1-T4, supplemental analgesia was needed by significantly less tapentadol patients compared to the control group. Similarly, regarding side effects, a significantly higher occurrence of post-op nausea, vomit, itching and constipation was observed in the control group (p < 0.001 in all cases). Conclusion: Results from the present study support the use of tapentadol in combination with ketoprofen for the management of moderate-severe pain in the setting of major orthopedic surgery, given its effectiveness in reducing pain intensity, and its satisfactory tolerance.

© 2019 Wiley Periodicals, Inc. Background: To test the effect of radical cystectomy (RC) with chemotherapy vs only chemotherapy on overall mortality (OM) in metastatic urothelial carcinoma of the urinary bladder (mUCUB). Methods: Within the Surveillance, Epidemiology, and End Results registry (2004–2016), we identified patients with mUCUB. Stratification was made according to treatment: RC with chemotherapy vs only chemotherapy. Kaplan-Meier plots and multivariable Cox regression models were used before and after 1:1 propensity score (PS) matching and inverse probability of treatment weighting (IPTW). Results: Of 2414 patients with mUCUB, 500 (21.0%) vs 1914 (79.0%) were treated with RC with chemotherapy vs only chemotherapy, respectively. In multivariable Cox regression models, RC with chemotherapy was associated with lower OM in the overall cohort (hazard ratio [HR], 0.5; P <.001), after 1:1 PS matching (HR, 0.5; P <.001), after IPTW (HR, 0.5; P <.001) and after accounting for number and location of metastases (HR, 0.5; P <.001). However, higher overall survival after RC with chemotherapy was only observed in patients with one metastatic site (21 vs 16 months; P =.001). Conclusion: In contemporary patients with mUCUB, RC with chemotherapy is associated with lower OM rates, relative to chemotherapy alone, but only in patients with a single metastatic site. These individuals accounted for the vast majority of patients in whom an RC was performed, despite the presence of metastatic disease.

© 2019 Elsevier B.V. Most of the on-site approaches for inferring of the post-mortem interval are still based on observative data from the direct body inspection, whereas, objective and quantitative analyses, such as potassium in the vitreous humor, are require laboratory instrumentation and skilled personnel. The present paper presents a simple and low cost analytical method suitable for use at the crime scene for inferring the time since death. The method uses a microfluidic paper-based device (μPAD) for the determination of ammonium in the vitreous humor (VH) based on the selective interaction between the ammonium and the Nessler's reagent. The color change was measured in terms of “RGB distance” by using a simple and free smartphone application. The optimized device showed a limit of detection of 0.4 mmol L−1, with between days precision less than 9.3% expressed as relative standard deviation, and accuracy between days from 94.5% to 104.5%. The selectivity of the Nessler's reaction was tested towards the main vitreous humor compounds, and no significant interferences were found. This paper-based analytical device was successfully used for the determination of ammonium ion in VH samples from forensic autopsies. The results obtained with the proposed method, although for a limited number of cases (n = 25), showed a close correlation with the data obtained with an instrumental analysis based on capillary electrophoresis. Moreover, in order to make the evaluation of results as simple as possible, a direct correlation between the color intensity, expressed as RGB distance, and the post-mortem interval was studied and a significant correlation was found (R2 > 0.78). In conclusion, the present preliminary study showes that the proposed device could be an additional tool to the traditional methods for a more accurate, although still presumptive, estimation of the time of death directly at the crime scene.

© 2019 The Author(s). Background: Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies. Methods: We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients. Results: We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies. Conclusion: Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines.

© 2019 Elsevier Ltd What was the impact of one-way radio messages aimed at hostages kidnapped by the FARC and held captive in the Colombian jungle? Messages were read out every Saturday night (reception in the Colombian jungle is best between 01:00am and 04:00am) for 22 years. Here, radio animated emotional registers of lived experience as one-way radio messages intensified novel forms of imagination for both speaker, hearer and the ‘community’ of other hearers, in this case thousands of hostages dotted around the jungle. This article examines the linguistic instrumentality of the radio voice. By analysing the Voces del Secuestro messages, it is shown how a phenomenological listening of the radio voice gave hope in times of anguish.

© 2019 Wiley Periodicals, Inc. Background: Despite advances in treatment, the recurrence rates for laryngeal cancer range from 16% to 40%. Methods: Patients with recurrent laryngeal cancer treated at Memorial Sloan Kettering (MSK) from 1999 to 2016 were reviewed. Survival outcomes were analyzed. Results: Of 241 patients, 88% were male; the median age was 67 years; 71% had primary glottic tumors. At initial treatment, 72% of patients were seen with early stage disease; primary treatment was radiation (68%), chemoradiation (29%), and surgery (3%). The most common salvage surgery was total laryngectomy (74%). Forty-seven percentage were upstaged at salvage surgery. The 2- and 5-year disease-specific survival (DSS) was 74% and 57%, respectively. Patients with cT4 disease treated with nonsurgical primary management had a 0% 5-year DSS. Independent predictors of DSS were tumor location, perineural invasion, margin, and stage. Conclusions: Salvage surgery results in acceptable oncologic outcomes. Stage, disease site, perineural invasion, and margins are associated with inferior DSS.

© 2019 Elsevier B.V. S-Methyl methanethiosulfonate (MMTS) is used in experimental biochemistry for alkylating thiol groups of protein cysteines. Its applications include mainly trapping of natural thiol-disulfide states of redox-sensitive proteins and proteins which have undergone S-nitrosylation. The reagent can also be employed as an inhibitor of enzymatic activity, since nucleophilic cysteine thiolates are commonly present at active sites of various enzymes. The advantage of using MMTS for this purpose is the reversibility of the formation of methylthio mixed disulfides, compared to irreversible alkylation using conventional agents. Additional benefits include good accessibility of MMTS to buried protein cysteines due to its small size and the simplicity of the protection and deprotection procedures. In this study we report examples of MMTS application in experiments involving oxidoreductase (glyceraldehyde-3-phosphate dehydrogenase, GAPDH), redox-regulated protein (recoverin) and cysteine protease (triticain-α). We demonstrate that on the one hand MMTS can modify functional cysteines in the thiol enzyme GAPDH, thereby preventing thiol oxidation and reversibly inhibiting the enzyme, while on the other hand it can protect the redox-sensitive thiol group of recoverin from oxidation and such modification produces no impact on the activity of the protein. Furthermore, using the example of the papain-like enzyme triticain-α, we report a novel application of MMTS as a protector of the primary structure of active cysteine protease during long-term purification and refolding procedures. Based on the data, we propose new lines of MMTS employment in research, pharmaceuticals and biotechnology for reversible switching off of undesirable activity and antioxidant protection of proteins with functional thiol groups.

© 2019 Elsevier Ltd Introduction: Contemporary research papers have highlighted the issue of lesion-aphasia discordance in reference to the classic ‘associationist’ model provided by Wernicke-Lichtheim. The objective of the present study is to explore frequency, pattern and evolution of lesion-discordant aphasia following first ever acute stroke in Bengali-speaking subjects. Methods: Bengali version of Western Aphasia Battery, a validated scale, was used for language assessment in our study subjects. Lesion localization was done by using Magnetic resonance imaging (MRI) (3T) for ischemic stroke (if not contraindicated) and computed tomography (CT) for hemorrhagic stroke. Among 515 screened cases of first-ever acute stroke, 208 presented aphasia. Language assessment was done between 7 and 14 days in all study subjects and was repeated between 90 and 100 days in patients available for follow-up. Ischemic stroke cases with contraindication for MRI underwent CT imaging. Discordance between lesion and aphasic phenotype was determined only for right-handed subjects with cortical involvement (isolated or in combination with sub-cortical white matter) in the left hemisphere. Appropriate statistical tests were used to analyze the collected data. Results: Lesion-aphasia discordance was found in 20 out of 134 patients with aphasia who were dextral and had cortical involvement in the left hemisphere (14.92%). The pattern of discordance observed were- posterior lesion with Broca's aphasia (4; 20%); posterior lesion with global aphasia (8; 40%); anterior lesion with global aphasia (4; 20%), and posterior lesion with mixed transcortical aphasia (4; 20%). On univariate analysis, the factors significantly associated with lesion-aphasia discordance were hemorrhagic stroke (p = 0.000); posterior perisylvian location (p = 0.002), and higher education (p = 0.048). After adjusting for all other variables, hemorrhagic stroke was found to have strong association with lesion-aphasia discordance (p = 0.001, OR = 11.764, 95% CI, 2.83–50.0). Discordant cases were more likely to recover or change to a milder type compared to concordant cases (p = 0.007, OR = 11.393, 95% CI, 1.960–66.231), after adjusting for all other variables including initial severity of aphasia (p = 0.006, OR = 8.388, 95% CI, 1.816–38.749). Conclusion: Lesion-aphasia discordance following acute stroke is not uncommon among Bengali-speaking subjects. In the discordant group, preponderance towards non-fluent aphasia was observed. Discordance occurred more frequently after hemorrhagic stroke. Subjects with lesion-discordant aphasia presented better recovery during early post-stroke phase.

© The Author(s) 2019. Responses of five rotary blood pumps, namely HeartAssist 5, HeartMate II, HeartWare, Sputnik 1, and Sputnik 2, were extensively assessed in six test cases using a mathematical model of the cardiovascular system. Data for the rotary pumps were derived from pressure–flow curves reported in the literature. The test cases were chosen to attempt to cover most common clinical conditions, such as partial or full support or transitions between different levels of ventricular support. The investigated parameters are collected in a table and presented in figures, such as pressure–volume loops, H-Q curves, pump flow, and aortic pressure waveforms. HeartAssist, Sputnik 1, and Sputnik 2 pumps provide comparable level of aortic pressure, pump flow pulsatility PI(QP), and aortic pressure pulsatility PI(AoP) due to the similarity of pressure–flow characteristic curves of these pumps. HeartMate II provides a minimal backflow among other investigated rotary blood pumps due to the maximum pressure head at zero flow. HeartWare provides minimal pulsation of flow, which is confirmed by a flow range from −2 to 7 L/min in case 1. At the same time, the greatest degree of unloading was demonstrated by the HeartWare due to the flatness of the pressure–flow curve shape. The conclusions were made based on the obtained results, including the influence of pressure–flow curve shape on the pump performance and occurrences of adverse events, such as backflow or suction. For example, the increase of the pressure head at zero flow decreases the likelihood of backflow through the pump, and with it, increasing the flow under minimal pressure head increases the likelihood of suction.

© 2018 Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility with prevalence 1:20 000. Its incidence is probably underestimated due to unknown number of subjects having mild symptoms who may have never been diagnosed through entire life time. Classical EDS is characterized by pathogenic variants of genes encoding type V collagen. The biological effects and health risks of patients with EDS exposure to low doses of ionizing radiation is poorly understood. The aim of this study was to investigate biological effect of low doses of ionizing radiation in children with EDS. Background values of chromosome aberrations in children suffering from classical EDS were determined and compared with control subjects. The in vitro experiment was performed by γ-irradiation of blood lymphocytes from EDS patients and healthy subjects at low doses (0.1, 0.2 and 0.3 Gy). Results show a significant increase level of spontaneous and radiation-induced chromosomal aberrations in children suffering from EDS in comparison with the control subjects (p < 0.05). In conclusion, children with EDS express higher background chromosome aberration frequency and increased radiosensitivity. These findings suggest specific susceptibility of EDS patients and importance of future investigation on risks of diagnostics and therapy which include radiation and genotoxic agents.

© 2019 International Union of Crystallography. This study of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, C17H10N2O3, 1, and 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2H-chromen-2-one, C16H9ON3O3, 2, was performed on the assumption of the potential anticancer activity of the compounds. Three polymorphic structures for 1 and two polymorphic structures for 2 have been studied thoroughly. The strongest intermolecular interaction is stacking of the 'head-to-head' type in all the studied crystals. The polymorphic structures of 1 differ with respect to the intermolecular interactions between stacked columns. Two of the polymorphs have a columnar or double columnar type of crystal organization, while the third polymorphic structure can be classified as columnar-layered. The difference between the two structures of 2 is less pronounced. Both crystals can be considered as having very similar arrangements of neighbouring columns. The formation of polymorphic modifications is caused by a subtle balance of very weak intermolecular interactions and packing differences can be identified only using an analysis based on a study of the pairwise interaction energies.

© 2019 American Academy of Allergy, Asthma  &  Immunology Background: Mepolizumab is an anti–IL-5 antibody approved for the treatment of severe eosinophilic asthma. However, the prevalence of patients with severe asthma eligible for mepolizumab remains unknown, especially among children. Objective: To determine, in a population of patients with severe asthma from a tertiary referral center, the proportion of patients with an eosinophilic phenotype who would be eligible for mepolizumab, when stratified for the age of onset of asthma, and the prevalence of phenotypic features that favor mepolizumab therapy. Methods: An extensive database of 245 adults and children referred for severe asthma was used. The prevalence of severe asthma was estimated by using the European Respiratory Society/American Thoracic Society criteria. Patients with an eosinophilic uncontrolled phenotype qualified for mepolizumab. Results: In our cohort, 216 (88%) had severe asthma. Based on blood eosinophils of either greater than or equal to 150 cells/μL or greater than or equal to 300 cells/μL, 61%/41% had an eosinophilic phenotype, while 49%/34% were eligible for mepolizumab therapy. A greater percentage of adults (60%/47% of adults with asthma onset in adulthood [AoA] and 48%/26% adults with childhood-onset asthma [<18 years, CoA]) were eligible compared with children (33%/24%), for eosinophil counts of ≥150 and ≥300 cells/μL, respectively; P < .05. Compared with adults, children had a similar number of exacerbations while having better lung function (P < .05). Among adults, those with AoA were older, were more likely to have nasal polyps (28% vs 5%; P < .05), and had higher blood eosinophil counts (272 vs 150 cells/μL; P < .05) compared with those with CoA, with no difference in lung function noted between the 2 groups. Subjects showing greater than or equal to 500 eosinophils/μL, a strong indicator for mepolizumab therapy, had more nasal polyps, higher inhaled steroid dose, lower lung function, and AoA predominance than did those with less than 500 eosinophils/μL (P < .05). Conclusions: A smaller percentage of children with severe asthma were eligible for mepolizumab compared with their adult peers. Severe AoA has distinct phenotypic features that favor treatment with mepolizumab, including greater eosinophilia and nasal polyposis, in contrast to CoA, which appears to have fewer features of type 2 mucosal inflammation.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Background: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is the major cause of viral persistence in patients with chronic HBV infection. Understanding the mechanisms underlying stability and persistence of HBV cccDNA in hepatocytes is critical for developing novel therapeutics and managing chronic hepatitis B. In this study, we observed an unexpected increase in HBV cccDNA levels upon suppression of transcription by de novo DNA methyltransferase DNMT3A and uncovered additional mechanisms potentially involved in HBV cccDNA maintenance. Methods: HBV-expressing cell lines were transfected with a DNMT3A-expressing plasmid. Real-time PCR and HBsAg assays were used to assess the HBV replication rate. Cell cycling was analyzed by fluorescent cell sorting. CRISPR/Cas9 was utilized to abrogate expression of APOBEC3A and APOBEC3B. Alterations in the expression of target genes were measured by real-time PCR. Results: Similar to previous studies, HBV replication induced DNMT3A expression, which in turn, led to reduced HBV transcription but elevated HBV cccDNA levels (4-to 6-fold increase). Increased levels of HBV cccDNA were not related to cell cycling, as DNMT3A accelerated proliferation of infected cells and could not contribute to HBV cccDNA expansion by arresting cells in a quiescent state. At the same time, DNMT3A suppressed transcription of innate immunity factors including cytidine deaminases APOBEC3A and APOBEC3B. CRISPR/Cas9-mediated silencing of APOBEC3A and APOBEC3B transcription had minor effects on HBV transcription, but significantly increased HBV cccDNA levels, similar to DNMT3A. In an attempt to further analyze the detrimental effects of HBV and DNMT3A on infected cells, we visualized γ-H2AX foci and demonstrated that HBV inflicts and DNMT3A aggravates DNA damage, possibly by downregulating DNA damage response factors. Additionally, suppression of HBV replication by DNMT3A may be related to reduced ATM/ATR expression. Conclusion: Formation and maintenance of HBV cccDNA pools may be partially suppressed by the baseline expression of host inhibitory factors including APOBEC3A and APOBEC3B. HBV inflicts DNA damage both directly and by inducing DNMT3A expression.

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Background: Epidemiologic studies that investigated alcohol consumption in relation to the risk of bladder cancer (BCa) have demonstrated inconsistent results. We conducted a systematic review and meta-analysis of the literature to investigate the association of alcohol including different types of alcoholic beverages consumption with the risk of BCa. Materials and methods: A systematic search of Web of Science, Medline/PubMed and Cochrane library was performed in May 2018. Studies were considered eligible if they assessed the risk of BCa due to alcohol consumption (moderate or heavy dose) and different types of alcoholic beverages (moderate or heavy dose) in multivariable analysis in the general population (all genders, males or females) or compared with a control group of individuals without BCa. Study design: observational cohorts or case–control. Results: Sixteen studies were included in this meta-analysis. Moderate and heavy alcohol consumption did not increase the risk of BCa in the entire population. Sub-group and sensitivity analyses revealed that heavy alcohol consumption increased significantly the risk of BCa in the Japanese population, RR 1.31 (95% CI 1.08–1.58, P < 0.01) in the multivariable analysis, and in males RR of 1.50 (95% CI 1.18–1.92, P < 0.01), with no significant statistical heterogeneity. Moreover, heavy consumption of spirits drinks increased the risk of BCa in males, RR 1.42 (95% CI 1.15–1.75, P < 0.01). Conclusion: In this meta-analysis, moderate and heavy alcohol consumption did not increase the risk of bladder cancer significantly. However, heavy consumption of alcohol might increase the risk of BCa in males and in some specific populations.

© 2019 Context: This overview presents the updated European Association of Urology (EAU) guidelines for non–muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ (CIS). Objective: To provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation and recommendations. Evidence acquisition: A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines has been performed annually since the last published version in 2017. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned. Evidence synthesis: Tumours staged as Ta, T1, and/or CIS are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of the tissue obtained by transurethral resection (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a T1 tumour is detected, a second TURB should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system. Stratification of patients into low-, intermediate-, and high-risk groups is pivotal to the recommendation of adjuvant treatment. In patients with tumours presumed to be at a low risk and in those presumed to be at an intermediate risk with a low previous recurrence rate and an expected EORTC recurrence score of <5, one immediate chemotherapy instillation is recommended. Patients with intermediate-risk tumours should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at the highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-unresponsive tumours. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. Conclusions: These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary: The European Association of Urology Non–muscle-invasive Bladder Cancer (NMIBC) Panel has released an updated version of their guidelines, which contains information on classification, risk factors, diagnosis, prognostic factors, and treatment of NMIBC. The recommendations are based on the current literature (until the end of 2018), with emphasis on high-level data from randomised clinical trials and meta-analyses. Stratification of patients into low-, intermediate-, and high-risk groups is essential for deciding appropriate use of adjuvant intravesical chemotherapy or bacillus Calmette-Guérin (BCG) instillations. Surgical removal of the bladder should be considered in case of BCG-unresponsive tumours or in NMIBCs with the highest risk of progression.

Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.

© 2019 Elsevier Inc. The article introduces a finite-volume method for the Darcy problem in heterogeneous anisotropic media. The method is based on the mixed formulation for the pressure and its gradient. The method is stable despite collocation of both pressure and its gradient at cell centers and demonstrates the first order convergence on numerous benchmarks as well as good monotonicity property. The method produces quasi-definite matrix, which is numerically shown to have good asymptotics of the condition number. Our flux discretization method is a realization of our more general concept of stable flux discretization for saddle-point systems with vector of several unknowns. In this paper this vector is composed of pressure and its gradient and the saddle-point system is the mixed formulation of the Darcy problem.

© 2019 by the authors. Oligonucleotides with an antiproliferative activity for human cancer cells have attracted attention over the past decades; many of them have a G-quadruplex structure (GQ), and a cryptic target. In particular, DNA oligonucleotide HD1, a minimal GQ, could inhibit proliferation of some cancer cell lines. The HD1 is a 15-nucleotide DNA oligonucleotide that folds into a minimal chair-like monomolecular antiparallel GQ structure. In this study, for eight human cancer cell lines, we have analyzed the antiproliferative activities of minimal bimodular DNA oligonucleotide, biHD1, which has two HD1 modules covalently linked via single T-nucleotide residue. Oligonucleotide biHD1 exhibits a dose-dependent antiproliferative activity for lung cancer cell line RL-67 and cell line of central nervous system cancer U87 by MTT-test and Ki-67 immunoassay. The study of derivatives of biHD1 for the RL-67 and U87 cell lines revealed a structure-activity correlation of GQ folding and antiproliferative activity. Therefore, a covalent joining of two putative GQ modules within biHD1 molecule provides the antiproliferative activity of initial HD1, opening a possibility to design further GQ multimodular nanoconstructs with antiproliferative activity—either as themselves or as carriers.