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Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetően gyógyíthatatlan betegség, ezért nagy klinikai jelentőségük van az eredményes mentő kezeléseknek. A szájon át adható első proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekből álló kombináció, mely hazánkban 2015 áprilisától kezdődően a „Named Patient Program” keretén belül vált elérhetővé relabált, refrakter myeloma multiplexes betegek kezelésére. Célkitűzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélők célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeső beteg részesült e triplet kezelésben, adataikat retrospektíven elemeztük. Leíró statisztikai és Kaplan–Meier-analízist végeztünk. Eredmények: A betegek nagyobb hányada reagált: 63,75%-os válaszarány mellett 14 (17,5%) betegnél nem volt terápiás válasz/stabil betegség alakult ki, és 15-nél (18,75%) a betegség a kezelés mellett is progrediált. A progressziómentes túlélés a teljes betegcsoportban 10,6 hónapnak adódott, ugyanakkor 16 beteg (18,75%) két éven túl progressziómentesnek bizonyult, sőt közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélő betegcsoport tulajdonságait tárjuk fel. Megbeszélés: A folyamatos terápia a myeloma multiplex kezelésében meghatározóvá vált. Ezért fontos ismernünk, hogy kik lehetnek azok a betegek, akik különösen sokat profitálnak egy bizonyos terápiából. A hosszú távon progressziómentes túlélők között az immunglobulin-nehézláncot érintő transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezőbb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét mérő nemzetközi stádiumbeosztás (ISS) nem jelezte előre a hosszú túlélést. Gyógyszerelhagyáshoz vezető mellékhatást a hosszú távú túlélő csoportban egyet sem regisztráltunk; az észlelt mellékhatások nagy része enyhe volt. Következtetések: Munkánk során az ixazomib-lenalidomid-dexametazon kombinációt effektívnek és biztonságosnak találtuk relabált, refrakter myeloma multiplex kezelésére, mely a betegek mintegy hatodánál több éven át eredményesen alkalmazható. Cikkünkkel a hazai beteganyagon szerzett tapasztalatainkat szeretnénk megosztani a COVID–19-világjárvány alatt különösen aktuálissá vált, tisztán orális terápiás lehetőségről. Orv Hetil. 2021; 162(36): 1451–1458. Summary. Introduction: Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program. Objective: Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet. Method: We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed. Results: Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup. Discussion: The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation. Conclusion: Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID–19 pandemic. Orv Hetil. 2021; 162(36): 1451–1458.

Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation (including funduscopy, fluorescein angiography, Doppler sonography, optical coherence tomography [OCT] and optical coherence tomography angiography [OCTA]) are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered.

Összefoglaló. A Bruton-féle tirozin-kinázt gátló ibrutinib és a B-sejtes lymphoma-2-t gátló venetoklax a krónikus lymphoid leukaemia (CLL) kezelésének egyre korábbi vonalában alkalmazható, és ezek mellett a progressziómentes túlélés növekedése figyelhető meg. A célzott kismolekulákkal végzett kezelés nemcsak a CLL lefolyását, de a betegek gondozását is alapvetően megváltoztatta. A tartósan adagolt orális szerek mellett a betegek nagyobb valószínűséggel jelennek meg a panaszaiknak megfelelő szakrendeléseken. Az új típusú szerek hatásai és mellékhatásai mellett az alapvető gyógyszer-interakciókra is fel kell hívni a figyelmet. Kiemelt fontosságú az ibrutinib hypertoniát provokáló hatása, illetve a 6–16%-ban megjelenő pitvarfibrilláció. Ez utóbbi ellátását a gyógyszer-interakciókon túl az ibrutinib vérzékenységet okozó hatása is nehezíti. A CLL-lel, illetve annak kezelésével kapcsolatos ismeretek a másodlagos daganatok, néhány gastrointestinalis és bőrgyógyászati betegség megközelítése szempontjából is fontosak. A venetoklax mellett potenciálisan kialakuló tumorlízis-szindróma alkalmanként a nefrológusok bevonását igényli. A betegek gondozása, megfelelő szakszerű ellátása és a betegutak optimalizálása érdekében a háziorvosok, a sürgősségi ellátók és az egyéb szakellátó helyek szoros együttműködése szükséges szakorvosi konzultáció keretei között. Orv Hetil. 2021; 162(9): 336–343. Summary. Chronic lymphocytic leukemia (CLL) is ubiquitously treated with novel agents. The Bruton’s tyrosine kinase inhibitor ibrutinib and the B-cell lymphoma 2 inhibitor venetoclax can be used increasingly in earlier lines of treatment with improved progression-free survival. Treatment with targeted small molecules fundamentally changed not only the course of CLL but also the care of patients. With the administration of long-term oral medications, patients are more likely to show up at specialist clinics that match their complaints. In addition to the effects and side effects of the new drugs, attention should also be drawn to basic drug interactions. The effect of ibrutinib on blood pressure and the ability to provoke atrial fibrillation in 6–16% of cases are of paramount importance. In addition to drug interactions, the treatment of the latter is also complicated by the hemorrhagic effect of ibrutinib. Knowledge on CLL and its treatment is also important in the approach to secondary tumors, some gastrointestinal and dermatological diseases. The potential for tumor lysis syndrome of venetoclax requires close collaboration with nephrologists. In order to provide appropriate professional care and optimize patient pathways, close co-operation between GPs, emergency care providers and other specialist care facilities is required within the framework of professional consultation. Orv Hetil. 2021; 162(9): 336–343.

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups. Key Points: • The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations. • Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL.

Summary Background Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov , NCT02654990 . Findings Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8–24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8–72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8–75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4–61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3–4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3–4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. Funding Novartis Pharmaceuticals and Secura Bio.

Today’s consumers require food products with fresh, or fresh-like characteristics. Minimal processing technologies are indicated as technologies with a gentle impact on sensorial and techno-functional properties. High Hydrostatic Pressure (HHP) is a widely used minimal technology considered as a cold pasteurization method in food preservation. The effect of applied pressure of HHP is well understood, but the holding time of HHP treatment is not extensively investigated in topic of proteins. One of the most important attribute of liquid egg products are the great foaming ability, foaming stability as well as emulsifying properties. These techno-functional properties are highly influenced by the protein structures of egg products. In our study, liquid egg products were pressurized at 400 MPa, for 1, 3, 5 7 and 10 minutes. The protein structures of liquid egg white (LEW), liquid egg yolk (LEY) and liquid whole egg (LWE) were investigated using Differential Scanning Calorimetry (DSC).Our study pointed out that after HHP treatment at 400 MPa, for 10 minutes 12% decrease in denaturation enthalpy of LWE was observed. In LEY 30% decrease was detected after 10 minutes HHP treatment. The highest impact of HHP treatment (35% decrease in denaturation enthalpy) in LWE was noted. The changes in protein structures of liquid egg products were smaller, than the effects of higher pressure applied for preservation. In aspects of techno-functional properties applying a longer holding time is more favourable, than applying a higher pressure.

Mid-infrared (IR) ellipsometry of thin films and molecule layers at solid–liquid interfaces has been a challenge because of the absorption of light in water. It has been usually overcome by using c...

Cognitive impairment and dementia are major medical, social, and economic public health issues worldwide with significant implications for life quality in older adults. The leading causes are Alzheimer’s disease (AD) and vascular cognitive impairment/dementia (VCID). In both conditions, pathological alterations of the cerebral microcirculation play a critical pathogenic role. Currently, the main pathological biomarkers of AD—β-amyloid peptide and hyperphosphorylated tau proteins—are detected either through cerebrospinal fluid (CSF) or PET examination. Nevertheless, given that they are invasive and expensive procedures, their availability is limited. Being part of the central nervous system, the retina offers a unique and easy method to study both neurodegenerative disorders and cerebral small vessel diseases in vivo. Over the past few decades, a number of novel approaches in retinal imaging have been developed that may allow physicians and researchers to gain insights into the genesis and progression of cerebromicrovascular pathologies. Optical coherence tomography (OCT), OCT angiography, fundus photography, and dynamic vessel analyzer (DVA) are new imaging methods providing quantitative assessment of retinal structural and vascular indicators—such as thickness of the inner retinal layers, retinal vessel density, foveal avascular zone area, tortuosity and fractal dimension of retinal vessels, and microvascular dysfunction—for cognitive impairment and dementia. Should further studies need to be conducted, these retinal alterations may prove to be useful biomarkers for screening and monitoring dementia progression in clinical routine. In this review, we seek to highlight recent findings and current knowledge regarding the application of retinal biomarkers in dementia assessment.

Purpose: To compare the macular morphology of good and poor responders to eplerenone treatment in chronic central serous chorioretinopathy (CSCR) patients. Methods: 30 eyes of 29 patients with chronic CSCR were treated with 50 mg/day oral eplerenone and followed up for one year. The integrity of outer retinal layers at baseline was assessed using optical coherence tomography. Patients who showed complete resolution of subretinal fluid at one year were assigned to the good responder group (Group 1), whilst those who showed moderate or no resolution were classified as poor responders (Group 2). Results: Ellipsoid zone interruption, ELM interruption and hyperreflective foci in outer segment (OS) and outer nuclear layer (ONL) was significantly more frequent in Group 2 than in Group 1 (pConclusion: There is higher chance of the resolution of subretinal fluid after eplerenone treatment in CSCR patients with intact outer retinal layers at baseline. Baseline morphologic evaluation of the outer retinal layers on OCT scans can be useful in predicting the response to mineralocorticoid receptor antagonist therapy in these patients.

Pincer ligands occupy three coplanar sites at metal centers and often support both stability and reactivity. The five-coordinate [FeIIICl2(tia-BAI)] complex (tia-BAI&minus, = 1,3-bis(2&rsquo, thiazolylimino)isoindolinate(&minus, )) was considered as a potential pre-catalyst for water oxidation providing the active form via the exchange of chloride ligands to water molecules. The tia-BAI&minus, pincer ligand renders water-insolubility to the Fe&ndash, (tia-BAI) assembly, but it tolerates the presence of water in acetone and produces electrocatalytic current in cyclic voltammetry associated with molecular water oxidation catalysis. Upon addition of water to [FeIIICl2(tia-BAI)] in acetone the changes in the Fe3+/2+ redox transition and the UV-visible spectra could be associated with solvent-dependent equilibria between the aqua and chloride complex forms. Immobilization of the complex from methanol on indium-tin-oxide (ITO) electrode by means of drop-casting resulted in water oxidation catalysis in borate buffer. The O2 detected by gas chromatography upon electrolysis at pH 8.3 indicates &gt, 80% Faraday efficiency by a TON &gt, 193. The investigation of the complex/ITO assembly by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS) before and after electrolysis, and re-dissolution tests suggest that an immobilized molecular catalyst is responsible for catalysis and de-activation occurs by depletion of the metal.

BACKGROUND: Hypertriglyceridemia is the third most common cause of acute pancreatitis (AP). It has been shown that hypertriglyceridemia aggravates the severity and related complications of AP; however, detailed analyses of large cohorts are contradictory. Our aim was to investigate the dose-dependent effect of hypertriglyceridemia on AP. METHODS: AP patients over 18 years old who underwent triglyceride measurement within the initial three days were included into our cohort analysis from a prospective international, multicenter AP registry operated by the Hungarian Pancreatic Study Group. Data on 716 AP cases were analyzed. Six groups were created based on the highest triglyceride level (

Herein, we compare the electrochemical and electrocatalytic properties of two selected, water-insoluble Fe(II) coordination complexes made with the non-symmetric, bidentate ligands, 2-(2′-pyridyl)benzimidazole (PBI) in [Fe(PBI)3](OTf)2 (1, OTf− = trifluoromethyl sulfonate anion) and 2-(2′-pyridyl)benzoxazole (PBO) in [Fe(PBO)2(OTf)2] (2) . Cyclic voltammetry in water/acetonitrile mixture indicates considerable activity for both compounds. However, only 1 acts as homogeneous catalyst. The complexes have been successfully immobilized on indium-tin-oxide (ITO) electrode surface. The hydrophobic ligands allowed for a simple dip-coating and drop-casting of 1 and 2 onto ITO. Both 1/ITO and 2/ITO showed increased activity in electrocatalytic O2 evolution in borate buffer at pH 8.3. According to scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), moreover, re-dissolution tests, the Fe remains in complex with PBI during electrolysis in the drop-casted, nano-porous films of 1/ITO. In contrast, the PBO complex in 2/ITO undergoes a rapid in situ decomposition yielding a mineralized form that is responsible for catalysis.

Sitagliptin (SITA) is an antidiabetic drug consumed worldwide in high quantities. Because of the low removal rate of this compound in conventional wastewater treatment plants (WWTPs), it enters receiving surface waters with the discharged WWTP effluents. SITA can be detected up to μg/L concentration in rivers. In this study, UV (254 nm) and (V)UV (185 nm + 254 nm) irradiation was applied in laboratory scale to degrade SITA. The effect of three parameters was evaluated on the degradation rate, namely i) the efficiency in UV and (V)UV irradiation, ii) the presence or absence of dissolved oxygen, iii) the matrix effect of WWTP effluent. Degradation rate of SITA was largely increased by (V)UV irradiation, and decreased in WWTP effluent as expected. The presence of dissolved oxygen increased the degradation rate only in UV experiments and did not have a considerable effect in (V)UV experiments. In total, 14 transformation products (TPs) were identified (twelve new); their structures were proposed based on high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy analyses. The most characteristic reaction steps of the degradation of SITA involved nucleophilic aromatic photosubstitution whereas hydroxide ions acted as attacking nucleophiles and replaced F atoms of the phenyl moiety by hydroxide groups, in agreement with the increase in photolysis rate with increasing pH. The photochemical degradation pathway of SITA was also interpreted. Kinetic profiles revealed TP 421, TP 208 and TP 192 to be the most recalcitrant TPs.

PURPOSE Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). METHODS Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of progression-free survival (PFS). RESULTS Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. CONCLUSION In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

TiO2-C (carbon) hybrid materials are promising electrocatalyst supports because the presence of TiO2 results in enhanced stability. Use of new types of carbonaceous materials such as reduced graphene oxide (rGO) instead of traditional active carbon provides certain benefits. Although the rutile polymorph of TiO2 seems to have the most beneficial properties in these hybrid materials, the anatase type is more frequent in TiO2-rGO composites, especially in graphite oxide (GO) derived ones, as GO has several properties which may interfere with rutile formation. To explore and evaluate these peculiarities and their influence on the composite formation, we compared TiO2-C systems formulated with GO and Black Pearls (BP) carbon. Various physicochemical methods, such as attenuated total reflection infrared (ATR-IR)-, solid state NMR-, Raman- and X-ray photoelectron spectroscopy, X-ray powder diffraction (XRD), electron microscopy, etc. were used to characterize the samples from the different stages of our multistep sol-gel synthesis. Our experiments demonstrated that utilization of GO is indeed feasible for composite preparation, although its sodium contamination has to be removed during the synthesis. On the other hand, high temperature treatment and/or solvothermal treatment during composite synthesis resulted in decomposition of the functional groups of the GO and the functional properties of the final product were similar in case of both composites. However, Pt/TiO2-GO derived sample showed higher oxygen reduction reaction (ORR) activity than Pt/TiO2-BP derived one. Based on the decrease of electrochemical surface area, the stability order was the following: Pt/C (commercial) < Pt/TiO2-BP derived C < Pt/TiO2-GO derived C.

Plant-based meat analogues (i.e., plant-based meat alternatives or substitutes, or vegan meats) are becoming more and more popular. The quality of the available products is constantly increasing therefore their consumption is also increasing. The primary role of meat analogues is to replace the meat component in meals while appropriate nutrient content and hedonic value will be provided as well. The food safety aspects of these newly emerging food products are less investigated. The aim of this study is to compare the microbial spoilage of identical meals prepared with meat and meat analogues to evaluate the food safety risk of meat analogues. In this work, raw protein materials were tested. Moreover, three pairs of meals prepared with or without meat were microbiologically examined during a storage experiment. Microbial contaminants were low in raw protein sources. In the case of hot meals, the microbial proliferation was faster in samples containing meat analogue, especially if the meals were not cooled. The food safety risk of meals prepared with meat analogues is slightly higher than their meat-containing counterparts, therefore more attention needs to be paid to the preparation, processing, and storage of these foods.

Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs >75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients >75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Carotid artery stenosis (CAS) is among the leading causes of mortality and permanent disabilities in the Western world. CAS is a consequence of systemic atherosclerotic disease affecting the majority of the aging population. Optical coherence tomography angiography (OCTA) is a novel imaging technique for visualizing retinal blood flow. It is a noninvasive, fast method for qualitative and quantitative assessment of the microcirculation. Cerebral and retinal circulation share similar anatomy, physiology, and embryology; thus, retinal microvasculature provides a unique opportunity to study the pathogenesis of cerebral small vessel disease in vivo. In this study, we aimed to analyze the effect of systemic risk factors on retinal blood flow in the eyes of patients with significant carotid artery stenosis using OCT angiography. A total of 112 eyes of 56 patients with significant carotid stenosis were included in the study. We found that several systemic factors, such as decreased estimated glomerular filtration rate (eGFR), hypertension, and carotid occlusion have a significant negative effect on retinal blood flow, while statin use and carotid surgery substantially improve ocular microcirculation. Neither diabetes, clopidogrel or acetylsalicylic acid use, BMI, serum lipid level, nor thrombocyte count showed a significant effect on ocular blood flow. Our results demonstrate that a systematic connection does exist between certain systemic risk factors and retinal blood flow in this patient population. OCTA could help in the assessment of cerebral circulation of patients with CAS due to its ability to detect subtle changes in retinal microcirculation that is considered to represent changes in intracranial blood flow.

The properties of Sn99Ag0.3Cu0.7 (SACX0307) solder alloy reinforced with ZnO nanoparticles were investigated. The primary ZnO particle sizes were 50, 100, and 200 nm. They were added to a solder paste at a ratio of 1.0 wt %. The wettability, the void formation, the mechanical strength, and the thermoelectric parameters of the composite solder alloys/joints were investigated. Furthermore, microstructural evaluations were performed using scanning electron and ion microscopy. ZnO nanoparticles decreased the composite solder alloys’ wettability, which yielded increased void formation. Nonetheless, the shear strength and the thermoelectric parameters of the composite solder alloy were the same as those of the SACX0307 reference. This could be explained by the refinement effects of ZnO ceramics both on the Sn grains and on the Ag3Sn and Cu6Sn5 intermetallic grains. This could compensate for the adverse impact of lower wettability. After improving the wettability, using more active fluxes, ZnO composite solder alloys are promising for high-power applications.

Absztrakt: A kronikus limfocitas leukemia a nyugati vilagban leggyakrabban előfordulo felnőttkori leukemiatipus, mely heterogen klinikai lefolyassal es valtozatos genetikai hatterrel tarsul. A szel...

In this paper, the relationship between the crystallographic structure of Cu-Sn intermetallic grains and Sn whisker growth was investigated. In order to prevent the influence of the elements in the alloy composition and the effect of the soldering process on the formation of the intermetallic layer, 99.99% pure Sn was vacuum evaporated onto Cu substrates. The Sn layer thickness was sub-micron region (∼400 nm in average) to reach considerable and rapid compressive stress on the tin layer originated by the intermetallic formation. The samples were stored at room temperature for 1 month. Different types of whiskers (nodule and filament) and the layer structure underneath were studied with a scanning ion microscopy and transmission electron microscopy. It was found that not only the thickness of the intermetallic layer and shape of the intermetallic grains affects the whisker growth but the crystallographic structure of the intermetallic grains as well. The susceptibility of the Sn layer to whisker development is higher in those regions where the intermetallic layer is composed of monocrystalline grains instead of those regions, where it is composed of polycrystalline grains. This effect can be explained by the higher compressive stress generated by the monocrystalline intermetallics compared to the polycrystalline ones.

Antibacterial and antifungal ability of silver nanoparticles (Ag NPs) supported by functionalized magnetite (Fe 3 O 4 ) with 5-aminosalicylic acid (5-ASA) was tested against Gram-negative bacteria Escherichia coli, Gram-positive bacteria Staphylococcus aureus and yeast Candida albicans. Characterization of materials including transmission electron microscopy, X-ray diffraction analysis, and inductively coupled plasma optic emission spectroscopy technique followed each step during the course of nanocomposite preparation. The synthesized powder consists of 30–50 nm in size silver particles surrounded by clusters of smaller (∼10 nm) Fe 3 O 4 particles. The content of silver in the nanocomposite powder was found to be slightly above 40 wt.–%. Concentration-dependent and time-dependent bacterial reduction measurements in dark indicated that use of Ag NPs leads to the complete reduction of E. coli and S. aureus even at the concentration level of silver as low as 40 μg/mL. However, the negligible antifungal ability of synthesized nanocomposite was found against yeast C. albicans in the entire investigated concentration range (0.1-2.0 mg/mL of the nanocomposite, i. e., 40–800 μg/mL of silver). Complete inactivation of E. coli and S. aureus was achieved in five repeated cycles indicated that synthesized nanocomposite can perform under long-run working conditions. From the technological point of view, magnetic separation is the additional advantage of synthesized nanocomposite for potential use as an antibacterial agent. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Ferrofluids based on magnesium substituted magnetite nanoparticles MgxFe3−xO4 (x = 0.1; 0.2; 0.4) were synthesised by a chemical co-precipitation method. Their physical properties have been compared with those of the magnetite based ferrofluid obtained by the same synthesis route. Both XRD and TEM studies showed particle size decrease with the increased Mg content while DLS experiments pointed to the more prominent aggregation of Mg-containing nanoparticles. Magnetic properties investigation conducted on the powder (i.e. dried) specimens showed decrease of magnetization values with increased Mg content except for the lowest concentration of x = 0.1 where substantial saturation magnetization rise of about 40% was recorded at room temperature. Heating abilities of the studied ferrofluids under the applied AC fields (SAR values) also showed decreasing trend with the increased Mg content even for x = 0.1 sample despite its elevated magnetization value. This trend has been understood as a consequence of the changed intrinsic nanoparticle properties such as size and magnetic anisotropy, as well as contribution of a collective behaviour due to an increased nanoparticle aggregation in Mg-doped systems.

The Fenton reaction, Fe(H2O)62+ + H2O2 → Oxidizing product, is of major importance in biology as the major cause of oxidative stress, and in advanced oxidation processes. It is commonly assumed that ·OH is the product of the Fenton reaction. The results presented herein point out that ·OH is indeed the oxidizing product in acidic solutions for [Fe(H2O)62+] > [H2O2]; FeIVaq is the active oxidizing product in neutral solutions; in slightly acidic solutions for [H2O2] > [Fe(H2O)62+] a mixture of ·OH and FeIVaq is formed. However CO3·- is the active oxidizing product in neutral solutions containing HCO3- even at low concentrations, i.e. under physiological conditions. The implications to our understanding of the origins of oxidative stress and of catalytic oxidations in advanced oxidation processes are discussed.

Silica-supported Ni catalyst (6.6 wt% Ni) was prepared and tested in solvent-free hydroconversion of levulinic acid (LA) using flow-through fixed-bed tube-type microreactor at 250 and 275 °C in the pressure and space time range of 1–30 bar and 0.1–1.0 gcat g LA −1 h, respectively. The catalyst was characterized by XRD, adsorption/desorption N2 isotherms, temperature-programmed H2-reduction (H2-TPR), FT-IR spectra of adsorbed pyridine (Py), and temperature-programmed H2 desorption (H2-TPD). At 250 °C and 1 bar total pressure LA was dehydrated to α-angelica lactone (AL) intermediate that was hydrogenated to γ-valerolactone (GVL). At space time 0.25 gcat g LA −1 h 82% GVL selectivity was achieved at virtually full LA conversion. The GVL became partially converted to pentanoic acid (PA). At longer space time, 1.0 gcat g LA −1 h, the PA selectivity increased to 37%. At pressure > 1 bar the favored reaction of GVL was the hydrogenolysis of its ester bond and dehydration of the intermediate 1,4-pentanediol (1,4-PD) to 2-methyltetrahydrofuran (2-MTHF). At 250 °C and 30 bar the yield of 2-MTHF was 56 mol%. The product distribution is controlled by the relative activity of the Ni/SiO2 catalyst in the hydrogenolysis of the GVL C–O bonds.

The presented research aimed to confirm that the differences in the lipid peroxidation of three maize (Zea mays L.) hybrids with different genotypes and maturity are due to different nitrogen levels, which was observed based on the amount of malondialdehyde (MDA) measured in the leaves at the main phenological stages of plants. The experiments were performed in a multi-factorial long term fertilisation field trial. In the study, phosphorus and potassium were constantly provided at the optimal level for the plants. The phosphorus and potassium fertilisation were applied in autumn. However, N levels varied from 0 to 300 kg ha−1. Sampling was done at different growth stages 5 times during the growing season (4 leaves, 6 leaves, 8 leaves, 14 leaves, silking). The 300 kg ha−1 N (dose 3) resulted in a significant increase in lipid peroxidation (MDA level), but not a statistically significant difference between the control (dose 1) and the 120 kg ha−1 (dose 2) N doses. The H1 hybrid had the lowest level of lipid peroxidation at the first sampling date. High volume nitrogen fertilisation (dose 3: 300 kg ha−1) increased lipid peroxidation in the hybrids. Averaging the values obtained for the same hybrid at the different sampling times, the medium (dose 2) 120 kg ha−1 N treatment had no significant effect on the lipid peroxidation of the hybrids compared to the values of the control plants. Based on the lipid peroxidation response of the hybrids to N treatment, the exact N dose inflection point can be determined to make the fertiliser utilisation of plants more efficient. Based on our results, we found that inadequate, low (120 kg ha−1) or high (300 kg ha−1) nitrogen fertilisation could affect the MDA levels of plants, thereby affecting the functioning of the lipid peroxidation mechanism.

Background Despite therapeutic advances, multiple myeloma remains incurable. Venetoclax, a selective bcl-2 inhibitor may be a step toward personalised therapy for t(11;14) patients, but questions remain about its optimal use. Methods We retrospectively evaluated hematologic response, survival and safety after venetoclax treatment in t(11;14) myeloma patients in Hungary. Results Overall, 49 patients from seven clinical centers were reported. We divided patients into two groups based on the clinical setting: 32 relapsed/refractory patients, who received venetoclax after multiple lines of therapy, often in an ultimate effort; and 17 frontline patients, who achieved unsatisfactory response to standard first line therapy and were treated with venetoclax as reinduction before intended ASCT. We observed remarkably good hematological response rates (ORR): 94% in the relapsed/refractory group and 100% in the frontline setting. This translated into a median PFS of 9.6 months and a median OS of 14.6 months in the relapsed group; median PFS and OS were not reached in the reinduction group. Known adverse prognostic factors, such as 17p deletion, kidney failure or 1q21 amplification did not convey significantly worse prognosis in our study. Almost one third of patients had impaired kidney function during venetoclax therapy, including three patients requiring dialysis. Clinically relevant improvement was observed in 42% of these patients; dialysis could be stopped in all three cases. Notably, our study also included six plasma cell leukemia patients, with a remarkable median PFS of 10 months and over one year median OS in relapsed disease. Vulnerable patients with PCL, renal failure or refractory disease reported more adverse events, requiring supportive measures or dose adjustment, but cessation of venetoclax therapy did not become necessary. Conclusion Venetoclax therapy is a promising option with few side effects and very good response rates for t(11;14) patients, both in the frontline and in the relapsed setting

The environmental monitoring of Ni is targeted at a threshold limit value of 0.34 mu M, as set by the World Health Organization. This sensitivity target can usually only be met by time-consuming and expensive laboratory measurements. There is a need for inexpensive, field-applicable methods, even if they are only used for signaling the necessity of a more accurate laboratory investigation. In this work, bioengineered, protein-based sensing layers were developed for Ni detection in water. Two bacterial Ni-binding flagellin variants were fabricated using genetic engineering, and their applicability as Ni-sensitive biochip coatings was tested. Nanotubes of mutant flagellins were built by in vitro polymerization. A large surface density of the nanotubes on the sensor surface was achieved by covalent immobilization chemistry based on a dithiobis(succimidyl propionate) cross-linking method. The formation and density of the sensing layer was monitored and verified by spectroscopic ellipsometry and atomic force microscopy. Cyclic voltammetry (CV) measurements revealed a Ni sensitivity below 1 mu M. It was also shown that, even after two months of storage, the used sensors can be regenerated and reused by rinsing in a 10 mM solution of ethylenediaminetetraacetic acid at room temperature.

Synthesis atmosphere (i.e., air and nitrogen) effects on the physical properties and formation mechanism of spinel iron oxide nanoparticles prepared via the co-precipitation method have been investigated using a multi-technique approach. The obtained magnetic nanoparticles (MNPs) were characterized using the X-ray diffraction, transmission electron microscopy (TEM), SQUID magnetometry, Mössbauer spectroscopy and X-ray absorption near-edge Structure spectroscopy techniques. The synthesis procedure leads to the formation of a spinel structure with an average crystallite size of 9.0(9) nm. The morphology of the particles synthetized under an inert atmosphere was quasi-spherical, while the nanoparticles prepared in air present a faceted shape. The small differences observed in morphological properties are explained by the influence of the reaction atmosphere on the formation mechanism of the MNPs. The magnetic characterization indicates that both samples exhibit superparamagnetic behavior at 300 K. The investigation by means of the Langevin approach at 300 K also leads to equal values for the mean size of the magnetic cores (Dm). Additionally, the analysis of the Mössbauer spectra revealed the lack of spin disorder for both samples, resulting in a high saturation magnetization. The fit of XANES spectrum suggests that about 2/3 of the iron ions reside in a local environment close to that of γ-Fe2O3 and about 1/3 close to that of Fe3O4 for the sample synthetized in inert atmosphere.

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

Trans fatty acids are formed during the industrial processing of food, and are proven to be harmful for the human body. They have been associated with increased risk of cardiovascular disease, abdominal obesity, diabetes, and certain types of cancer. Decree 71/2013. (XI. 20.) of the Ministry of Human Capacities, which has been in force since 2014, defines the highest permitted amount of trans fats in food products placed on the market in Hungary. The impact of the decree on the industrially produced trans fatty acids (iTFA) availability and population intake was assessed in 2017. Results demonstrated that iTFA were replaced by other fatty acids due to the legislation. In 2019, we investigated food groups which had high measured TFA content before the regulation entered into force and compared the total fat and fatty acid profiles to the same brand or similar products being on the market afterwards. In collaboration with the World Health Organization, this was the first assessment to determine to which extent manufacturers increased saturated fat (SFA) content of foodstuffs to reduce iTFA content. In those product groups, which were identified as significant food sources of iTFA before introducing the regulation (biscuits, coffee creamers and flavorings, sweets, bakery products, confectionary, wafers, margarines) we found no significant changes in the total fat content, while in most foodstuffs the average proportion of SFA was higher after reformulation, as iTFA were mainly substituted with SFA in 61% of the products, with cis-MUFA in 25% and cis-PUFA in 14% of the products, respectively. Evidence from this analysis supports concerns that eliminating iTFA in certain foodstuffs leads to unwanted substitution with saturated fat, hence reducing the possible health benefits. Given the high SFA intake and the unfavourable cardiovascular statistics in Hungary, the consumption frequency and portion size control of these products are advised. Key messages Monitoring the changes of food composition is important in order to evaluate the effect of the regulation. Manufacturers should be encouraged to reduce the SFA content to a technologically feasible level.

Face masks are becoming one of the most useful personal protective equipment with the outbreak of the coronavirus (CoV) pandemic. The entire world is experiencing shortage of disposable masks and melt-blown non-woven fabrics, which is the raw material of the mask filter. Recyclability of the discarded mask is also becoming a big challenge for the environment. Here, we introduce a facile method based on electrospinning and three-dimensional printing to make changeable and biodegradable mask filters. We printed polylactic acid (PLA) polymer struts on a PLA nanofiber web to fabricate a nanoporous filter with a hierarchical structure and transparent look. The transparent look overcomes the threatening appearance of the masks that can be a feasible way of reducing the social trauma caused by the current CoV disease-19 pandemic. In this study, we investigated the effects of nozzle temperature on the optical, mechanical, and morphological and filtration properties of the nanoporous filter.

Background and Aims The prevalence of end-stage renal disease (ESRD) has increased ten times higher in the past twenty years, where renal replacement therapy (dialysis or kidney transplantation (KTx)) is the sole life-saving treatment. KTx is the preferred option as it is associated with improved survival and quality of life as well. Delayed graft function (DGF) is one of the main problems affecting long-term kidney survival. Brain-derived neurotrophic factor (BDNF) signalling pathways play pivotal role in mitigating cerebral ischemia/reperfusion injury (IRI), however the relation of BDNF and IRI in KTx is unknown. The aim of our human clinical study was to explore the relationship between serum BDNF concentration, BDNF gene polymorphism and renal graft function after KTx. Method Study characteristics: We enrolled 59 ESRD patients with average age of 54.8±12 years who received KTx. Proportion of male patients was 57%. Average cold ischemic time was 927±310 min, warm ischemic time was 54.5±39 min. DGF occurred in 5 cases. Baseline triple immunosuppression therapy consisted of tacrolimus, mycophenolate or everolimus, and prednisolone. Until now, 44 patients completed the 2 years follow-up. For a comparable control group, we collected blood samples from 79 healthy volunteers with average age of 53.9±16 years and with male gender proportion of 52%. Serum BDNF, creatinine, blood urea nitrogen, haemoglobin, blood glucose level and thrombocyte numbers were measured before KTx and 1 week, 1-, 3-, 6 months, and 1-, 2 years after transplantation, as well as in controls. GFR was estimated based on the CKD-EPI formula. BDNF Val66Met polymorphism was determined by PCR-RFLP. Results There was no difference in genotype or allele distribution between any of the groups, and no correlation could be observed between serum BDNF and different genotypes either. Serum BDNF level was lower in ESRD patients than healthy controls (p=0.03). There was a weak correlation and marginal significance (p=0.056) between eGFR and serum BDNF level in controls, while in KTx recipients this correlation reached higher significance (p=0.01). Above median BDNF values at 1 month after KTx were predictive for better graft function during the 2 observed years. Conclusion Our preliminary human study proposes that BDNF could be a novel biomarker of posttransplant graft function, however further clinical studies with significantly larger population are definitely needed to confirm these results.

Accurate reference dielectric functions play an important role in the research and development of optical materials. Libraries of such data are required in many applications in which amorphous semiconductors are gaining increasing interest, such as in integrated optics, optoelectronics or photovoltaics. The preparation of materials of high optical quality in a reproducible way is crucial in device fabrication. In this work, amorphous Ge (a-Ge) was created in single-crystalline Ge by ion implantation. It was shown that high optical density is available when implanting low-mass Al ions using a dual-energy approach. The optical properties were measured by multiple angle of incidence spectroscopic ellipsometry identifying the Cody-Lorentz dispersion model as the most suitable, that was capable of describing the dielectric function by a few parameters in the wavelength range from 210 to 1690 nm. The results of the optical measurements were consistent with the high material quality revealed by complementary Rutherford backscattering spectrometry and cross-sectional electron microscopy measurements, including the agreement of the layer thickness within experimental uncertainty.

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P

Bacterial adhesion is a crucial event of intestinal pathological conditions evoked by bacterial infections. Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide having a widespread distribution throughout the entire body including the digestive tract. It has diverse physiological functions in the gastrointestinal system, including protective effects in several models of intestinal inflammatory conditions. However, its effects on bacterial adherence and the inflammatory reactions as a result of that have not been elucidated yet. The aim of our study was therefore to investigate the effect of PACAP on bacterial adherence and cytokine expression upon lipopolysaccharide (LPS) exposure. Small intestinal INT407 and colonic Caco-2 cells were treated with PACAP prior to exposure to bacteria (Escherichia coli, Salmonella Typhimurium, Klebsiella pneumoniae, Enterococcus faecalis) and colonies were counted. PACAP had no significant influence on bacterial adhesion, as it did not change the number of colonies of investigated bacteria. However, PACAP was able to counteract the LPS-induced increases in the expression of the cytokines IL-8 and CXCL-1 in INT407 cells, as assessed by cytokine array. These results indicate that while PACAP has no direct effect on bacterial adherence, it can influence the cytokine expression of intestinal cells upon endotoxin-induced exposure, possibly contributing to the known anti-inflammatory actions of PACAP in the intestinal system.

Biocompatible magnetite nanoparticles (MNPs) were prepared by post-coating the magnetic nanocores with a synthetic polymer designed specifically to shield the particles from non-specific interaction with cells. Poly(ethylene glycol) methyl ether methacrylate (PEGMA) macromonomers and acrylic acid (AA) small molecular monomers were chemically coupled by quasi-living atom transfer radical polymerization (ATRP) to a comb-like copolymer, P(PEGMA-co-AA) designated here as P(PEGMA-AA). The polymer contains pendant carboxylate moieties near the backbone and PEG side chains. It is able to bind spontaneously to MNPs; stabilize the particles electrostatically via the carboxylate moieties and sterically via the PEG moieties; provide high protein repellency via the structured PEG layer; and anchor bioactive proteins via peptide bond formation with the free carboxylate groups. The presence of the P(PEGMA-AA) coating was verified in XPS experiments. The electrosteric (i.e., combined electrostatic and steric) stabilization is efficient down to pH 4 (at 10 mM ionic strength). Static magnetization and AC susceptibility measurements showed that the P(PEGMA-AA)@MNPs are superparamagnetic with a saturation magnetization value of 55 emu/g and that both single core nanoparticles and multicore structures are present in the samples. The multicore components make our product well suited for magnetic hyperthermia applications (SAR values up to 17.44 W/g). In vitro biocompatibility, cell internalization, and magnetic hyperthermia studies demonstrate the excellent theranostic potential of our product.

Hyperfine interactions in tin-base alloys Sn-x%Ag-y%Cu (x = 0, 0.3, 3; y ∈ 0 ÷ 3) were studied using 119Sn Mossbauer spectroscopy in order to detect the conditions that promote α-Sn phase formation in metallic tin (β-Sn). In many engineering applications, so-called grey tin or tin pest (α-Sn) is a parasitic phase that weakens the mechanical properties of solder joints. In particular, the chemical composition of commercially available Sn-rich solders and their working temperature conditions could significantly affect the durability of tin joints. The Mossbauer results confirmed that the above mentioned factors have a significant impact on the growth rate of tin pest. The most visible α-Sn phase increase (28.5%) was observed for alloy containing 1% Cu. In turn, the addition of even a small amount of Ag could effectively suppress tin pest formation, which indicates that the composition of tin solder alloys is still demanding for commercial applications due to their time stability. On the other hand, the temperature dependence of Sn-rich solder degradation is a less dominant factor, although the thermal treatment effect can be measured quite well using Mossbauer spectroscopy.