Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

[Effect of the structure of the brassinosteroid side chain on monooxygenase activity of liver microsomes].

Possible pathways by which brassinosteroids affect the monooxygenase enzymatic system of mammalian liver microsomes, which is involved in the transformation of a broad spectrum of xenobiotics, were studied. The role of the structure of the side chain of brassinosteroids in the regulation of monooxygenase activity was studied using two natural compounds (24-epibrassinolide and 28-homobrassinolide) and two synthetic analogues, (22S, 23S-dihydroxy) stereoisomers. The results of this study show that brassinosteroids can directly influence the functioning of the microsomal enzymatic system. It was found that the degree of this influence depends on the side chain structure. This suggests the possibility of targeted modification of natural compounds to ensure the desired physiological effects.

What do patterns of noise in a teaching hospital and nursing home suggest?

INTRODUCTION: Noise pollution is known to cause deleterious effects on human health and may especially affect frail elderly patients with poor mental and physiologic reserve. AIMS OF THE STUDY: (i) to learn levels and time- and place-patterns of noise in an urban community teaching hospital (TH) and affiliated urban nursing home (NH); (ii) to compare levels and patterns of noise in both institutions. RESULTS: Recordings were obtained in three areas of the TH: emergency room (ER), intensive care units (ICU), and medical-surgical floors (HF) - nurses' stations and patients' rooms. On nursing home floors (NHF), noise levels were recorded at nurses' stations and in patients' rooms. In all areas of the hospital and NH, noise levels were in range of 55-70 dB and exceeded the 40-50 dB limit recommended by the EPA. In ER and ICU, noise level was higher on weekdays than weekends. In ICU and on HF, noise level was higher during mid-day hours during mornings and evenings. The highest noise level was recorded in ER followed by ICU and HF. On HF, nurses' stations were noisier than patients' rooms. Noise level was higher in the TH than in the NH. On NHF, noise level was similar on weekdays and weekends. Noise was stronger at nurses' stations than in patients' rooms and stronger in the mornings and evenings than during mid-day hours. Patterns of noise followed the human factor activities observed in both facilities. CONCLUSIONS: The level of noise in both facilities was above the recommended limit and presents an environmental stressor for a frail elderly patient. With transfer from NH to TH exposure to this stressor is increased. Time- and place-patterns of noise in both institutions suggest that human factor is a major source of noise pollution. This pollution is, therefore, potentially modifiable.

Hemoglobin conversion to hemichrome under the influence of fatty acids.

The effect of free fatty acids on the process of hemoglobin conversion and lipid peroxidation has been studied in model systems and erythrocytes. It has been found that methemoglobin and oxyhemoglobin are converted to the low spin oxidized form, namely, reversible hemichrome under the action of fatty acids. In the case of oxyhemoglobin, an increase in the level of active oxygen forms is observed in the system which initiates the formation of primary and secondary lipid peroxidation products. Incubation of erythrocytes with free fatty acids causes the formation of Heinz bodies and is accompanied by an increase of the lipid peroxidation level.

Low-energy Mg2+-induced temperature transitions in liver microsomes.

The differential scanning microcalorimetry and fluorescence methods, using probes ANS and pyrene, have been employed to study thermotropic behaviour of rat liver microsomes in the presence and absence of Mg2+. Addition of Mg2+ yields three partially reversible phase transitions at 18, 27 and 32 degrees C, respectively. A character of Mg2+-induced rearrangements in a membrane and their relation to a catalytic function of a cytochrome P-450-dependent enzymatic system is discussed.

[Interaction of cytochrome P-450 with phospholipids in dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol mixtures]. / Vzaimodeistvie tsitokhroma P450 s fosfolipidami v smesiakh dimiristoilfosfatidilkholina s dimiristoilfosfatidilglitserinom.

ESR and microcalorimetry methods were employed to investigate the thermotropic properties and structure of proteoliposomes that incorporate cytochrome P450 and DMPC-DMPG binary mixtures depending on cytochrome P450 content and phospholipid composition. The microcalorimetry data demonstrated that the incorporation of cytochrome P450 into the phospholipid mixture resulted in bilayer thermal stabilization. The maximum shift of the temperature and proteoliposome transition enthalpy were achieved at the protein/lipid molar ratio of 1:1000 in almost equimolar phospholipid mixture. Using fatty acids that were spin-labeled at different positions (C5, C12, C16), it has been shown that the incorporation of cytochrome P450 into lipid mixtures containing 0-100% DMPG decreases C12 and C16 mobility and increases the C5 order parameter at transition phase (30 degrees C) and liquid crystal phase (37 degrees C) of bilayer. The maximum alteration amplitude of the probes used was not characteristic for the separate DMPC and DMPG but rather for the mixture at the molar ratio close to equimolar value. It is proposed that cytochrome P450 incorporation into the binary mixture initiated the formation of the bilayer crystal-like phase.

[Cyclic GMP-induced structural transitions of photoreceptor membranes]. / Strukturnye perestroiki fotoretseptornykh membran, indutsirovannye tsiklicheskim guanozinmonofosfatom.

The influence of cyclic GMP on the structural state of photoreceptor membranes was studied. The spin probe technique was used to obtain the dependences of microviscosity of lipid domains of membranes on cGMP concentration. It was shown that microviscosity of 5-doxylsteraric acid environment in rod outer segment, disc and plasma mambranes changed at concentrations of 2.10(7); 5.10(-6) and 6.10(-6). Non-cyclic GMP was ineffective. The ultrasound treatment of membraneous samples resulted on disappearance of the structural changes.

[High performance liquid chromatography of fluorescent insulin derivatives]. / Vysokoéffektivnaia zhidkostnaia khromatografiia fluorestsentnykh proizvodnykh insulina.

The reversed-phase HPLC of porcine insulin modified by fluorescent labeling with dansyl chloride, fluorescein isothiocyanate, and an N-hydroxysuccinimide ester of 3-carboxyl derivative of Nile Red was studied. Mono-, di-, and tri-Dns-insulins (substituted at residues Gly1 of the A-chain and Phe1 and Lys29 of the B-chain), as well as isomeric 5'- and 6'-fluorescein thiocarbamoyl-Phe1 insulin derivatives were separated on the analytical and semipreparative scale. The results were interpreted in terms of conservation of the globular structure in the modified proteins and their surface-mediated interaction with the reversed-phase sorbent. Observed retention times correlated with the total hydrophobicity of the surface region containing the incorporated label (in the case of monosubstituted derivatives) or with the total hydrophobicity of chromatographic contact regions located between labels (in the case of di- and trisubstituted derivatives).

[Temperature quenching of cytochrome P-450 fluorescence in proteoliposomes with different physical states of the lipid bilayer]. / Temperaturnoe tushenie fluorestsentsii tsitokhroma P-450 v proteoliposomakh s razlichnym fizicheskim sostoianiem lipidnogo bisloia.

Studies were carried out of temperature quenching of self-fluorescence of cytochrome P-450 in solution and liposomes from natural phosphatidylcholine, dimiristoylphosphatidylcholine, dipalmitoylphosphatidylcholine. The fluorescence spectrum of cytochrome P-450 is a superposition of triptophane and tyrosine components. During protein incorporation into liposomes a significant short-wave shift of the emission spectrum takes place. Temperature dependence of the intensity of cytochrome P-450 self-fluorescence in solution has bends at 30, 45 and 50 degrees C. When protein is incorporated into liposomes the location of bends depends on individual properties of lipids forming the bilayer. Effect of lipid surrounding on temperature conformational rearrangements of cytochrome P-450 molecule is discussed.

[Bromoacyl analogues of phosphatidylcholine with intramolecular fluorescence quenching and their use as substrates for continuous monitoring of phospholipase A2 activity]. / Bromatsil'nye analogi fosfatidilkholina s vnutrimolekuliarno potushennoi fluorestsentsiei v kachestve substratov dlia nepreryvnoi registratsii aktivnosti fosfolipazy A2.

Two new derivatives of phosphatidylcholine with intramolecular fluorescence quenching were obtained by substituting residues of pyrene butyric and bromine-containing fatty acids for acyl chains. The two compounds can be used for quantitative evaluation of catalytic activity of pancreatic phospholipase A2 in kinetic mode.

[The use of hemoglobin for determination of phospholipase A2 activity]. / Primenenie gemoglobina dlia opredeleniia aktivnosti fosfolipazy A2.

A spectrophotometric method is proposed for determining phospholipase A2 activity, which is based on the conversion of hemoglobin into hemichrome under the fatty acid action. The spectral difference between hemoglobin and hemichrome was registered by the difference spectrum with a minimum at 405 nm and a maximum at 423 nm. The absorption value determined as the difference between the spectrum maximum and minimum was proportional to the amount of the fatty acid derived from hydrolysis of phospholipids. The method enables the enzyme activity to be determined directly in the spectrophotometric cell.

[The interaction of symmetrical cortical descending influences on lumbar motoneurons]. / Vzaimodeistvie simmetrichnykh kortikal'nykh niskhodiashchikh vliianii v poiasnichnykh motoneironakh

Postsynaptic potentials (PSPs) of the cat motoneurons elicited by stimulation of contralateral and ipsilateral motor cortex, and their changes during combination of both kinds of stimulation were studied with use of the intracellular recording technique. For elicitation of ipsilateral PSPs, the cortex stimulation of greater intensity was needed as compared with contralateral activation. The ipsilateral synaptic reactions had a longer latency and time of segmental delay than the contralateral ones. Conditioning stimulation of the ipsilateral cortex exerted an inhibitory effect upon contralateral cortically evoked EPSP and IPSP of motoneurons and upon potential recorded at the spinal cord surface. Suppression of conditioned PSPs occurred without changes of their sign or pattern in most cases. The data obtained suggest that inhibitory interaction of cortically evoked descending activities involves segmentary inhibitory interneurons and is realized at an interneuronal level and/or at the membrane of the motoneurons.

[Initiation of lipid peroxidation as a result of hemoglobin transformation into hemichrome induced by free fatty acids]. / Initsiirovanie perekisnogo okisleniia lipidov v rezul'tate prevrashcheniia gemoglobina v gemikhrom pod deistviem svobodnykh zhirnykh kislot.

The effects of free fatty acids on hemoglobin conversion and lipid peroxidation were studied in hemoglobin-containing liposomes (hemosomes) formed from an equimolar mixture of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). It was shown that in hemosomes oxyhemoglobin is converted into hemichrome by the interaction of saturated fatty acids (arachidic, stearic, palmitic, myristic and lauric). This is accompanied by accumulation of primary and secondary products of lipid peroxidation. All fatty acids, except for lauric acid, have a stabilizing effect on lipid peroxidation in liposomes prepared from an equimolar mixture of PC and PE. The formation of lipid peroxidation products is inhibited by superoxide dismutase, D-alpha-tocopherol, D-mannitol and thiourea. The relationships between hemoglobin conversion and lipid peroxidation in hemosomes under effects of fatty acids were studied. The mechanisms of these reactions are discussed.