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Aims: Renal insufficiency is a common comorbidity in patients with haematological malignancies. This study aimed to assess how end‐stage renal disease (ESRD) might affect the pharmacokinetics of venetoclax, a Bcl‐2 inhibitor, in participants with ESRD undergoing haemodialysis. Methods: Venetoclax was administered as a single 100‐mg dose to 6 female participants with ESRD (estimated glomerular filtration rate <15 mL/min) both prior to haemodialysis and between haemodialysis days and 7 healthy female participants with normal renal function (estimated glomerular filtration rate >90 mL/min). Intensive pharmacokinetic and protein binding samples were collected from all participants. Arterial and venous samples were collected from ESRD participants during haemodialysis to assess the effect of haemodialysis on venetoclax pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. Results: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that haemodialysis did not affect the pharmacokinetics of venetoclax. The fraction unbound (fu) of venetoclax was ~2‐fold higher for participants with ESRD compared to participants with normal renal function. The unbound maximum plasma concentration and area under the plasma concentration–time curve from time 0 to 48 h were comparable between ESRD and normal function groups. The mean half‐life ranged from 10.4 to 12.2 h across groups, demonstrating that ESRD did not affect the half‐life of venetoclax. No new safety signals were observed during this study. Conclusion: ESRD and dialysis do not alter unbound venetoclax plasma concentrations. No pharmacokinetics driven dose adjustment is needed for patients with renal insufficiency. [ABSTRACT FROM AUTHOR]

Venetoclax, a potent BCL‐2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure–response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression‐free survival [PFS] and overall survival [OS]) as well as safety (treatment‐emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment‐emergent adverse effects) was evaluated. In the t(11;14)‐positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure‐safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment‐emergent adverse events or any grade serious treatment‐emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)‐positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013. [ABSTRACT FROM AUTHOR]

The aim of this study is to produce Ti–AlN via selective laser melting. The results show that the microstructure of the produced alloy is not uniform. The X‐ray diffraction measurements show that the Ti–AlN composite is composed of a Ti matrix, AlN compounds, as well as (TiN)0.88, Al6Ti19, and Al1.1Ti0.9 intermetallics. The as‐printed Ti–AlN is also composed of dendrites of two typical titanium nitrides (TiN and Ti2N) and titanium aluminum nitride (Ti2AlN). Subsequent quenching and annealing slightly change the phase composition of the alloy and is the main reason for their different corrosion behaviors in acidic and chloride‐containing solutions. The results of this study show that the formation of Al‐rich ternary phases improved the corrosion resistance of the three‐dimensional‐printed Ti–AlN after quenching. [ABSTRACT FROM AUTHOR]

Corrosion monitoring station was installed at 'Geotermia Mazowiecka' geothermal plant in Poland. Linear polarisation resistance and electrochemical impedance spectroscopy techniques were applied to estimate the corrosion rate and the surface changes of K55 carbon steel, L80‐13CR and 316 stainless steels directly in the geothermal water flux. The enhanced corrosion of K55 carbon steel and corrosion rate of L80‐13CR and 316 stainless steels was observed. The formation of biofilm increased the resistivity of the surface. [ABSTRACT FROM AUTHOR]

Objective: We evaluated ibrutinib, a once‐daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1‐3 prior therapies. Methods: This was a phase 2, single‐arm, open‐label, multicentre study (NCT02902965). The primary endpoint was progression‐free survival (PFS). Results: Seventy‐six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow‐up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2‐10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45‐68), and median duration of response was 9.5 months (95% CI: 6.9‐10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk‐minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs. Conclusion: Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated. [ABSTRACT FROM AUTHOR]

Corrosion tests were carried out to study the corrosive behaviour of medium carbon steels with a ferrite-pearlite microstructure during exposure to a synthetic flowback facturing fluid saturated with carbon dioxide. Metallographic investigations, screening tests, surface morphology investigations and identification of surface products were used for this purpose. The results obtained indicate that the corrosion of N80-1 carbon steel was significantly lower than that of K55 carbon steel. The layer of corrosion products consisted of an outer layer of carbonates and an inner layer with cementite lamellas. Higher grain refinement of N80-1 steel compared to that of K55 steel caused the formation of a denser, more homogenous layer of corrosion products, which significantly reduced the corrosion of the base material. [ABSTRACT FROM AUTHOR]

ABSTRACT Biallelic loss-of-function mutations in SPG11 cause a wide spectrum of recessively inherited, neurodegenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with 'small' mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for ∼19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP. [ABSTRACT FROM AUTHOR]

We recently reported SMARCE1 mutations as a cause of spinal clear cell meningiomas. Here, we have identified five further cases with non- NF2 spinal meningiomas and six with non- NF2 cranial meningiomas. Three of the spinal cases and three of the cranial cases were clear cell tumours. We screened them for SMARCE1 mutations and investigated copy number changes in all point mutation-negative samples. We identified two novel mutations in individuals with spinal clear cell meningiomas and three mutations in individuals with cranial clear cell meningiomas. Copy number analysis identified a large deletion of the 5′ end of SMARCE1 in two unrelated probands with spinal clear cell meningiomas. Testing of affected and unaffected relatives of one of these individuals identified the same deletion in two affected female siblings and their unaffected father, providing further evidence of incomplete penetrance of meningioma disease in males. In addition, we found loss of SMARCE1 protein in three of 10 paraffin-embedded cranial clear cell meningiomas. Together, these results demonstrate that loss of SMARCE1 is relevant to cranial as well as spinal meningiomas. Our study broadens the spectrum of mutations in the SMARCE1 gene and expands the phenotype to include cranial clear cell meningiomas. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd [ABSTRACT FROM AUTHOR]