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Abstract Background While multiple myeloma continues to be an incurable cancer, advances in its understanding and management have led to significantly improved survival rates. Survivorship interventions for those living with multiple myeloma remain scarce, despite mounting evidence for multiple unmet support needs among multiple myeloma survivors. The current study aimed to evaluate the feasibility and preliminary effectiveness of a novel multidisciplinary group-based multiple myeloma survivorship intervention. Methods A mixed-method, repeated measures feasibility study was conducted within a routine cancer support service. Seven participants, aged over 18, who had a multiple myeloma diagnosis and were clinically assessed as suitable for the intervention by their haemato-oncologist, attended online for six weekly group sessions of physical exercise and self-management input, completing qualitative, physical and self-report measures at baseline, post-intervention and follow-up. Results The intervention was deemed overall feasible, with relatively high uptake, participants describing it as largely acceptable and appropriate and providing recommendations for feasibility-enhancing intervention refinements. Findings regarding the preliminary effectiveness of the intervention were mixed. While qualitative analyses stressed the benefits of the intervention (e.g. peer support, connectedness, improved well-being) and large effect sizes were observed for most physical outcomes, no improvements in self-reported outcomes (i.e. quality of life, fatigue) were reported. Conclusions This study represents the first investigation of a promising novel survivorship intervention for those living with multiple myeloma, highlighting the importance of peer support in particular, on which future clinical trials, aiming to establish the intervention’s effectiveness for routine care, will be able to build.

DP600 steels are characterized by a dual phase ferritic-martensitic microstructure, to which they owe their exceptionally favourable combination of high strength and good ductility. One of the production methods for this grade of steel is the hot rolling process. Despite the fact that these steels have been produced on an industrial scale for almost 40 years, they are still being studied intensively, with new research on the formation of their microstructure and properties published every year. This article focuses on the characteristics of DP600 steel produced on a hot rolling mill for applications in automotive industry. The article presents the results of mechanical properties tests and microstructure analysis of DP600 steel obtained in an industrial hot rolling process. The general characteristic of DP600 steel presented in this article, is supplemented with statistical analysis of correlations between chemical composition, selected process parameters and mechanical properties of hot rolled DP600 steel.

This article presents the results of an experimental study of cold rolling TRB strips of S235JR steel applying one grooved roll and another plain roll. The purpose of the study was to determine the possibility of rolling TRB strips with the technology studied, depending on the dimensions of the charge and the number of rolling passes. In addition, the possibility of reducing the magnitude of TRB strip curvature due to the introduction of asymmetry into the process was investigated. The effect of the rolling process and shape variation on the material’s hardening was evaluated by measuring hardness. Based on the results, it was determined that the greater the initial thickness of the charge, the higher the shape tolerances can be obtained. In addition, hardness variation was observed on the cross-section of TRB strips, which decreased with increasing values of plastic deformation. It has also been shown that it is possible to reduce the curvature of the TRB strip due to the use of double asymmetry.

Alloyed high-carbon steels are materials primarily intended for components operating under conditions of intense tribological wear. The carbides present in the microstructure of these materials significantly contribute to improving the wear resistance of such alloys. However, changes in the morphology of these precipitates can considerably alter the wear rate, leading to a deterioration in the properties of the materials. Therefore, this study aims to analyze the influence of several factors on the tribological wear of alloyed high-carbon steel. The research included friction tests under various load conditions and different sliding paths. Additionally, the samples were subjected to heat treatment to change the morphology of the observed precipitates. The tribological tests were conducted in a block-on-ring configuration under dry friction conditions. The tribological tests were analyzed statistically using analysis of variance (ANOVA). The results of the statistical analysis indicated that the primary factor influencing the observed differences between the samples was the heat treatment time of the material. Additionally, there were no significant statistical differences when pressure and friction path were varied. These findings, in conjunction with the SEM studies, allowed for the evaluation of the wear mechanism. The results demonstrated that, within the adopted tribological system, no alterations in the wear mechanism were observed with changes in test parameters. The observed differences in wear properties between the samples were found to be related to their heat treatment. The heat treatment resulted in alterations to the particle size distribution, with the annealing of the material at an elevated temperature leading to the dissolution of finer particles within the material. An increase in the average diameter of the carbide present in the material was observed to improve the wear resistance of the alloy tested.

Developmental and epileptic encephalopathies (DEEs) are a group of severe, early-onset epilepsies which are often caused by genetic mutations in ion channels. Mutations in KCNQ2, which encodes the voltage-gated potassium channel Kv7.2, is known to cause DEE. Here, we generated three iPSC lines from dermal fibroblasts of a 5 year-old male patient with the KCNQ2 c.881C > T (p.Ala294Val) pathogenic heterozygous variant and three iPSC lines from a healthy sibling control. These iPSC lines have been validated by SNP karyotyping, STR analysis, expression of pluripotent genes, the capacity to differentiate into three germ layers and confirmation of the mutation in the patient.

This paper presents the effect of the complex strain state resulting from the asymmetric rolling of TRB products on the changes and distribution of the stress state in the material. The evaluation of the stress state in the material was based on measurements of the magnetoelastic parameter (MP) using the Barkhausen magnetic noise method. The key characteristics of the material under study that enabled the use of changes in the MP parameter to assess the stress state were ferromagnetism and a lack of texture. The first of these enabled the detection of the magnetic signals produced when a magnetic field is applied to the material, causing magnetic domains to align and sudden changes in magnetization. On the other hand, the absence of texture in the material precluded the occurrence of magnetocrystalline anisotropy, which could disturb the results of measurements of the magnetoelastic parameter in the material. In order to determine these features in the material under study, its chemical composition was determined, and a phase analysis was carried out using the X-ray diffraction method. The results of these tests showed the possibility of determining the stress state of the material by means of changes in the values of the MP parameter. On this basis, it was shown that in the TRB strips studied, there is a complex state of stress, the values of which and the nature of the changes depending on the direction of the measurements carried out, as well as on the amount of rolling reduction in the studied area of the strip.

Grain-oriented electrical steel (GOES) has been used for many years for application in transformed cores due to its excellent magnetic properties. Magnetic properties are strongly influenced by obtaining a texture with a certain orientation (110) [001] for BCC structure. This is related to the easy direction of magnetization [001]. So far, the main research has been focused on obtaining a strong texture in the last stages of the process. The aim of the present study was to additionally trace textural changes for a slab after the continuous casting (CC) process and for a sheet after the hot rolling process. The scope of such an analysis has not been conducted before. With regard to the state after continuous casting (CC), the texture was related to measurements of the anisotropy of Barkhausen magnetic noises and the macrostructure of the slab. Based on the X-ray diffraction examinations that compared the texture intensity calculated from the texture coefficient of the slab, the hot rolled steel and the final product of grain-oriented electrical steel contained 3.1% of Si. The studies performed with the material taken from three different production steps showed high differences in the values of textural intensity indicating the occurrence of a crystallization texture, especially in the area of the columnar crystal zone; textural weakness after the hot rolling process and high texturing in the final product for textural components corresponding to the desired Goss texture.

The types and volume fractions of the carbonaceous phases present in the microstructures of cast irons strongly influence their properties. In the case of materials used commercially for tools, an important parameter with regard to their use is the resistance to abrasion wear. Cementite is the main reinforcing phase in cast irons and is present in significant quantities. In addition, cast irons contain graphite precipitates, which also affect wear by interacting with the matrix of the alloys. In this study, abrasive wear tests were carried out on a group of cast irons with different chemical compositions and, consequently, different microstructural morphologies. Due to the wide scatter of the results and the commercial rather than laboratory nature of the alloys studied, it was decided to use analysis of variance (ANOVA) to determine whether there was a statistically significant difference between the volume fractions of the carbonaceous phases. The volume fractions of graphite and ledeburite were then related to the results of the tribological tests. Statistical analysis confirmed significant differences in the results obtained for the alloys tested. A continuous increase in the volume fractions of both graphite and ledeburitic cementite is unfavourable in terms of the wear resistance and friction coefficient values. Optimum results can be obtained by balancing the volume fractions of the two phases observed. In addition, the phase composition of the material matrix plays an important role in wear, as the differences in the matrix of the tested alloys modify the nature of the influence of cementite and graphite on the wear.

Abstract Background NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. Methods In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. Results NRXN1α + / - cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α + / - cortical neurons. Conclusions Together with recent evidence of increased calcium transients, our results showed that human NRXN1α + / - isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α + / - patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

Titanium alloys are characterized by insufficient ductility. One of the parameters affecting their ductility is their crystal structure and texture. The present study characterizes the changes in the crystallographic texture of the Ti-3Al-8V-6Cr-4Zr-4Mo alloy in solution-treated and aged conditions on the basis of texture intensity indices and pole figures. Analysis of crystal structure changes was performed before and after tensile testing. The investigated alloy in the solution-treated condition showed a single-phase β-solution structure with a body-centered cubic (BCC) crystal structure. The process of β phase aging affected the result of the tensile test, affecting the parameters of the texture of the β phase. The analysis of the texture intensity indices for each set of planes (hkl) related to the intensity for the plane (110) indicated that the highest texture intensity occurs for β titanium alloy aged at 550 °C both before and after tensile test. After plastic deformation, the largest difference with respect to the benchmark value was observed for the (220) and (310) planes. The least amount of texture intensity occurred after aging at 450 °C. The most varied values of diffraction peak intensity in relation to the benchmark were obtained for the alloy aged at 450 °C for the (310), and (200) and (211) planes, indicating the dominance of the (211) orientation, where an elongation of 10.4% was achieved. For the highest elongation of 14.2%, achieved for the sample solution-treated at 550 °C, the diffraction peak intensities were intermediate with the dominance of peaks from the planes (200) and (310).

Summary: Background: This report describes recurrent A. xylosoxidans bloodstream and PICC (peripherally-inserted central catheter) line infection in an immunocompromised patient. Presentation of Case: A 64-year-old female with acute promyelocytic leukaemia presented during a non-neutropenic febrile episode, and A. xylosoxidans was isolated from multiple PICC and peripheral blood cultures, and from the tip of the line on removal. The patient was treated with meropenem and a new PICC line was inserted after sterile blood cultures. Six weeks later, she represented with A. xylosoxidans from multiple cultures from the line. She was treated with piperacillin-tazobactam and the line was removed. There was no evidence of deep-seated infection. Further discussion revealed that the patient was using a sponge to clean, and a sleeve to cover her PICC-line while bathing. A. xylosoxidans was cultured from both the sponge and the swab. Whole Genome Sequencing performed on two blood culture isolated and both environmental isolates confirmed all four isolates were indistinguishable. The patient was advised not to use the sponge/sleeve in future and we have incorporated specific advice in this regard into our patient information. Discussion: Achromobacter xylosoxidans is an aerobic, non-lactose fermenting gram-negative bacillus usually considered an opportunistic pathogen. It is associated with infection in immunocompromised patients, and is an emerging pathogen in catheter-related infections, sometimes associated with contaminated water. Conclusion: This case of recurrent A. xylosoxidans line infection highlights diagnostic and management challenges associated with catheter-related infections. Treatment is challenging because of intrinsic and acquired resistance mechanisms. Empiric treatment with anti-pseudomonal penicillins or carbapenems with line removal is typically required.

In recent years mesenchymal stromal cells (MSCs) have received a great deal of interest for the treatment of major diseases, but clinical translation and market authorization have been slow. This has been due in part to a lack of standardization in cell manufacturing protocols, as well as a lack of biologically meaningful cell characterization tools and release assays. Cell production strategies to date have involved complex manual processing in an open environment which is costly, inefficient and poses risks of contamination. The NANT 001 bioreactor has been developed for the automated production of small to medium cell batches for autologous use. This is a closed, benchtop system which automatically performs several processes including cell seeding, media change, real-time monitoring of temperature, pH, cell confluence and cell detachment. Here we describe a validation of the bioreactor in an environment compliant with current good manufacturing practice (cGMP) to confirm its utility in replacing standardized manual processing. Stromal vascular fraction (SVF) was isolated from lipoaspirate material obtained from healthy donors. SVF cells were seeded in the bioreactor. Cell processing was performed automatically and cell harvesting was triggered by computerized analysis of images captured by a travelling microscope positioned beneath the cell culture flask. For comparison, the same protocol was performed in parallel using manual methods. Critical quality attributes (CQA) assessed for cells from each process included cell yield, viability, surface immunophenotype, differentiation propensity, microbial sterility and endotoxin contamination. Cell yields from the bioreactor cultures were comparable in the manual and automated cultures and viability was >90% for both. Expression of surface markers were consistent with standards for adipose-derived stromal cell (ASC) phenotype. ASCs expanded in both automated and manual processes were capable of adipogenic and osteogenic differentiation. Supernatants from all cultures tested negative for microbial and endotoxin contamination. Analysis of labor commitment indicated considerable economic advantage in the automated system in terms of operator, quality control, product release and management personnel. These data demonstrate that the NANT 001 bioreactor represents an effective option for small to medium scale, automated, closed expansion of ASCs from SVF and produces cell products with CQA equivalent to manual processes.

MicroRNAs (miRNAs) are non-coding RNAs which modulate gene expression via multiple post-transcriptional mechanisms. They are involved in a variety of biological processes, including cell proliferation, metastasis, metabolism, tumorigenesis, and apoptosis. Dysregulation of miRNA expression has been implicated in human cancers, and they may also serve as biomarkers of disease progression and prognosis. The miR-17-92 cluster is one of the most widely studied miRNA clusters, which was initially reported as an oncogene, but was later reported to exhibit tumour suppressive effects in some human cancers. This review summarizes the recent progress and context-dependant role of this cluster in various cancers. We summarize the known mechanisms which regulate miR-17-92 expression and molecular pathways that are in turn controlled by it. We discuss examples where it acts as an oncogene or a tumour suppressor along with key targets affecting hallmarks of cancer. We discuss how cellular contexts regulate the biological effects of miR-17-92. The plausible mechanisms of its paradoxical roles are explained, and mechanisms are described that may contribute to cell fate regulation by miR-17-92. Further, we discuss recently developed strategies to target miR-17-92 cluster in human cancers. MiR-17-92 may serve as a potential biomarker for prognosis and response to therapy as well as a target for cancer prevention and therapeutics.

Poniższy artykuł dotyczy przydatności koncepcji "miejsc pamięci" Nory w zachowaniu i interpretacji tych historycznych budynków i struktur, które już korzystają z ochrony prawnej jako zabytki. Po pierwsze, zestawiono denotacje pojęcia lieux de mémoire Pierre'a Nory i pojęcia Denkmal (lub monumentu) Aloisa Riegla. Po drugie, w artykule przedstawiono problemy metodologiczne związane z badaniem miejsc pamięci i zaproponowano wskazówki inspirowane pracami Aleidy i Jana Assmanów na temat pamięci kulturowej. Po trzecie, te teoretyczne koncepcje są następnie odnoszone do praktycznych doświadczeń zebranych podczas realizacji projektu "Kościół Pokoju w Jaworze jako miejsce pamięci"; spostrzeżenia z projektu prowadzą do wniosków dotyczących możliwości badania społecznych aspektów konserwacji dziedzictwa budowlanego. W podsumowaniu artykułu wskazano cechy i właściwości lieux de mémoire, które mogą być pomocne w identyfikacji miejsc pamięci z perspektywy ochrony dziedzictwa.

Skin punch biopsy was donated by a healthy 51-year-old Caucasian male and the dermal fibroblasts were reprogrammed into human induced pluripotent stem cell (hiPSC) lines by using non-integrative Sendai viruses expressing OCT4, SOX2, KLF4 and c-MYC. Three iPSC lines (NUIGi046-A, NUIGi046-B, NUIGi046-C) highly expressed the pluripotent markers and were capable of differentiating into cells of endodermal, mesodermal, and ectodermal origin. These iPSCs can be offered as controls and in combination with genome-editing and three-dimensional (3D) system. They may be used for human disease modelling and drug screening.

Long QT syndrome type 2 (LQT2) is associated with KCNH2, which encodes the α subunit of the ion channel that controls the K+ current in the heart. Mutations of KCNH2 cause loss of Kv11.1 channel function by disrupting subunit folding, assembly, or trafficking of the channel to the cell surface. Here we generated two induced pluripotent stem cell (iPSC) lines from two patients carrying mutation in KCNH2 gene. These iPSCs express the pluripotent markers and have the capacity of differentiation into other cell types. These patient-derived iPSCs are useful for investigating the disease pathology and identifying the therapeutic target.

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1α +/− deletions. Seven control and six NRXN1α +/− iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca2+) imaging was performed using Fluo4-AM, and the properties of Ca2+ transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1α +/− neurons. Results NRXN1α +/− neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca2+ transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1α +/− neurons identified by STRING and GSEA analyses. Conclusions This is the first report to show that human NRXN1α +/− neurons derived from ASD patients’ iPSCs present novel phenotypes of upregulated VGCCs and increased Ca2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.

The study presents an investigation of hot deformation behaviour of 4340 steel and optimization of its processing parameters. The isothermal compression tests were performed at the temperatures ranging from 800 to 1200 °C and at the strain rates in the range of 0.01–100 s−1. The changes in the microstructure of 4340 steel, resulting from processing, have also been studied. The workability parameters and processing windows were determined, and the processing maps were correlated with microstructural changes. The optimal parameters for the forging process were also determined and then the numerical modelling and also the industrial tests of closed-die forging with flash were performed. Thermomechanical processing parameters as well as their influence on the investigated steel microstructure evolution, mechanisms of plastic deformation and its formability were discussed. Keywords: Processing maps, Dynamic recovery, Dynamic recrystallization, Forging

We report the generation of three human induced pluripotent stem cell (hiPSC) lines (NUIGi047-A, NUIGi047-B, NUIGi047-C) from a healthy 7-year-old boy using non-integrational Sendai re-programming method expressing OCT4, SOX2, KLF4 and C-MYC. Stem cell characterization was confirmed through morphology, immunofluorescence staining and RT-qPCR. Differentiation potential in vitro was demonstrated to all three germ layers with STR lineage verification and normal molecular karyotyping through the process of re-programming.

NRXN1 deletions are commonly found in autism spectrum disorder (ASD) and other neurodevelopmental/neuropsychiatric disorders. Derivation of induced pluripotent stem cells (iPSCs) from different diseases involving different deletion regions are essential, as NRXN1 may produce thousands of splicing variants. We report here the derivation of iPSCs from a sibling control and an ASD proband carrying de novo heterozygous deletions in the middle region of NRXN1, using a non-integrating Sendai viral kit. The genotype and karyotype of the iPSCs were validated by whole genome SNP array. All iPSC lines highly expressed pluripotency markers and could be differentiated into three germ layers.

NRXN1 encodes thousands of splicing variants categorized into long NRXN1α, short NRXN1β and extremely short NRXN1γ, which exert differential roles in neuronal excitation/inhibition. NRXN1α deletions are common in autism spectrum disorder (ASD) and other neurodevelopmental/neuropsychiatric disorders. We derived induced pluripotent stem cells (iPSCs) from one sibling control and two ASD probands carrying NRXN1α+/−, using non-integrating Sendai viral method. All iPSCs highly expressed pluripotency markers and could be differentiated into ectodermal/mesodermal/endodermal cells. The genotype and karyotype of the iPSCs were validated by whole genome SNP array. The availability of the iPSCs offers an opportunity for understanding NRXN1α function in human neurons and in ASD.

Abstract: Two human induced pluripotent stem cell (hiPSC) lines (NUIGi038-A, NUIGi038-B) were generated from dermal fibroblasts of a healthy 47 year old female using non-integrational Sendai reprogramming method expressing OCT4, SOX2, KLF4 and C-MYC. Characterization of both hiPSC lines was confirmed by the expression of typical pluripotency markers and differentiation potential in vitro.

Long QT syndrome (LQTS), an inherited cardiac ion channelopathy, is associated with ventricular arrhythmias and risk of sudden death. LQTS sub-type 2 (LQT2) is caused by pathogenic variants in KCNH2 encoding the α-subunit of Kv11.1, thus affecting the rapid component of delayed rectifier K+ current (IKr) channel during the action potential. In this study, non-integrational Sendai reprogramming method was used to generate an induced-pluripotent-stem-cell (iPSC) line carrying the KCNH2 c.2464G>A (p.Val822Met) pathogenic variant from a LQT2 patient. This patient-specific iPSC line NUIGi003-A harbouring the c.2464G>A variant expressed pluripotency markers and demonstrated the differentiation potential to all three germ layers.

The induced pluripotent stem cell (iPSC) technology has offered an unprecedented opportunity for disease modelling and drug discovery. Here we used non-integrating Sendai viral method and derived iPSCs from three young healthy Caucasian donors. All iPSCs expressed pluripotency markers highly and could be differentiated into three germ lineages. They possess normal karyotype which was confirmed by whole genome SNP array. The availability of the healthy control iPSCs offers an opportunity for phenotypic comparison and genome editing for a variety of diseases.

De novo pathogenic variants in KCNA2 are implicated in causing a spectrum of human neurological disorders, in particular developmental and epileptic encephalopathies. KCNA2 encodes the voltage-gated delayed rectifier potassium channel Kv1.2, which is vital in regulating neuronal membrane potential and repolarization. In this study, we generated three iPSC lines with non-integrating Sendai viral vectors from dermal fibroblasts of an 11-year old female patient harboring the KCNA2 c.869T>G (p.Leu290Arg) pathogenic variant. The iPSC lines were validated with standardized procedures including the targeted mutation, free of transgene integration, SNP karyotyping, pluripotent gene expression, and differentiation capacity into three embryonic germ layers.

Hundreds of rare risk factors have been identified for ASD, however, the underlying causes for ~70% of sporadic cases are unknown. Sporadic ASD models are thus essential for validating phenotypic commonality and drug suitability to the majority of patients. Here, we derived induced pluripotent stem cells (iPSCs) from one sporadic ASD child and one paternal control, using non-integrating Sendai viral methods. The iPSCs strongly expressed pluripotency markers and could be differentiated into three germ layers. Their normal karyotype was validated by genome SNP array. The availability of sporadic ASD-derived iPSCs offers an opportunity for phenotypic comparison with genetic ASD models.

Abstract. The alkylating agent cyclophosphamide has been used in the treatment of multiple myeloma for over 60 years. At low doses, cyclophosphamide also has significant immunomodulatory activity, which can be used to modify the immunosuppressive tumor microenvironment in order to augment responses to existing therapies. Immune-mediated therapies are becoming more widespread in modern approaches to myeloma treatment. In this review, we discuss the effects cyclophosphamide has on the immune system, and how it can be used synergistically with other treatment modalities including the immunomodulatory agents, monoclonal antibodies and cellular therapies.

Retinitis Pigmentosa (RP) is an inherited disorder of retinal degeneration with progressive loss of rod and cone photoreceptors. RPE65 is a gene encoding the trans-cis isomerase which is essential for the classical visual cycle. While most RPE65 mutations associated with RP have been reported as autosome, an Irish c.1430A > G (p.D477G) mutation is the first case reported to cause dominantly inherited RP. In this study, we used the non-integrational Sendai virus to generate induced pluripotent stem cell (iPSC) lines carrying the c.1430A > G (p.D477G) mutation from three familial RP patients.

Abstract Background Platelet-rich plasma (PRP) is a concentrate of autologous blood growth factors which has been shown to provide some symptomatic relief in early osteoarthritis (OA) of the knee. The objective of this study was to test the feasibility and efficacy potential of platelet rich plasma (PRP) in primary care. Methods Feasibility study to assess safety of the intervention procedures and assess primary and secondary outcome measures. Consecutive patients presenting with symptomatic knee OA were recruited in a primary care setting in Ireland. All participants received three injections of PRP 4 weeks apart. The following self-reported clinical outcomes were evaluated before and after therapy (4 months): Pain and disability (ICOAP questionnaire); health utility (EUROQol); adverse events; patient satisfaction and goal-orientated outcomes. Results Seventeen potential patients were identified of whom 14 were eligible to participate. Twelve consented and completed the intervention and all outcome measures. There were no losses to follow-up. One patient reported pain and stiffness for 2 days after the first injection but did complete the study. No growth was detected from nine consecutive samples sent for microbiology analysis. Changes in constant, intermittent and total pain scores were reported; pain fully resolved in two patients. In addition, health utility, patient satisfaction and goal-orientated outcomes also demonstrated improvement. Conclusions Platelet-rich plasma therapy is a simple and minimally invasive intervention which is feasible to deliver in primary care to treat osteoarthritis of the knee joint. Well-designed randomised controlled trials are needed to measure outcomes, durability of effect and cost effectiveness.

In this study, we describe the generation and characterization of induced pluripotent stem cell (iPSC) lines from familial long QT syndrome type 1 (LQT1) patients carrying the KCNQ1 c.1201dupC (p.Arg401fs) frame shift mutation by using non-integrational Sendai reprogramming method. The patient-specific iPSC lines harboring the c.1201dupC mutation on KCNQ1 gene expressed pluripotency markers and had the capacity to differentiate into three germ layers.

NRXN1 copy number variation is a rare genetic factor commonly shared among autism spectrum disorder (ASD), schizophrenia, intellectual disability, epilepsy and developmental delay. Human induced pluripotent stem cells (iPSCs) are essential for disease modeling and drug discovery, but familial cases are particularly rare. We report here the derivation of familial iPSC lines from two controls and three ASD patients carrying NRXN1α+/−, using a non-integrating Sendai viral kit. The genotype and karyotype of the resulting iPSCs were validated by whole genome SNP array. All iPSC lines expressed comparable levels of pluripotency markers and could be differentiated into three germ layers.

Long QT Syndrome type 1 (LQT1), an inherited cardiac ion channelopathy associated with arrhythmias and risk of sudden death, is caused by mutations in KCNQ1 encoding the α-subunit of Kv7.1, that affects the slow component of delayed rectifier K+ current (IKs) channel. In this study, the non-integrational Sendai reprogramming method was used to express four Yamanaka factors and to generate induced pluripotent stem cell (iPSC) lines carrying the KCNQ1 c.1697C>A (p.S566Y) mutation from familial LQT1 patients. The patient-specific iPSC lines harbouring the c.1697C>A mutation expressed pluripotency markers and had the capacity to differentiate into three germ layers.

Abstract Background Cellular reprogramming is a stressful process, which requires cells to engulf somatic features and produce and maintain stemness machineries. Autophagy is a process to degrade unwanted proteins and is required for the derivation of induced pluripotent stem cells (iPSCs). However, the role of autophagy during iPSC maintenance remains undefined. Methods Human iPSCs were investigated by microscopy, immunofluorescence, and immunoblotting to detect autophagy machinery. Cells were treated with rapamycin to activate autophagy and with bafilomycin to block autophagy during iPSC maintenance. High concentrations of rapamycin treatment unexpectedly resulted in spontaneous formation of round floating spheres of uniform size, which were analyzed for differentiation into three germ layers. Mass spectrometry was deployed to reveal altered protein expression and pathways associated with rapamycin treatment. Results We demonstrate that human iPSCs express high basal levels of autophagy, including key components of APMKα, ULK1/2, BECLIN-1, ATG13, ATG101, ATG12, ATG3, ATG5, and LC3B. Block of autophagy by bafilomycin induces iPSC death and rapamycin attenuates the bafilomycin effect. Rapamycin treatment upregulates autophagy in iPSCs in a dose/time-dependent manner. High concentration of rapamycin reduces NANOG expression and induces spontaneous formation of round and uniformly sized embryoid bodies (EBs) with accelerated differentiation into three germ layers. Mass spectrometry analysis identifies actin cytoskeleton and adherens junctions as the major targets of rapamycin in mediating iPSC detachment and differentiation. Conclusions High levels of basal autophagy activity are present during iPSC derivation and maintenance. Rapamycin alters expression of actin cytoskeleton and adherens junctions, induces uniform EB formation, and accelerates differentiation. IPSCs are sensitive to enzyme dissociation and require a lengthy differentiation time. The shape and size of EBs also play a role in the heterogeneity of end cell products. This research therefore highlights the potential of rapamycin in producing uniform EBs and in shortening iPSC differentiation duration.

The article offers a systematic approach to the method of developing mathematical models of a chemical-technological system (CTS) in conditions of deficit and fuzziness of initial information using available data of various types. Based on the results of research and processing of the collected quantitative and qualitative information, mathematical models of the reactor are constructed. Formalized and obtained mathematical statements of the control problem for choosing effective modes of operation of technological systems are based on mathematical modeling. Based on the obtained expert information, linguistic variables were described and a database of rules describing the operation of the input parameters of the reactor unit of the catalytic cracking unit was obtained.

Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair ectopic calcification. Bioactive small molecule discovery is critical to address ectopic tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort.

Dyskusja dotycząca włączenia idei miejsc pamięci we współczesną teorię konserwatorską, a co za tym idzie także w działania praktyczne oraz tworzenie długoterminowych polityk konserwatorskich, jest istotna dla przyszłości ochrony dziedzictwa.

The anti-apoptotic proteins Bcl-XL and Bcl-2 are abundantly expressed in hematopoietic stem cells and/or progenitor cells. Furthermore, leukemic cells expressing these proteins are enriched in minimal residual disease cell populations. This prompted us to test the BH3-mimetic compound ABT-737 for its ability to eradicate putative leukemic stem cells. ABT-737 demonstrated potent cytotoxic effects in all patient samples tested. The efficacy of ABT-737 against AML blasts and the primitive CD34+/CD38− population was equal and independent of sensitivity to cytarabine/daunorubicin. These results, together with previously reported synergistic effects of ABT-737 with chemotherapeutics make BH3-mimetics promising candidates for future AML treatment regimens.

The way the criterion of authenticity was being applied in the evaluation of material relics did depend, among other things, on the kind of object and on the nature of its cultural status metamorphoses. The issue is discussed on the example of two pieces of furniture from the first Polish museum. The author analyses possible sources of inspiration for the conservation practice of that time.

While most patients with chronic myeloid leukemia (CML) express either e13a2 or e14a2 BCR-ABL1 transcripts, a significant minority expresses variant transcripts, of which e19a2 is the most common. Although considered to have a relatively favourable outcome, reported responses to tyrosine kinase inhibitor (TKI) therapy are variable with molecular monitoring in CML patients with e19a2 BCR-ABL1 transcripts rarely reported. A case of e19a2 BCR-ABL1 CML with marked thrombocytosis is described in which the value of molecular monitoring is emphasised during treatment interruptions, dose reductions, and changes. This case serves to demonstrate the requirement for prospective real-time quantitative PCR (RQ-PCR) assays for patients with variant BCR-ABL1 transcript types and standardisation of such assays to enable modern patient management.